Medicine

CHARACTERISTICS OF ANTIMICROBIAL DRUGS

CHARACTERISTICS OF ANTIMICROBIAL DRUGS. CLINICAL PHARMACOLOGY OF ANTIBIOTICS. FLUOROQUINOLONES. ANTIVIRAL DRUGS

CLINICAL PHARMACOLOGY OF ANTIBIOTICS

Antimicrobial drugs are used to prevent or treat infections caused by pathogenic (disease-producing) microorganisms. The human body and the environment contain many microorganisms, most of which live in a state of balance with the human host and do not cause disease. When the balance is upset and infection occurs, characteristics of the infecting microorganism(s) and the adequacy of host defense mechanisms are major factors in the severity of the infection and the person’s ability to recover. Conditions that impair defense mechanisms increase the incidence and severity of infections and impede recovery. In addition, use of antimicrobial drugs may lead to serious infections caused by drug-resistant microorganisms.

To help prevent infectious diseases and participate effectively in antimicrobial drug therapy, the nurse must be knowledgeable about microorganisms, host responses to microorganisms, and antimicrobial drugs.

Terms and Concepts

Several terms are used to describe these drugs. Anti-infective and antimicrobial include antibacterial, antiviral, and antifungal drugs; antibacterial and antibiotic usually refer only to drugs used in bacterial infections. Most of the drugs in this section are antibacterials. Antiviral and antifungal drugs are discussed in Chapters 39 and 40, respectively. Additional terms for antibacterial drugs include broad spectrum, for those effective against several groups of microorganisms, and narrow spectrum, for those effective against a few groups. The action of an antibacterial drug is usually described as bactericidal (kills the microorganism) or bacteriostatic (inhibits growth of the microorganism). Whether a drug is bactericidal or bacteriostatic often depends on its concentration  at the infection site and the susceptibility of the microorganism to the drug. Successful treatment with bacteriostatic antibiotics depends on the ability of the host’s immune system to eliminate the inhibited bacteria and an adequate duration of drug therapy. Stopping an antibiotic prematurely can result in rapid resumption of bacterial growth. Bactericidal drugs are preferred in serious infections, especially in people with impaired immune function.

 

Actions of antibacterial drugs on bacterial cells

Mechanisms of Action

Most antibiotics act on a specific target in the bacterial cell. Almost any structure unique to bacteria, such as proteins or nucleic acids, can be a target for antibiotics. Specific mechanisms include the following:

 

1. Inhibition of bacterial cell wall synthesis or activation of enzymes that disrupt bacterial cell walls (eg, penicillins, cephalosporins, vancomycin)

2. Inhibition of protein synthesis by bacteria or production of abnormal bacterial proteins (eg, aminoglycosides, clindamycin, erythromycin, tetracyclines). These drugs bind irreversibly to bacterial ribosomes, intracellular structures that synthesize proteins. When antimicrobial drugs are bound to the ribosomes, bacteria cannot synthesize the proteins necessary for cell walls and other structures.

3. Disruption of microbial cell membranes (eg, antifungals)

4. Inhibition of organism reproduction by interfering with nucleic acid synthesis (eg, fluoroquinolones, rifampin, anti–acquired immunodeficiency syndrome antivirals)

5. Inhibition of cell metabolism and growth (eg, sulfonamides, trimethoprim)

INDICATIONS FOR USE

Antimicrobial drugs are used to treat and prevent infections. Because laboratory tests (except Gram’s stain and a rapid test for group A streptococci) to identify causative organisms usually take 24 hours or longer, empiric therapy against the most likely pathogens is often begun. Once organisms are identified, more specific therapy is instituted. Prophylactic therapy is recommended to prevent:

1. Group A streptococcal infections and possibly rheumatic fever, rheumatic heart disease, and glomerulonephritis. Penicillin is commonly used.

2. Bacterial endocarditis in clients with cardiac valvular disease who are having dental, surgical, or other invasive procedures

3. Tuberculosis. Isoniazid is used.

4. Perioperative infections in high-risk clients (eg, those whose resistance to infection is lowered because of age, poor nutrition, disease, or drugs) and for high-risk surgical procedures (eg, cardiac or GI surgery, certain orthopedic procedures, organ transplants)

5. Sexually transmitted diseases (eg, gonorrhea, syphilis, chlamydial infections) after exposure has occurred

6. Recurrent urinary tract infections in premenopausal, sexually active women. A single dose of trimethoprimsulfamethoxazole, cinoxacin, or cephalexin, taken after

sexual intercourse, is often effective.

Antibiotic resistance

 

Antimicrobials are among the most frequently used drugs worldwide. Their success in saving lives and decreasing severity and duration of infectious diseases has encouraged their extensive use. Authorities believe that much antibiotic use involves overuse, misuse, or abuse of the drugs. That is, an antibiotic is not indicated at all or the wrong drug, dose, route, or duration is prescribed. Inappropriate use of antibiotics increases adverse drug effects, infections with drugresistant microorganisms, and health care costs. In addition, it decreases the number of effective drugs for serious or

antibiotic-resistant infections. Guidelines to promote more appropriate use of the drugs include:

1. Avoid the use of broad-spectrum antibacterial drugs to treat trivial or viral infections; use narrow-spectrum agents when likely to be effective.

2. Give antibacterial drugs only when a significant bacterial infection is diagnosed or strongly suspected or when there is an established indication for prophylaxis. These drugs are ineffective and should not be used to treat viral infections.

3. Minimize antimicrobial drug therapy for fever unless other clinical manifestations or laboratory data indicate infection.

4. Use the drugs along with other interventions to decrease microbial proliferation, such as universal precautions, medical isolation techniques, frequent and thorough handwashing, and preoperative skin and bowel cleansing.

5. Follow recommendations of the Centers for Disease Control and Prevention for prevention and treatment of infections, especially those caused by drug-resistant organisms (eg, gonorrhea, penicillin-resistant streptococcal infections, methicillin-resistant staphylococcal infections, vancomycin-resistant enterococcal infections, and MDR-TB).

6. Consult infectious disease physicians, infection control nurses, and infectious disease pharmacists about local patterns of drug-resistant organisms and treatment of complicated infections.

 

Drug Selection

Once an infection requiring treatment is diagnosed, numerous factors influence the choice of an antimicrobial drug or combination of drugs.

Initial, empiric therapy. Because most laboratory tests to definitively identify causative organisms and to determine susceptibility to antibiotics require 48 to 72 hours, the physician usually prescribes for immediate administration a drug that is likely to be effective. This empiric therapy is based on an informed estimate of the most likely pathogen, given the client’s signs and symptoms and apparent site of infection. A single broad-spectrum antibiotic or a combination of drugs is often chosen.

Culture and susceptibility studies allow the therapist to “match the drug to the bug.” Culture identifies the causative organism; susceptibility tests determine which drugs are likely to be effective against the organism. Culture and susceptibility studies are especially important with suspected gram-negative infections because of the high incidence of drugresistant microorganisms. However, drug-resistant gram-positive organisms are being identified with increasing frequency.

When a specific organism is identified by a laboratory culture, tests can be performed to measure the organism’s susceptibility to particular antibiotics. Laboratory reports indicate whether the organism is susceptible (S) or resistant (R) to the tested drugs. One indication of susceptibility is the minimum inhibitory concentration (MIC). The MIC is the lowest concentration of an antibiotic that prevents visible growth of microorganisms. Some laboratories report MIC instead of, or in addition to, susceptible (S) or resistant (R). Susceptible organisms have low or moderate MICs that can be attained by giving usual doses of an antimicrobial agent. For the drug to be effective, serum and tissue concentrations should usually exceed the MIC of an organism for a period of time. How much and how long drug concentrations need to exceed the MIC depend on the drug class and the bacterial species. With betalactam agents (eg, penicillins, cephalosporins), the drug concentration usually needs to be maintained above the MIC of the infecting organism for a majority of the dosing interval. With the aminoglycosides (eg, gentamicin, others), the drug concentration does not need to be maintained above the MIC for the entire dosing interval.

Aminoglycosides have a postantibiotic effect, defined as a persistent effect of an antimicrobial on bacterial growth after brief exposure of the organisms to a drug. Some studies demonstrate that large doses of aminoglycosides, given once daily, are as effective as more frequent dosing and may cause less nephrotoxicity. Resistant organisms have high MICs and may require higher concentrations of drug than can be achieved in the body, even with large doses. In some cases the minimum bactericidal concentration (MBC) is reported, indicating no growth of the organism in the presence of a particular antibiotic. The MBC is especially desirable for infected hosts with impaired immune functions.

Clients’ responses to antimicrobial therapy cannot always be correlated with the MIC of an infecting pathogen. Thus, reports of drug susceptibility testing must be applied in the context of the site of infection, the characteristics of the drug, and the clinical status of the client.

Knowledge of antibiotic resistance patterns in the community and agency. Because these patterns change, continuing efforts must be made. Pseudomonas aeruginosa is resistant to many antibiotics. Those strains resistant to gentamicin may be susceptible to amikacin, ceftazidime, imipenem, or aztreonam. Some gramnegative organisms have become increasingly resistant to aminoglycosides, third-generation cephalosporins, and aztreonam, but may be susceptible to imipenem.

Knowledge of the organisms most likely to infect particular body tissues. For example, urinary tract infections are often caused by E. coli, and a drug effective against this organism is indicated.

A drug’s ability to penetrate infected tissues. Several antimicrobials are effective in urinary tract infections because they are excreted in the urine. However, the choice of an effective antimicrobial drug may be limited in infections of the brain, eyes, gallbladder, or prostate gland because many drugs are unable to reach therapeutic concentrations in these tissues.

A drug’s toxicity and the risk-to-benefit ratio. In general, the least toxic drug should always be used. However, for  serious infections, more toxic drugs may be necessary.

Drug costs. If an older, less expensive drug meets the criteria for rational drug selection and is likely to be effective in a given infection, it should be used as opposed to a more expensive agent. For hospitals and nursing homes, personnel costs in relation to preparation and administration should be considered as well as purchasing costs.

Antibiotic Combination Therapy

Antimicrobial drugs are often used in combination. Indications for combination therapy may include:

• Infections caused by multiple microorganisms (eg, abdominal and pelvic infections)

• Nosocomial infections, which may be caused by many different organisms

• Serious infections in which a combination is synergistic (eg, an aminoglycoside and an antipseudomonal penicillin for pseudomonal infections)

• Likely emergence of drug-resistant organisms if a single drug is used (eg, tuberculosis). Although drug combinations to prevent resistance are widely used, the only clearly effective use is for treatment of tuberculosis.

• Fever or other signs of infection in clients whose immune systems are suppressed. Combinations of antibacterial plus antiviral and/or antifungal drugs may be needed.

 

Dosage

Dosage (amount and frequency of administration) should be individualized according to characteristics of the causative organism, the chosen drug, and the client’s size and condition (eg, type and severity of infection, ability to use and excrete the chosen drug). For example, dosage may need to be increased for more resistant organisms such as Pseudomonas and for infections in which antibiotics have difficulty penetrating to the site of infection (eg, meningitis). Dosage often must be reduced if the client has renal impairment or other disorders that delay drug elimination.

Route of Administration

 

Most antimicrobial drugs are given orally or IV for systemic infections. The route of administration depends on the client’s condition (eg, location and severity of the infection, ability to take oral drugs) and the available drug dosage forms. In serious infections, the IV route is preferred for most drugs.

 

Duration of Therapy

Duration of therapy varies from a single dose to years, depending on the reason for use. For most acute infections, the average duration is approximately 7 to 10 days or until the recipient has been afebrile and asymptomatic for 48 to 72 hours.

Beta-Lactam Antibacterials

 

Beta-lactam antibacterials derive their name from the betalactam ring that is part of their chemical structure. An intact beta-lactam ring is essential for antibacterial activity. Several gram-positive and gram-negative bacteria produce betalactamase enzymes that disrupt the beta-lactam ring and inactivate the drugs. This is a major mechanism by which microorganisms acquire resistance to beta-lactam antibiotics.

Penicillinase and cephalosporinase are beta-lactamase enzymes that act on penicillins and cephalosporins, respectively. Despite the common element of a beta-lactam ring, characteristics of beta-lactam antibiotics differ widely because of variations in their chemical structures. The drugs may differ in antimicrobial spectrum of activity, routes of administration, susceptibility to beta-lactamase enzymes, and adverse effects. Beta-lactam antibiotics include penicillins, cephalosporins, carbapenems, and monobactams.

 

Mechanism of Action

 

Beta-lactam antibacterial drugs inhibit synthesis of bacterial cell walls by binding to proteins (penicillin-binding proteins) in bacterial cell membranes. This binding produces a defective cell wall that allows intracellular contents to leak out, destroying the microorganism. In sub-bactericidal concentrations, the drugs may inhibit growth, decrease viability, and alter the shape and structure of organisms. The latter characteristic may help to explain the development of mutant strains of microorganisms exposed to the drugs. Betalactam antibiotics are most effective when bacterial cells are dividing.

PENICILLINS

The penicillins are effective, safe, and widely used antimicrobial agents. The group includes natural extracts from the Penicillium mold and several semisynthetic derivatives.

When penicillin G, the prototype, was introduced, it was effective against streptococci, staphylococci, gonococci, meningococci, Treponema pallidum, and other organisms. It had to be given parenterally because it was destroyed by gastric acid, and injections were painful. With extensive use, strains of drug-resistant staphylococci appeared. Later penicillins were developed to increase gastric acid stability, betalactamase stability, and antimicrobial spectrum of activity, especially against gram-negative microorganisms. Semisynthetic derivatives are formed by adding side chains to the penicillin nucleus.

After absorption, penicillins are widely distributed and achieve therapeutic concentrations in most body fluids, including joint, pleural, and pericardial fluids and bile. Therapeutic levels are not usually obtained in intraocular and cerebrospinal fluids (CSF) unless inflammation is present because normal cell membranes act as barriers to drug penetration.

Penicillins are rapidly excreted by the kidneys and produce high drug concentrations in the urine (an exception is nafcillin, which is excreted by the liver). The most serious, and potentially fatal, adverse effect of the penicillins is hypersensitivity. Seizures, interstitial nephritis, and nephropathy may also occur.

Indications for Use

Clinical indications for use of penicillins include bacterial infections caused by susceptible microorganisms. As a class,  penicillins usually are more effective in infections caused by gram-positive bacteria than those caused by gram-negative bacteria. However, their clinical uses vary significantly according to the subgroup or individual drug and microbial patterns of resistance. The drugs are often useful in skin/ soft tissue, respiratory, gastrointestinal, and genitourinary infections. However, the incidence of resistance among streptococci, staphylococci, and other microorganisms continues to grow.

Contraindications to Use

Contraindications include hypersensitivity or allergic reactions to any penicillin preparation. An allergic reaction to one penicillin means the client is allergic to all members of the penicillin class. The potential for cross-allergenicity with cephalosporins and carbapenems exists, so other alternatives should be selected in pencillin-allergic clients when possible.

 

Penicillinase-Resistant (Antistaphylococcal)Penicillins

This group includes four drugs (cloxacillin, dicloxacillin, nafcillin, and oxacillin) that are effective in some infections caused by staphylococci resistant to penicillin G. An older member of this group, methicillin, is no longer marketed for clinical use. However, susceptibility of bacteria to the antistaphylococcal penicillins is determined by exposing the bacteria to methicillin (methicillin-susceptible or -resistant) or oxacillin (oxacillinsusceptible or -resistant) in bacteriology laboratories. These drugs are formulated to resist the penicillinases that inactivate other penicillins. They are recommended for use in known or suspected staphylococcal infections, except for methicillin-resistant Staphylococcus aureus (MRSA) infections. Although called “methicillin-resistant,” these staphylococcal microorganisms are also resistant to other antistaphylococcal penicillins.

Aminopenicillins

Ampicillin is a broad-spectrum, semisynthetic penicillin that is bactericidal for several types of gram-positive and gramnegative bacteria. It has been effective against enterococci, Proteus mirabilis, Salmonella, Shigella, and Escherichia coli, but resistant forms of these organisms are increasing. It is ineffective against penicillinase-producing staphylococci and gonococci. Ampicillin is excreted mainly by the kidneys; thus, it is useful in urinary tract infections (UTI). Because some is excreted in bile, it is useful in biliary tract infections not caused by biliary obstruction. It is used in the treatment of bronchitis, sinusitis, and otitis media.

 

 

Amoxicillin is similar to ampicillin except it is only available orally. It is better absorbed and produces therapeutic blood levels more rapidly than oral ampicillin. It also causes less gastrointestinal distress.

 

Extended-Spectrum (Antipseudomonal) Penicillins

The drugs in this group (carbenicillin, ticarcillin, mezlocillin, and piperacillin) have a broad spectrum of antimicrobial activity, especially against gram-negative organisms such as Pseudomonas and Proteus species and E. coli. For pseudomonal infections, one of these drugs is usually given concomitantly with an aminoglycoside or a fluoroquinolone. Carbenicillin is available as an oral formulation for UTI or prostatitis caused by susceptible pathogens. The other drugs are usually given by intermittent IV infusion, although most can be given IM.

Piperacillin

 

 

Penicillin/Beta-Lactamase Inhibitor Combinations

Beta-lactamase inhibitors are drugs with a beta-lactam structure but little antibacterial activity. They bind and inactivate the beta-lactamase enzymes produced by many bacteria (eg, E. coli, Klebsiella, Enterobacter, and Bacteroides species, and S. aureus). When combined with a penicillin, the betalactamase inhibitor protects the penicillin from destruction by the enzymes and extends the penicillin’s spectrum of antimicrobial activity. Thus, the combination drug may be effective in infections caused by bacteria that are resistant to a beta-lactam antibiotic alone. Clavulanate, sulbactam, and tazobactam are the beta-lactamase inhibitors available in combinations with penicillins.

Unasyn is a combination of ampicillin and sulbactam available in vials with 1 g of ampicillin and 0.5 g of sulbactam or 2 g of ampicillin and 1 g of sulbactam.

Augmentin contains amoxicillin and clavulanate. It is available in 250-, 500-, and 875-mg tablets, each of which contains 125 mg of clavulanate. Thus, two 250-mg tablets are not equivalent to one 500-mg tablet.

Augmentin (Amoxicillin / Clavulanate) is a penicillin antibiotic used to treat bacterial infections.

Timentin is a combination of ticarcillin and clavulanate in an IV formulation containing 3 g ticarcillin and 100 mg clavulanate.

 Zosyn is a combination of piperacillin and tazobactam in an IV formulation. Three dosage strengths are available, with 2 g piperacillin and 0.25 g tazobactam, 3 g piperacillin and 0.375 g tazobactam, or 4 g piperacillin and 0.5 g tazobactam.

 

Resistance to penicillins and other b-lactams is due to one of four general mechanisms: (1) inactivation of antibiotic by b-lactamase, (2) modification of target PBPs, (3) impaired penetration of drug to target PBPs, and (4) efflux. b-Lactamase production is the most common mechanism of resistance. Many hundreds of different b-lactamases have been identified. Some, such as those produced by Staphylococcus aureus, Haemophilus sp, and Escherichia coli, are relatively narrow in substrate specificity, preferring penicillins to cephalosporins. Other b-lactamases, eg, AmpC b-lactamase produced by Pseudomonas aeruginosa and Enterobacter sp, and extended-spectrum b-lactamases (ESBLs), hydrolyze both cephalosporins and penicillins. Carbapenems are highly resistant to hydrolysis by penicillinases and cephalosporinases but they are hydrolyzed by metallo- b-lactamase and carbapenemases.

Altered target PBPs are the basis of methicillin resistance in staphylococci and of penicillin resistance in pneumococci and enterococci. These resistant organisms produce PBPs that have low affinity for binding b-lactam antibiotics, and consequently they are not inhibited except at relatively high, often clinically unachievable, drug concentrations.

Resistance due to impaired penetration of antibiotic to target PBPs occurs only in gram-negative species because of their impermeable outer cell wall membrane, which is absent in gram-positive bacteria. b-Lactam antibiotics cross the outer membrane and enter gram-negative organisms via outer membrane protein channels (porins). Absence of the proper channel or down-regulation of its production can greatly impair drug entry into the cell. Poor penetration alone is usually not sufficient to confer resistance, because enough antibiotic eventually enters the cell to inhibit growth. However, this barrier can become important in the presence of a b-lactamase, even a relatively inactive one, as long as it can hydrolyze drug faster than it enters the cell. Gram-negative organisms also may produce an efflux pump, which consists of cytoplasmic and periplasmic protein components that efficiently transport some b-lactam antibiotics from the periplasm back across the outer membrane.

CEPHALOSPORINS

Cephalosporins are a widely used group of drugs that are derived from a fungus. Although technically cefoxitin and cefotetan (cephamycins derived from a different fungus) and loracarbef (a carbacephem) are not cephalosporins, they are categorized with the cephalosporins because of their similarities to the group. Cephalosporins are broad-spectrum agents with activity against both gram-positive and gram-negative bacteria. Compared with penicillins, they are in general less active against gram-positive organisms but more active against gram-negative ones. Once absorbed, cephalosporins are widely distributed into most body fluids and tissues, with maximum concentrations in the liver and kidneys. Many cephalosporins do not reach therapeutic levels in CSF; exceptions are cefuroxime, a secondgeneration drug, and the third-generation agents. These drugs reach therapeutic levels when meninges are inflamed. Most cephalosporins are excreted through the kidneys. Exceptions include cefoperazone, which is excreted in bile, and ceftriaxone, which undergoes dual elimination via the biliary tract and kidneys. Cefotaxime is primarily metabolized in the liver to an active metabolite, desacetylcefotaxime, which is eliminated by the kidneys.

 

 

First-Generation Cephalosporins

The first cephalosporin, cephalothin, is no longer available for clinical use. However, it is used for determining susceptibility to first-generation cephalosporins, which have essentially the same spectrum of antimicrobial activity. These drugs are effective against streptococci, staphylococci (except methicillin-resistant S. aureus), Neisseria, Salmonella, Shigella, Escherichia, Klebsiella, and Bacillus species, Corynebacterium diphtheriae, Proteus mirabilis, and Bacteroides species (except Bacteroides fragilis). They are not effective against Enterobacter, Pseudomonas, and

Serratia species.

 

Second-Generation Cephalosporins

Second-generation cephalosporins are more active against some gram-negative organisms than the first-generation drugs. Thus, they may be effective in infections resistant to other antibiotics, including infections caused by Hemophilus influenzae, and Klebsiella species, E. coli, and some strains of Proteus. Because each of these drugs has a different antimicrobial spectrum, susceptibility tests must be performed for each drug rather than for the entire group, as may be done with first-generation drugs. Cefoxitin (Mefoxin), for example, is active against B. fragilis, an anaerobic organism resistant to most drugs.

 

Third-Generation Cephalosporins

Third-generation cephalosporins further extend the spectrum of activity against gram-negative organisms. In addition to activity against the usual enteric pathogens (eg, E. coli, Proteus and Klebsiella species), they are also active against several strains resistant to other antibiotics and to first- and second-generation cephalosporins. Thus, they may be useful in infections caused by unusual strains of enteric organisms such as Citrobacter, Serratia, and Providencia. Another difference

is that third-generation cephalosporins penetrate inflamed meninges to reach therapeutic concentrations in CSF.

Thus, they may be useful in meningeal infections caused by common pathogens, including H. influenzae, Neisseria meningitidis, and Streptococcus pneumoniae. Although some of the drugs are active against Pseudomonas organisms, drug-resistant strains may emerge when a cephalosporin is used alone for treatment of pseudomonal infection.

Overall, cephalosporins gain gram-negative activity and lose gram-positive activity as they move from the first to the third generation. The second- and third-generation drugs are more active against gram-negative organisms because they are more resistant to the beta-lactamase enzymes (cephalosporinases) produced by some bacteria to inactivate cephalosporins.

 

Fourth-Generation Cephalosporins

Fourth-generation cephalosporins have a greater spectrum of antimicrobial activity and greater stability against breakdown by beta-lactamase enzymes compared with third-generation drugs. Cefepime is the first fourth-generation cephalosporin to be developed. It is active against both gram-positive and gram-negative organisms. With gram-positive organisms, it is active against streptococci and staphylococci (except for methicillin-resistant staphylococci). With gram-negative organisms, its activity against Pseudomonas aeruginosa is similar to that of ceftazidime and its activity against Enterobacteriaceae is greater than that of third-generation cephalosporins. Moreover, cefepime retains activity against strains of Enterobacteriaceae and P. aeruginosa that have acquired resistance to third-generation agents.

 

Indications for Use

 

Clinical indications for the use of cephalosporins include surgical prophylaxis and treatment of infections of the respiratory tract, skin and soft tissues, bones and joints, urinary tract, brain and spinal cord, and bloodstream (septicemia). In most infections with streptococci and staphylococci, penicillins are more effective and less expensive. In infections caused by methicillin-resistant S. aureus, cephalosporins are not clinically effective even if in vitro testing indicates susceptibility. Infections caused by Neiserria gonorrhoeae, once susceptible to penicillin, are now preferentially treated with a third-generation cephalosporin such as ceftriaxone.

Cefepime is indicated for use in severe infections of the lower respiratory and urinary tracts, skin and soft tissue, female reproductive tract, and infebrile neutropenic clients. It may be used as monotherapy for all infections caused by susceptible organisms except P. aeruginosa; a combination of drugs should be used for serious pseudomonal infections.

 

Contraindications to Use

A major contraindication to the use of a cephalosporin is a previous severe anaphylactic reaction to a penicillin. Because cephalosporins are chemically similar to penicillins, there is a risk of cross-sensitivity. However, incidence of cross-sensitivity is low, especially in clients who have had delayed reactions (eg, skin rash) to penicillins. Another contraindication is cephalosporin allergy. Immediate allergic reactions with anaphylaxis, bronchospasm, and urticaria occur less often than delayed reactions with skin rash, drug fever, and eosinophilia.

 

CARBAPENEMS

 

Carbapenems are broad-spectrum, bactericidal, beta-lactam antimicrobials. Like other beta-lactam drugs, they inhibit synthesis of bacterial cell walls by binding with penicillinbinding proteins. The group consists of three drugs.

Imipenem/cilastatin (Primaxin) is given parenterally and distributed in most body fluids. Imipenem is rapidly broken down by an enzyme (dehydropeptidase) in renal tubules and therefore reaches only low concentrations in urine. Cilastatin was synthesized to inhibit the enzyme and reduce potential renal toxicity of the antibacterial agent. Recommended doses indicate the amount of imipenem; the solution contains an equivalent amount of cilastatin.

The drug is effective in infections caused by a wide range of bacteria, including penicillinase-producing staphylococci, E. coli, Proteus species, Enterobacter–Klebsiella–Serratia species, P. aeruginosa, and Enterococcus faecalis. Its main indication for use is treatment of infections caused by organisms resistant to other drugs. Adverse effects are similar to those of other beta-lactam antibiotics, including the risk of crosssensitivity in clients with penicillin hypersensitivity. Central nervous system toxicity, including seizures, has been reported. Seizures are more likely in clients with a seizure disorder or when recommended doses are exceeded; however, they have occurred in other clients as well. To prepare the solution for IM injection, lidocaine, a local anesthetic, is added to decrease pain. This solution is contraindicated in people allergic to this type of local anesthetic or who have severe shock or heart block.

Meropenem (Merrem) has a broad spectrum of antibacterial activity and may be used as a single drug for empiric therapy before causative microorganisms are identified. It is effective against penicillin-susceptible staphylococci and S. pneumoniae, most gram-negative aerobes (eg, E. coli, H. influenzae, Klebsiella pneumoniae, P. aeruginosa), and some anaerobes, including B. fragilis. It is indicated for use in intra-abdominal infections and bacterial meningitis caused by susceptible organisms. Compared with imipenem, meropenem costs more and seems to offer no clinical advantages. Adverse effects are similar to those of imipenem.

Ertapenem (Invanz) also has a broad spectrum of antibacterial activity, although more limited than imipenem and meropenem. It is approved for complicated intra-abdominal, skin and skin structure, acute pelvic, and urinary tract infections. It can be used to treat community-acquired pneumonia caused by penicillin-susceptible S. pneumoniae. Unlike imipenem and meropenem, ertapenem does not have in vitro activity against Pseudomonas aeruginosa and Acinetobacter baumannii.

Ertapenem shares the adverse effect profile of the other carbapenems. Lidocaine is also used in preparation of the solution for IM injection, and the same cautions should be used as with imipenem.

 

MONOBACTAM

 

Aztreonam (Azactam) is active against gram-negative bacteria, including Enterobacteriaceae and P. aeruginosa, and many strains that are resistant to multiple antibiotics. Activity against gram-negative bacteria is similar to that of the aminoglycosides, but the drug does not cause kidney damage or hearing loss. Aztreonam is stable in the presence of beta-lactamase enzymes. Because gram-positive and anaerobic bacteria are resistant to aztreonam, the drug’s ability to preserve normal gram-positive and anaerobic flora may be an advantage over

most other antimicrobial agents.

Indications for use include infections of the urinary tract, lower respiratory tract, skin and skin structures, as well as intra-abdominal and gynecologic infections and septicemia. Adverse effects are similar to those for penicillin, including possible hypersensitivity reactions.

Drug Selection

Choice of a beta-lactam antibacterial depends on the organism causing the infection, severity of the infection, and other factors. With penicillins, penicillin G or amoxicillin is the drug of choice in many infections; an antipseudomonal penicillin is indicated in most Pseudomonas infections; and an antistaphylococcal penicillin is indicated in staphylococcal infections. Antistaphylococcal drugs of choice are nafcillin for IV use and dicloxacillin for oral use.

With cephalosporins, first-generation drugs are often used for surgical prophylaxis, especially with prosthetic implants, because gram-positive organisms such as staphylococci cause most post-implant infections. They may also be used alone for treatment of infections caused by susceptible organisms in body sites where drug penetration and host defenses are adequate.

Cefazolin (Kefzol) is a frequently used parenteral agent. It reaches a higher serum concentration, is more protein bound, and has a slower rate of elimination than other firstgeneration drugs. These factors prolong serum half-life, so cefazolin can be given less frequently. Cefazolin may also be administered IM.

Second-generation cephalosporins are also often used for surgical prophylaxis, especially for gynecologic and colorectal surgery. They are also used for treatment of intraabdominal infections such as pelvic inflammatory disease, diverticulitis, penetrating wounds of the abdomen, and other infections caused by organisms inhabiting pelvic and colorectal areas.

Third-generation cephalosporins are recommended for serious infections caused by susceptible organisms that are resistant to first- and second-generation cephalosporins. They are often used in the treatment of infections caused by E. coli, Proteus, Klebsiella, and Serratia species, and other Enterobacteriaceae, especially when the infections occur in body sites not readily reached by other drugs (eg, CSF, bone) and in clients with immunosuppression. Although effective against many Pseudomonas strains, these drugs should not be used alone in treating pseudomonal infections because drug resistance develops.

Fourth-generation drugs are most useful in serious gramnegative infections, especially infections caused by organisms resistant to third-generation drugs. Cefepime has the same indications for use as ceftazidime, a third-generation drug.

VANCOMYCIN

Introduction

Vancomycin is an antibiotic produced by Streptococcus orientalis. With the single exception of flavobacterium, it is active only against gram-positive bacteria, particularly staphylococci. Vancomycin is a glycopeptide of molecular weight 1500. It is water-soluble and quite stable.

Mechanisms of Action
& Basis of Resistance

Vancomycin inhibits cell wall synthesis by binding firmly to the D-Ala-D-Ala terminus of nascent peptidoglycan pentapeptide. This inhibits the transglycosylase, preventing further elongation of peptidoglycan and cross-linking. The peptidoglycan is thus weakened, and the cell becomes susceptible to lysis. The cell membrane is also damaged, which contributes to the antibacterial effect.

Resistance to vancomycin in enterococci is due to modification of the D-Ala-D-Ala binding site of the peptidoglycan building block in which the terminal D-Ala is replaced by D-lactate. This results in the loss of a critical hydrogen bond that facilitates high-affinity binding of vancomycin to its target and loss of activity. This mechanism is also present in vancomycin-resistant S aureus strains (MIC
³ 32 mcg/mL), which have acquired the enterococcal resistance determinants. The mechanism for reduced vancomycin susceptibility of vancomycin-intermediate strains (MICs = 8-16 mcg/mL) is not known.

Antibacterial Activity

Vancomycin is bactericidal for gram-positive bacteria in concentrations of 0.5-10 mcg/mL. Most pathogenic staphylococci, including those producing
b-lactamase and those resistant to nafcillin and methicillin, are killed by 2 mcg/mL or less. Vancomycin kills staphylococci relatively slowly and only if cells are actively dividing; the rate is less than that of the penicillins both in vitro and in vivo. Vancomycin is synergistic in vitro with gentamicin and streptomycin against Enterococcus faecium and Enterococcus faecalis strains that do not exhibit high levels of aminoglycoside resistance.

Pharmacokinetics

Vancomycin is poorly absorbed from the intestinal tract and is administered orally only for the treatment of antibiotic-associated enterocolitis caused by C difficile. Parenteral doses must be administered intravenously. A 1-hour intravenous infusion of 1 g produces blood levels of 15-30 mcg/mL for 1-2 hours. The drug is widely distributed in the body. Cerebrospinal fluid levels 7-30% of simultaneous serum concentrations are achieved if there is meningeal inflammation. Ninety percent of the drug is excreted by glomerular filtration. In the presence of renal insufficiency, striking accumulation may occur. In functionally anephric patients, the half-life of vancomycin is 6-10 days. The drug is not removed by hemodialysis.

Clinical Uses

The main indication for parenteral vancomycin is sepsis or endocarditis caused by methicillin-resistant staphylococci. However, vancomycin is not as effective as an antistaphylococcal penicillin for treatment of serious infections such as endocarditis caused by methicillin-susceptible strains. Vancomycin in combination with gentamicin is an alternative regimen for treatment of enterococcal endocarditis in a patient with serious penicillin allergy. Vancomycin (in combination with cefotaxime, ceftriaxone, or rifampin) is also recommended for treatment of meningitis suspected or known to be caused by a highly penicillin-resistant strain of pneumococcus (ie, MIC
> 1 mcg/mL). The recommended dosage is 30 mg/kg/d in two or three divided doses. A typical dosing regimen for most infections in adults with normal renal function is 1 g every 12 hours. The dosage in children is 40 mg/kg/d in three or four divided doses. Clearance of vancomycin is directly proportional to creatinine clearance, and the dose is reduced accordingly in patients with renal insufficiency. For functionally anephric adult patients, a 1-g dose administered once a week is usually sufficient. Patients receiving a prolonged course of therapy should have serum concentrations checked. Recommended peak serum concentrations are 20-50 mcg/mL, and trough concentrations are 10-15 mcg/mL.

Oral vancomycin, 0.125-0.25 g every 6 hours, is used to treat antibiotic-associated enterocolitis caused by C difficile. However, because of the emergence of vancomycin-resistant enterococci and the strong selective pressure of oral vancomycin for these resistant organisms, metronidazole is strongly preferred as initial therapy and vancomycin should be reserved for treatment of refractory cases.

Adverse Reactions

Adverse reactions are encountered in about 10% of cases. Most reactions are minor. Vancomycin is irritating to tissue, resulting in phlebitis at the site of injection. Chills and fever may occur. Ototoxicity is rare and nephrotoxicity uncommon with current preparations. However, administration with another ototoxic or nephrotoxic drug, such as an aminoglycoside, increases the risk of these toxicities. Ototoxicity can be minimized by maintaining peak serum concentrations below 60 mcg/mL. Among the more common reactions is the so-called "red man" or "red neck" syndrome. This infusion-related flushing is caused by release of histamine. It can be largely prevented by prolonging the infusion period to 1-2 hours or increasing the dosing interval.

TEICOPLANIN

Teicoplanin is a glycopeptide antibiotic that is very similar to vancomycin in mechanism of action and antibacterial spectrum. Unlike vancomycin, it can be given intramuscularly as well as intravenously. Teicoplanin has a long half-life (45-70 hours), permitting once-daily dosing. This drug is available in Europe but has not been approved for use in the United States.

DAPTOMYCIN

Daptomycin is a cyclic lipopeptide fermentation product of Streptomyces roseosporus. Its spectrum of activity is similar to that of vancomycin except that it is more rapidly bactericidal in vitro and it is active against vancomycin-resistant strains of enterococci and vancomycin-intermediate and -resistant strains of S aureus. The precise mechanism of action is not known, but it appears to bind to and depolarize the cell membrane, causing potassium efflux and rapid cell death. Daptomycin is cleared renally. The recommended doses are 4 mg/kg dose for treatment of skin and soft tissue infections and 6 mg/kg dose for treatment of bacteremia and endocarditis once daily in patients with normal renal function and every other day in patients with creatinine clearance of less than 30 mL/min. In clinical trials powered for noninferiority, daptomycin was equivalent in efficacy to vancomycin. It can cause myopathy, and creatine phosphokinase levels should be monitored. Pulmonary surfactant antagonizes daptomycin and it should not be used to treat pneumonia. Scattered cases of treatment failures have been reported in association with an increase in daptomycin MIC for clinical isolates obtained during therapy. The relation between an increase in MIC and treatment failure is unclear at this point. Daptomycin is an effective alternative to vancomycin, and its ultimate role continues to unfold.

 

FOSFOMYCIN

Fosfomycin trometamol, a stable salt of fosfomycin (phosphonomycin), inhibits a very early stage of bacterial cell wall synthesis. An analog of phosphoenolpyruvate, it is structurally unrelated to any other antimicrobial agent. It inhibits the cytoplasmic enzyme enolpyruvate transferase by covalently binding to the cysteine residue of the active site and blocking the addition of phosphoenolpyruvate to UDP-N-acetylglucosamine. This reaction is the first step in the formation of UDP-N-acetylmuramic acid, the precursor of N-acetylmuramic acid, which is found only in bacterial cell walls. The drug is transported into the bacterial cell by glycerophosphate or glucose 6-phosphate transport systems. Resistance is due to inadequate transport of drug into the cell.

Fosfomycin is active against both gram-positive and gram-negative organisms at concentrations £ 125 mcg/mL. Susceptibility tests should be performed in growth medium supplemented with glucose 6-phosphate to minimize false-positive indications of resistance. In vitro synergism occurs when fosfomycin is combined with b-lactam antibiotics, aminoglycosides, or fluoroquinolones.

Fosfomycin trometamol is available in both oral and parenteral formulations, although only the oral preparation is approved for use in the USA. Oral bioavailability is approximately 40%. Peak serum concentrations are 10 mcg/mL and 30 mcg/mL following a 2-g or 4-g oral dose, respectively. The half-life is approximately 4 hours. The active drug is excreted by the kidney, with urinary concentrations exceeding MICs for most urinary tract pathogens.

Fosfomycin is approved for use as a single 3-g dose for treatment of uncomplicated lower urinary tract infections in women. The drug appears to be safe for use in pregnancy.

BACITRACIN

Bacitracin is a cyclic peptide mixture first obtained from the Tracy strain of Bacillus subtilis in 1943. It is active against gram-positive microorganisms. Bacitracin inhibits cell wall formation by interfering with dephosphorylation in cycling of the lipid carrier that transfers peptidoglycan subunits to the growing cell wall. There is no cross-resistance between bacitracin and other antimicrobial drugs.

Bacitracin is highly nephrotoxic when administered systemically and is only used topically. Bacitracin is poorly absorbed. Topical application results in local antibacterial activity without systemic toxicity. Bacitracin, 500 units/g in an ointment base (often combined with polymyxin or neomycin), is indicated for the suppression of mixed bacterial flora in surface lesions of the skin, in wounds, or on mucous membranes. Solutions of bacitracin containing 100-200 units/mL in saline can be used for irrigation of joints, wounds, or the pleural cavity.

CYCLOSERINE

Cycloserine is an antibiotic produced by Streptomyces orchidaceus. It is water-soluble and very unstable at acid pH. Cycloserine inhibits many gram-positive and gram-negative organisms, but it is used almost exclusively to treat tuberculosis caused by strains of Mycobacterium tuberculosis resistant to first-line agents. Cycloserine is a structural analog of D-alanine and inhibits the incorporation of D-alanine into peptidoglycan pentapeptide by inhibiting alanine racemase, which converts L-alanine to D-alanine, and D-alanyl- D-alanine ligase. After ingestion of 0.25 g of cycloserine blood levels reach 20-30 mcg/mL
¾sufficient to inhibit many strains of mycobacteria and gram-negative bacteria. The drug is widely distributed in tissues. Most of the drug is excreted in active form into the urine. The dosage for treating tuberculosis is 0.5 to 1 g/d in two or three divided doses.

Cycloserine causes serious dose-related central nervous system toxicity with headaches, tremors, acute psychosis, and convulsions. If oral dosages are maintained below 0.75 g/d, such effects can usually be avoided.

AMINOGLYCOSIDES

Aminoglycosides are bactericidal agents with similar pharmacologic, antimicrobial, and toxicologic characteristics. They are used to treat infections caused by gram-negative microorganisms such as Pseudomonas and Proteus species, Escherichia coli, and Klebsiella, Enterobacter, and Serratia species.

These drugs are poorly absorbed from the gastrointestinal (GI) tract. Thus, when given orally, they exert local effects in the GI tract. They are well absorbed from intramuscular injection sites and reach peak effects in 30 to 90 minutes if circula tory status is good. After intravenous (IV) administration, peak effects occur within 30 to 60 minutes. Plasma half-life is 2 to 4 hours with normal renal function.

After parenteral administration, aminoglycosides are widely distributed in extracellular fluid and reach therapeutic levels in blood, urine, bone, inflamed joints, and pleural and ascitic fluids. They accumulate in high concentrations in the kidney and inner ear. They are poorly distributed to the central nervous system, intraocular fluids, and respiratory tract secretions. Injected drugs are not metabolized; they are excreted unchanged in the urine, primarily by glomerular filtration. Oral drugs are excreted in feces.

Indications for Use

The major clinical use of parenteral aminoglycosides is to treat serious systemic infections caused by susceptible aerobic gram-negative organisms. Many hospital-acquired infections are caused by gram-negative organisms. These infections have become more common with control of other types of infections, widespread use of antimicrobial drugs, and diseases (eg, acquired immunodeficiency syndrome [AIDS]) or treatments (eg, radical surgery and therapy with antineoplastic or immunosuppressive drugs) that lower host resistance. Although they can occur anywhere, infections due to gram-negative organisms commonly involve the respiratory and genitourinary tracts, skin, wounds, bowel, and bloodstream. Any infection with gram-negative organisms may be serious and potentially life threatening. Management is difficult because the organisms are in general less susceptible to antibacterial drugs, and drug-resistant strains develop rapidly. In pseudomonal infections, an aminoglycoside is often given concurrently with an antipseudomonal penicillin (eg, piperacillin) for synergistic  therapeutic effects. The penicillin-induced breakdown of the bacterial cell wall makes it easier for the aminoglycoside to reach its site of action inside the bacterial cell. However, the drugs are chemically and physically incompatible. Therefore, they should not be mixed in a syringe or an IV fluid because the aminoglycoside will be deactivated.

A second clinical use is for treatment of tuberculosis. Streptomycin was often used before the development of isoniazid and rifampin. Now, it may be used for treatment of tuberculosis resistant to other antitubercular drugs. Multidrug-resistant strains of the tuberculosis organism, including strains resistant to both isoniazid and rifampin, are being identified with increasing frequency. This development is leading some authorities to recommend an aminoglycoside as part of a four- to six-drug regimen. A third clinical use is for synergistic action when combined with ampicillin, penicillin G, or vancomycin in the treatment of enterococcal infections. Regimens for enterococcal infections, particularly meningitis or endocarditis, should include gentamicin in divided doses rather than once-daily dosing. Some enterococcal strains are resistant to gentamicin, however, and microbiology results should be reviewed for each patient.

A final clinical use is oral administration to suppress intestinal bacteria. Neomycin and kanamycin may be given before bowel surgery and to treat hepatic coma. In hepatic coma, intestinal bacteria produce ammonia, which enters the bloodstream and causes encephalopathy. Drug therapy to suppress intestinal bacteria decreases ammonia production. Paromomycin is used mainly in the treatment of intestinal amebiasis.

Contraindications to Use

 

Aminoglycosides are contraindicated in infections for which less toxic drugs are effective. The drugs are nephrotoxic and ototoxic and must be used very cautiously in the presence of renal impairment. Dosages are adjusted according to serum drug levels and creatinine clearance. The drugs must also be used cautiously in clients with myasthenia gravis and other neuromuscular disorders because muscle weakness may be increased.

 

 

The choice of aminoglycoside depends on local susceptibility patterns and specific organisms causing an infection. Gentamicin is often given for systemic infections if resistant microorganisms have not developed in the clinical setting. If gentamicin-resistant organisms have developed, amikacin or tobramycin may be given because they are usually less susceptible to drug-destroying enzymes. In terms of toxicity, the aminoglycosides cause similar effects.

Guidelines for Reducing Toxicity of Aminoglycosides

In addition to the preceding recommendations, guidelines to decrease the incidence and severity of adverse effects include the following:

1. Identify clients at high risk for adverse effects (eg, neonates, older adults, clients with renal impairment, clients with disease processes or drug therapies that impair blood circulation and renal function).

2. Keep clients well hydrated to decrease drug concentration in serum and body tissues. The drugs reach higher concentrations in the kidneys and inner ears than in other body tissues. This is a major factor in nephrotoxicity and ototoxicity. The goal of an adequate fluid intake is to decrease the incidence and severity of these adverse effects.

3. Use caution with concurrent administration of diuretics. Diuretics may increase the risk of nephrotoxicity by decreasing fluid volume, thereby increasing drug concentration in serum and tissues. Dehydration is most likely to occur with loop diuretics such as furosemide.

4. Give the drug for no longer than 10 days unless necessary for treatment of certain infections. Clients are most at risk when high doses are given for prolonged periods.

5. Detect adverse effects early and reduce dosage or discontinue the drug. Changes in renal function tests that indicate nephrotoxicity may not occur until the client has received an aminoglycoside for several days. If nephrotoxicity occurs, it is usually reversible if the drug is stopped. Early ototoxicity is detectable only with audiometry and is generally not reversible.

TETRACYCLINE

 

A tetracycline is the drug of choice or alternate (sometimes as part of combination therapy) in a few infections (eg, brucellosis, chancroid, cholera, granuloma inguinale, psittacosis, Rocky Mountain spotted fever, syphilis, trachoma, typhus, gastroenteritis due to Vibrio cholerae or Helicobacter pylori). They are also useful in some animal bites and Lyme disease. Other drugs (eg, penicillins) are usually preferred in grampositive infections, and most gram-negative organisms are resistant to tetracyclines. However, a tetracycline may be used if bacterial susceptibility is confirmed.

Specific clinical indications for tetracyclines include:

1. Treatment of uncomplicated urethral, endocervical, or rectal infections caused by Chlamydia organisms.

2. Adjunctive treatment, with other antimicrobials, in the treatment of pelvic inflammatory disease and sexually transmitted diseases.

3. Long-term treatment of acne. Tetracyclines interfere with the production of free fatty acids and decrease Corynebacterium in sebum. These actions decrease the inflammatory, pustular lesions associated with severe acne.

4. As a substitute for penicillin in penicillin-allergic clients. Tetracyclines may be effective in treating syphilis when penicillin cannot be given. They should not be substituted for penicillin in treating streptococcal pharyngitis because microbial resistance is common, and tetracyclines do not prevent rheumatic fever. In addition, they should not be substituted for penicillin in any serious staphylococcal infection because microbial resistance commonly occurs.

5. Doxycycline may be used to prevent traveler’s diarrhea due to enterotoxic strains of E. coli.

6. Demeclocycline may be used to inhibit antidiuretic hormone in the management of chronic inappropriate antidiuretic hormone secretion.

 

Contraindications to Use

Tetracyclines are contraindicated in clients with renal failure,  in pregnant women and in children up to 8 years of  age. In the fetus and young child, tetracyclines are deposited in bones and teeth along with calcium. If given during active mineralization of these tissues, tetracyclines can cause permanent brown coloring (mottling) of tooth enamel and can depress bone growth. With the exception of doxycycline, they should not be used in renal failure because accumulation may increase the likelihood of liver toxicity. Increased photosensitivity is a common side effect, and clients should be warned to take precautions against sunburn while on these drugs.

 

PRINCIPLES OF THERAPY

1. Culture and susceptibility studies are needed before tetracycline therapy is started because many strains of organisms are either resistant or vary greatly in drug susceptibility. Cross-sensitivity and cross-resistance are common among tetracyclines.

2. The oral route of administration is usually effective and preferred. Intravenous (IV) therapy is used when oral administration is contraindicated or for initial treatment of severe infections.

3. Tetracyclines decompose with age, exposure to light, and extreme heat and humidity. Because the breakdown products may be toxic, it is important to store these drugs correctly. Also, the manufacturer’s expiration dates on containers should be noted and outdated drugs should be discarded.

 

MACROLIDES

 

The macrolides, which include erythromycin, azithromycin (Zithromax), clarithromycin (Biaxin), and dirithromycin (Dynabac), have similar antibacterial spectra and mechanisms of action. They are widely distributed into body tissues and fluids and may be bacteriostatic or bactericidal, depending on drug concentration in infected tissues. They are effective against gram-positive cocci, including group A streptococci, pneumococci, and most staphylococci. They are also effective against species of Corynebacterium, Treponema, Neisseria, and Mycoplasma and against some anaerobic organisms such as Bacteroides and Clostridia.

Azithromycin and clarithromycin also are active against the atypical mycobacteria that cause Mycobacterium avium complex (MAC) disease. MAC disease is an opportunistic infection that occurs mainly in people with advanced human immunodeficiency virus infection.

 

Erythromycin, the prototype, is now used less often because of microbial resistance, numerous drug interactions, and the development of newer macrolides. Erythromycin is metabolized in the liver and excreted mainly in bile; approximately

20% is excreted in urine. Depending on the specific salt formulation used, food can have a variable effect on the absorption of oral erythromycin. Compared with erythromycin, the newer drugs require less frequent administration and cause less nausea, vomiting, and diarrhea. Azithromycin and dirithromycin are excreted mainly in bile, and clarithromycin is metabolized to an active metabolite in the liver, which is then excreted in urine.

A relative of the macrolides, telithromycin (Ketek), is the first of a new class of antibiotics, named the ketolides. These drugs are expected to offer better activity against multidrug-resistant strains of Streptococcus pneumoniae, an increasingly common cause of infections in children and adults.

Mechanism of Action

The macrolides enter microbial cells and attach to 50S ribosomes, thereby inhibiting microbial protein synthesis.

 

 

INDICATIONS FOR USE

The macrolides are widely used for treatment of respiratory tract and skin/soft tissue infections caused by streptococci and staphylococci. Erythromycin is also used as a penicillin substitute in clients who are allergic to penicillin; for prevention of rheumatic fever, gonorrhea, syphilis, pertussis, and chlamy-dial conjunctivitis in newborns (ophthalmic ointment); and to treat other infections (eg, Legionnaire’s disease, genitourinary infections caused by Chlamydia trachomatis, intestinal amebiasis caused by Entamoeba histolytica). In addition, azithromycin is approved for treatment of urethritis and cervicitis caused by C. trachomatis organisms, and is being used for the prevention and treatment of MAC disease. Clarithromycin is approved for prevention and treatment of MAC disease. For prevention, clarithromycin may be used alone; for treatment, it is combined with one or two other drugs (eg, ethambutol or rifabutin) to prevent the emergence of drug-resistant organisms. Clarithromycin is also used to treat Helicobacter pylori infections associated with peptic ulcer disease.

 

Contraindications to Use

Macrolides are contraindicated in people who have had hypersensitivity reactions. They are also contraindicated or must be used with caution in clients with pre-existing liver disease.

 

CLINDAMYCIN

Introduction

Clindamycin is a chlorine-substituted derivative of lincomycin, an antibiotic that is elaborated by Streptomyces lincolnensis.
Antibacterial Activity

Streptococci, staphylococci, and pneumococci are inhibited by clindamycin, 0.5-5 mcg/mL. Enterococci and gram-negative aerobic organisms are resistant (in contrast to their susceptibility to erythromycin). Bacteroides sp and other anaerobes, both gram-positive and gram-negative, are usually susceptible. Clindamycin, like erythromycin, inhibits protein synthesis by interfering with the formation of initiation complexes and with aminoacyl translocation reactions. The binding site for clindamycin on the 50S subunit of the bacterial ribosome is identical with that for erythromycin. Resistance to clindamycin, which generally confers cross-resistance to macrolides, is due to (1) mutation of the ribosomal receptor site; (2) modification of the receptor by a constitutively expressed methylase (see section on erythromycin resistance, above); and (3) enzymatic inactivation of clindamycin. Gram-negative aerobic species are intrinsically resistant because of poor permeability of the outer membrane.

Pharmacokinetics

Oral dosages of clindamycin, 0.15-0.3 g every 8 hours (10-20 mg/kg/d for children), yield serum levels of 2-3 mcg/mL. When administered intravenously, 600 mg of clindamycin every 8 hours gives levels of 5-15 mcg/mL. The drug is about 90% protein-bound. Clindamycin penetrates well into most tissues, with brain and cerebrospinal fluid being important exceptions. It penetrates well into abscesses and is actively taken up and concentrated by phagocytic cells. Clindamycin is metabolized by the liver, and both active drug and active metabolites are excreted in bile and urine. The half-life is about 2.5 hours in normal individuals, increasing to 6 hours in patients with anuria. No dosage adjustment is required for renal failure.

Clinical Uses

Clindamycin is indicated for treatment of anaerobic infection caused by bacteroides and other anaerobes that often participate in mixed infections. Clindamycin, sometimes in combination with an aminoglycoside or cephalosporin, is used to treat penetrating wounds of the abdomen and the gut; infections originating in the female genital tract, eg, septic abortion and pelvic abscesses; and aspiration pneumonia. Clindamycin is now recommended rather than erythromycin for prophylaxis of endocarditis in patients with valvular heart disease who are undergoing certain dental procedures. Clindamycin plus primaquine is an effective alternative to trimethoprim-sulfamethoxazole for moderate to moderately severe Pneumocystis jiroveci pneumonia in AIDS patients. It is also used in combination with pyrimethamine for AIDS-related toxoplasmosis of the brain.

Adverse Effects

Common adverse effects are diarrhea, nausea, and skin rashes. Impaired liver function (with or without jaundice) and neutropenia sometimes occur. Severe diarrhea and enterocolitis have followed clindamycin administration. Administration of clindamycin is a risk factor for diarrhea and colitis due to Clostridium difficile.

CHLORAMPHENICOL

Introduction

It is soluble in alcohol but poorly soluble in water. Chloramphenicol succinate, which is used for parenteral administration, is highly water-soluble. It is hydrolyzed in vivo with liberation of free chloramphenicol.

Antimicrobial Activity

Chloramphenicol is a potent inhibitor of microbial protein synthesis. It binds reversibly to the 50S subunit of the bacterial ribosome and inhibits the peptidyl transferase step of protein synthesis. Chloramphenicol is a bacteriostatic broad-spectrum antibiotic that is active against both aerobic and anaerobic gram-positive and gram-negative organisms. It is active also against rickettsiae but not chlamydiae. Most gram-positive bacteria are inhibited at concentrations of 1-10 mcg/mL, and many gram-negative bacteria are inhibited by concentrations of 0.2-5 mcg/mL. H influenzae, N meningitidis, and some strains of bacteroides are highly susceptible, and for them chloramphenicol may be bactericidal.

Low-level resistance to chloramphenicol may emerge from large populations of chloramphenicol-susceptible cells by selection of mutants that are less permeable to the drug. Clinically significant resistance is due to production of chloramphenicol acetyltransferase, a plasmid-encoded enzyme that inactivates the drug.

Pharmacokinetics

The usual dosage of chloramphenicol is 50-100 mg/kg/d. After oral administration, crystalline chloramphenicol is rapidly and completely absorbed. A 1-g oral dose produces blood levels between 10 and 15 mcg/mL. Chloramphenicol palmitate is a prodrug that is hydrolyzed in the intestine to yield free chloramphenicol. The parenteral formulation is a prodrug, chloramphenicol succinate, which hydrolyzes to yield free chloramphenicol, giving blood levels somewhat lower than those achieved with orally administered drug. Chloramphenicol is widely distributed to virtually all tissues and body fluids, including the central nervous system and cerebrospinal fluid, such that the concentration of chloramphenicol in brain tissue may be equal to that in serum. The drug penetrates cell membranes readily.

Most of the drug is inactivated either by conjugation with glucuronic acid (principally in the liver) or by reduction to inactive aryl amines. Active chloramphenicol (about 10% of the total dose administered) and its inactive degradation products (about 90% of the total) are eliminated in the urine. A small amount of active drug is excreted into bile and feces. The systemic dosage of chloramphenicol need not be altered in renal insufficiency, but it must be reduced markedly in hepatic failure. Newborns less than a week old and premature infants also clear chloramphenicol less well, and the dosage should be reduced to 25 mg/kg/d.

Clinical Uses

Because of potential toxicity, bacterial resistance, and the availability of many other effective alternatives, chloramphenicol is rarely used. It may be considered for treatment of serious rickettsial infections such as typhus and Rocky Mountain spotted fever. It is an alternative to a
b-lactam antibiotic for treatment of meningococcal meningitis occurring in patients who have major hypersensitivity reactions to penicillin or bacterial meningitis caused by penicillin-resistant strains of pneumococci. The dosage is 50-100 mg/kg/d in four divided doses.

Chloramphenicol is used topically in the treatment of eye infections because of its broad spectrum and its penetration of ocular tissues and the aqueous humor. It is ineffective for chlamydial infections.

Adverse Reactions

A. GASTROINTESTINAL DISTURBANCES
Adults occasionally develop nausea, vomiting, and diarrhea. This is rare in children. Oral or vaginal candidiasis may occur as a result of alteration of normal microbial flora.

B. BONE MARROW DISTURBANCES
Chloramphenicol commonly causes a dose-related reversible suppression of red cell production at dosages exceeding 50 mg/kg/d after 1-2 weeks. Aplastic anemia, a rare consequence (1 in 24,000 to 40,000 courses of therapy) of chloramphenicol administration by any route, is an idiosyncratic reaction unrelated to dose, although it occurs more frequently with prolonged use. It tends to be irreversible and can be fatal.

C. TOXICITY FOR NEWBORN INFANTS
Newborn infants lack an effective glucuronic acid conjugation mechanism for the degradation and detoxification of chloramphenicol. Consequently, when infants are given dosages above 50 mg/kg/d, the drug may accumulate, resulting in the gray baby syndrome, with vomiting, flaccidity, hypothermia, gray color, shock, and collapse. To avoid this toxic effect, chloramphenicol should be used with caution in infants and the dosage limited to 50 mg/kg/d or less (during the first week of life) in full-term infants more than 1 week old and 25 mg/kg/d in premature infants.

D. INTERACTION WITH OTHER DRUGS
Chloramphenicol inhibits hepatic microsomal enzymes that metabolize several drugs. Half-lives are prolonged, and the serum concentrations of phenytoin, tolbutamide, chlorpropamide, and warfarin are increased. Like other bacteriostatic inhibitors of microbial protein synthesis, chloramphenicol can antagonize bactericidal drugs such as penicillins or aminoglycosides.

STREPTOGRAMINS

Quinupristin-dalfopristin is a combination of two streptogramins
¾quinupristin, a streptogramin B, and dalfopristin, a streptogramin A¾in a 30:70 ratio. It is rapidly bactericidal for most organisms except Enterococcus faecium, which is killed slowly. Quinupristin-dalfopristin is active against gram-positive cocci, including multidrug-resistant strains of streptococci, penicillin-resistant strains of S pneumoniae, methicillin-susceptible and -resistant strains of staphylococci, and E faecium (but not E faecalis). Resistance is due to modification of the quinupristin binding site (MLS-B type), enzymatic inactivation of dalfopristin, or efflux.

Quinupristin-dalfopristin is administered intravenously at a dosage of 7.5 mg/kg every 8-12 hours. Peak serum concentrations following an infusion of 7.5 mg/kg over 60 minutes are 3 mcg/mL for quinupristin and 7 mcg/mL for dalfopristin. Quinupristin and dalfopristin are rapidly metabolized, with half-lives of 0.85 and 0.7 hours, respectively. Elimination is principally by the fecal route. Dose adjustment is not necessary for renal failure, peritoneal dialysis, or hemodialysis. Patients with hepatic insufficiency may not tolerate the drug at usual doses, however, because of increased area under the concentration curve of both parent drugs and metabolites. This may necessitate a dose reduction to 7.5 mg/kg every 12 hours or 5 mg/kg every 8 hours. Quinupristin and dalfopristin significantly inhibit CYP3A4, which metabolizes warfarin, diazepam, astemizole, terfenadine, cisapride, nonnucleoside reverse transcriptase inhibitors, and cyclosporine, among others. Dosage reduction of cyclosporine may be necessary.

Quinupristin-dalfopristin is approved for treatment of infections caused by staphylococci or by vancomycin-resistant strains of E faecium, but not E faecalis, which is intrinsically resistant probably because of an efflux-type resistance mechanism. The principal toxicities are infusion-related events, such as pain at the infusion site, and an arthralgia-myalgia syndrome.

OXAZOLIDINONES

Linezolid is a member of the oxazolidinones, a new class of synthetic antimicrobials. It is active against gram-positive organisms including staphylococci, streptococci, enterococci, gram-positive anaerobic cocci, and gram-positive rods such as corynebacteria and Listeria monocytogenes. It is primarily a bacteriostatic agent except for streptococci, for which it is bactericidal. It is active in vitro against Mycobacterium tuberculosis.

Linezolid inhibits protein synthesis by preventing formation of the ribosome complex that initiates protein synthesis. Its unique binding site, located on 23S ribosomal RNA of the 50S subunit, results in no cross-resistance with other drug classes. Resistance is caused by mutation of the linezolid binding site on 23S ribosomal RNA.

The principal toxicity of linezolid is hematologic
¾reversible and generally mild. Thrombocytopenia is the most common manifestation (seen in approximately 3% of treatment courses), particularly when the drug is administered for longer than 2 weeks. Neutropenia may also occur, most commonly in patients with a predisposition to or underlying bone marrow suppression. Linezolid is 100% bioavailable after oral administration and has a half-life of 4-6 hours. It is metabolized by oxidative metabolism, yielding two inactive metabolites. It is neither an inducer nor an inhibitor of cytochrome P450 enzymes. Peak serum concentrations average 18 mcg/mL following a 600-mg oral dose. The recommended dosage for most indications is 600 mg twice daily, either orally or intravenously. Linezolid is approved for vancomycin-resistant E faecium infections; nosocomial pneumonia; community-acquired pneumonia; and skin infections, complicated or uncomplicated. It should be reserved for treatment of infections caused by multidrug-resistant gram-positive bacteria.

CLINICAL PHARMACOLOGY OF ANTIMICROBIAL AGENTS

SULFONAMIDES, TRIMETHOPRIM, & QUINOLONES
I. ANTIFOLATE DRUGS
SULFONAMIDES

The basic formula of the sulfonamides and their structural similarity to p-aminobenzoic acid (PABA).

Sulfonamides with varying physical, chemical, pharmacologic, and antibacterial properties are produced by attaching substituents to the amido group (-SO2-NH-R) or the amino group (-NH2) of the sulfanilamide nucleus. Sulfonamides tend to be much more soluble at alkaline than at acid pH. Most can be prepared as sodium salts, which are used for intravenous administration.

 

Antimicrobial Activity

Sulfonamide-susceptible organisms, unlike mammals, cannot use exogenous folate but must synthesize it from PABA. This pathway is thus essential for production of purines and nucleic acid synthesis. Because sulfonamides are structural analogs of PABA, they inhibit dihydropteroate synthase and folate production. Sulfonamides inhibit both gram-positive and gram-negative bacteria, nocardia, Chlamydia trachomatis, and some protozoa. Some enteric bacteria, such as E coli, klebsiella, salmonella, shigella, and enterobacter, are also inhibited. It is interesting that rickettsiae are not inhibited by sulfonamides but are actually stimulated in their growth. Activity is poor against anaerobes.

Combination of a sulfonamide with an inhibitor of dihydrofolate reductase (trimethoprim or pyrimethamine) provides synergistic activity because of sequential inhibition of folate synthesis.

 

Resistance

Mammalian cells (and some bacteria) lack the enzymes required for folate synthesis from PABA and depend on exogenous sources of folate; therefore, they are not susceptible to sulfonamides. Sulfonamide resistance may occur as a result of mutations that (a) cause overproduction of PABA, (b) cause production of a folic acid-synthesizing enzyme that has low affinity for sulfonamides, or (c) impair permeability to the sulfonamide. Dihydropteroate synthase with low sulfonamide affinity is often encoded on a plasmid that is transmissible and can disseminate rapidly and widely. Sulfonamide-resistant dihydropteroate synthase mutants also can emerge under selective pressure.

Pharmacokinetics

Sulfonamides can be divided into three major groups: (1) oral, absorbable; (2) oral, nonabsorbable; and (3) topical. The oral, absorbable sulfonamides can be classified as short-, intermediate-, or long-acting on the basis of their half-lives. They are absorbed from the stomach and small intestine and distributed widely to tissues and body fluids (including the central nervous system and cerebrospinal fluid), placenta, and fetus. Protein binding varies from 20% to over 90%. Therapeutic concentrations are in the range of 40-100 mcg/mL of blood. Blood levels generally peak 2-6 hours after oral administration.

A portion of absorbed drug is acetylated or glucuronidated in the liver. Sulfonamides and inactive metabolites are then excreted into the urine, mainly by glomerular filtration. In significant renal failure, the dosage of sulfonamide must be reduced.

Clinical Uses

Sulfonamides are infrequently used as single agents. Many strains of formerly susceptible species, including meningococci, pneumococci, streptococci, staphylococci, and gonococci, are now resistant. The fixed-drug combination of trimethoprim-sulfamethoxazole is the drug of choice for infections such as Pneumocystis jiroveci (formerly P carinii) pneumonia, toxoplasmosis, nocardiosis, and occasionally other bacterial infections.

A. ORAL ABSORBABLE AGENTS

Sulfisoxazole and sulfamethoxazole are short- to medium-acting agents used almost exclusively to treat urinary tract infections. The usual adult dosage is 1 g of sulfisoxazole four times daily or 1 g of sulfamethoxazole two or three times daily.

Sulfadiazine in combination with pyrimethamine is first-line therapy for treatment of acute toxoplasmosis. The combination of sulfadiazine with pyrimethamine, a potent inhibitor of dihydrofolate reductase, is synergistic because these drugs block sequential steps in the folate synthetic pathway blockade. The dosage of sulfadiazine is 1 g four times daily, with pyrimethamine given as a 75-mg loading dose followed by a 25-mg once-daily dose. Folinic acid, 10 mg orally each day, should also be administered to minimize bone marrow suppression.

Sulfadoxine is the only long-acting sulfonamide currently available in the United States and only as a combination formulation with pyrimethamine (Fansidar), a second-line agent in treatment for malaria.

B. ORAL NONABSORBABLE AGENTS
Sulfasalazine (salicylazosulfapyridine) is widely used in ulcerative colitis, enteritis, and other inflammatory bowel disease.

C. TOPICAL AGENTS
Sodium sulfacetamide ophthalmic solution or ointment is effective treatment for bacterial conjunctivitis and as adjunctive therapy for trachoma. Another sulfonamide, mafenide acetate, is used topically but can be absorbed from burn sites. The drug and its primary metabolite inhibit carbonic anhydrase and can cause metabolic acidosis, a side effect that limits its usefulness. Silver sulfadiazine is a much less toxic topical sulfonamide and is preferred to mafenide for prevention of infection of burn wounds.

Adverse Reactions

All sulfonamides, including antimicrobial sulfas, diuretics, diazoxide, and the sulfonylurea hypoglycemic agents, have been considered to be partially cross-allergenic. However, evidence for this is not extensive. The most common adverse effects are fever, skin rashes, exfoliative dermatitis, photosensitivity, urticaria, nausea, vomiting, diarrhea, and difficulties referable to the urinary tract (see below). Stevens-Johnson syndrome, although relatively uncommon (ie, less than 1% of treatment courses), is a particularly serious and potentially fatal type of skin and mucous membrane eruption associated with sulfonamide use. Other unwanted effects include stomatitis, conjunctivitis, arthritis, hematopoietic disturbances (see below), hepatitis, and, rarely, polyarteritis nodosa and psychosis.

A. URINARY TRACT DISTURBANCES
Sulfonamides may precipitate in urine, especially at neutral or acid pH, producing crystalluria, hematuria, or even obstruction. This is rarely a problem with the more soluble sulfonamides (eg, sulfisoxazole). Sulfadiazine when given in large doses, particularly if fluid intake is poor, can cause crystalluria. Crystalluria is treated by administration of sodium bicarbonate to alkalinize the urine and fluids to maintain adequate hydration. Sulfonamides have also been implicated in various types of nephrosis and in allergic nephritis.

B. HEMATOPOIETIC DISTURBANCES
Sulfonamides can cause hemolytic or aplastic anemia, granulocytopenia, thrombocytopenia, or leukemoid reactions. Sulfonamides may provoke hemolytic reactions in patients with glucose-6-phosphate dehydrogenase deficiency. Sulfonamides taken near the end of pregnancy increase the risk of kernicterus in newborns.

TRIMETHOPRIM
& TRIMETHOPRIM-SULFAMETHOXAZOLE MIXTURES
Trimethoprim, a trimethoxybenzylpyrimidine, selectively inhibits bacterial dihydrofolic acid reductase, which converts dihydrofolic acid to tetrahydrofolic acid, a step leading to the synthesis of purines and ultimately to DNA. Trimethoprim is about 50,000 times less efficient in inhibition of mammalian dihydrofolic acid reductase. Pyrimethamine, another benzylpyrimidine, selectively inhibits dihydrofolic acid reductase of protozoa compared with that of mammalian cells. As noted above, trimethoprim or pyrimethamine in combination with a sulfonamide blocks sequential steps in folate synthesis, resulting in marked enhancement (synergism) of the activity of both drugs. The combination often is bactericidal, compared with the bacteriostatic activity of a sulfonamide alone.
Resistance
Resistance to trimethoprim can result from reduced cell permeability, overproduction of dihydrofolate reductase, or production of an altered reductase with reduced drug binding. Resistance can emerge by mutation, although more commonly it is due to plasmid-encoded trimethoprim-resistant dihydrofolate reductases. These resistant enzymes may be coded within transposons on conjugative plasmids that exhibit a broad host range, accounting for rapid and widespread dissemination of trimethoprim resistance among numerous bacterial species.

Pharmacokinetics

Trimethoprim is usually given orally, alone or in combination with sulfamethoxazole, which has a similar half-life. Trimethoprim-sulfamethoxazole can also be given intravenously. Trimethoprim is well absorbed from the gut and distributed widely in body fluids and tissues, including cerebrospinal fluid. Because trimethoprim is more lipid-soluble than sulfamethoxazole, it has a larger volume of distribution than the latter drug. Therefore, when 1 part of trimethoprim is given with 5 parts of sulfamethoxazole (the ratio in the formulation), the peak plasma concentrations are in the ratio of 1:20, which is optimal for the combined effects of these drugs in vitro. About 30-50% of the sulfonamide and 50-60% of the trimethoprim (or their respective metabolites) are excreted in the urine within 24 hours. The dose should be reduced by half for patients with creatinine clearances of 15-30 mL/min.

Trimethoprim concentrates in prostatic fluid and in vaginal fluid, which are more acidic than plasma. Therefore, it has more antibacterial activity in prostatic and vaginal fluids than many other antimicrobial drugs.

Clinical Uses

A. ORAL TRIMETHOPRIM
Trimethoprim can be given alone (100 mg twice daily) in acute urinary tract infections. Most community-acquired organisms tend to be susceptible to the high concentrations that are found in the urine (200-600 mcg/mL).

B. ORAL TRIMETHOPRIM-SULFAMETHOXAZOLE (TMP-SMZ)
A combination of trimethoprim-sulfamethoxazole is effective treatment for a wide variety of infections including P jiroveci pneumonia, shigellosis, systemic salmonella infections, urinary tract infections, prostatitis, and some nontuberculous mycobacterial infections. It is active against most S aureus strains, both methicillin-susceptible and methicillin-resistant, and against respiratory tract pathogens such as the pneumococcus, Haemophilus species, Moraxella catarrhalis, and Klebsiella pneumoniae (but not Mycoplasma pneumoniae). However, the increasing prevalence of strains of E coli (up to 30% or more) and pneumococci that are resistant to trimethoprim-sulfamethoxazole must be considered before using this combination for empirical therapy of upper urinary tract infections or pneumonia.

One double-strength tablet (each tablet contains trimethoprim 160 mg plus sulfamethoxazole 800 mg) given every 12 hours is effective treatment for urinary tract infections and prostatitis. One half of the regular (single-strength) tablet given three times weekly for many months may serve as prophylaxis in recurrent urinary tract infections of some women. One double-strength tablet every 12 hours is effective treatment for infections caused by susceptible strains of shigella and salmonella. The dosage for children treated for shigellosis, urinary tract infection, or otitis media is 8 mg/kg trimethoprim and 40 mg/kg sulfamethoxazole every 12 hours.

Infections with P jiroveci and some other pathogens can be treated orally with high doses of the combination (dosed on the basis of the trimethoprim component at 15-20 mg/kg) or can be prevented in immunosuppressed patients by one double-strength tablet daily or three times weekly.

C. INTRAVENOUS TRIMETHOPRIM-SULFAMETHOXAZOLE
A solution of the mixture containing 80 mg trimethoprim plus 400 mg sulfamethoxazole per 5 mL diluted in 125 mL of 5% dextrose in water can be administered by intravenous infusion over 60-90 minutes. It is the agent of choice for moderately severe to severe pneumocystis pneumonia. It may be used for gram-negative bacterial sepsis, including that caused by some multidrug-resistant species such as enterobacter and serratia; shigellosis; typhoid fever; or urinary tract infection caused by a susceptible organism when the patient is unable to take the drug by mouth. The dosage is 10-20 mg/kg/d of the trimethoprim component.

D. ORAL PYRIMETHAMINE WITH SULFONAMIDE
Pyrimethamine and sulfadiazine have been used for treatment of leishmaniasis and toxoplasmosis. In falciparum malaria, the combination of pyrimethamine with sulfadoxine (Fansidar) has been used.

Adverse Effects

Trimethoprim produces the predictable adverse effects of an antifolate drug, especially megaloblastic anemia, leukopenia, and granulocytopenia. The combination trimethoprim-sulfamethoxazole may cause all of the untoward reactions associated with sulfonamides. Nausea and vomiting, drug fever, vasculitis, renal damage, and central nervous system disturbances occasionally occur also. Patients with AIDS and pneumocystis pneumonia have a particularly high frequency of untoward reactions to trimethoprim-sulfamethoxazole, especially fever, rashes, leukopenia, diarrhea, elevations of hepatic aminotransferases, hyperkalemia, and hyponatremia.

II. DNA GYRASE INHIBITORS

FLUOROQUINOLONES

The important quinolones are synthetic fluorinated analogs of nalidixic acid. Quinolones block bacterial DNA synthesis by inhibiting bacterial topoisomerase II (DNA gyrase) and topoisomerase IV. Inhibition of DNA gyrase prevents the relaxation of positively supercoiled DNA that is required for normal transcription and replication. Inhibition of topoisomerase IV interferes with separation of replicated chromosomal DNA into the respective daughter cells during cell division.
Earlier quinolones such as nalidixic acid did not achieve systemic antibacterial levels and were useful only for treatment of lower urinary tract infections. Fluorinated derivatives (ciprofloxacin, levofloxacin, and others) have greatly improved antibacterial activity compared with nalidixic acid and achieve bactericidal levels in blood and tissues.

Fluoroquinolones are synthetic bactericidal drugs with activity against gram-negative and gram-positive organisms. They may allow oral ambulatory treatment of infections that previously required parenteral therapy and hospitalization. Most are given orally, after which they are well absorbed, achieve therapeutic concentrations in most body fluids, and are metabolized to some extent in the liver. The kidneys are the main route of elimination, with approximately 30% to 60% of an oral dose excreted unchanged in the urine. Dosage should be reduced in renal impairment.

Resistance

During fluoroquinolone therapy, resistant organisms emerge about once in 107-109, especially among staphylococci, pseudomonas, and serratia. Resistance is due to one or more point mutations in the quinolone binding region of the target enzyme or to a change in the permeability of the organism. Resistance to one fluoroquinolone, particularly if it is of high level, generally confers cross-resistance to all other members of this class.

Pharmacokinetics

After oral administration, the fluoroquinolones are well absorbed (bioavailability of 80-95%) and distributed widely in body fluids and tissues. Serum half-lives range from 3 to 10 hours. The relatively long half-lives of levofloxacin, gemifloxacin gatifloxacin, and moxifloxacin permit once-daily dosing. Oral absorption is impaired by divalent cations, including those in antacids. Serum concentrations of intravenously administered drug are similar to those of orally administered drug. Most fluoroquinolones are eliminated by renal mechanisms, either tubular secretion or glomerular filtration. Dose adjustment is required for patients with creatinine clearances less than 50 mL/min, the exact adjustment depending on the degree of renal impairment and the specific fluoroquinolone being used. Dose adjustment for renal failure is not necessary for moxifloxacin. Nonrenally cleared fluoroquinolones are relatively contraindicated in patients with hepatic failure.

Antibacterial Activity

Fluoroquinolones were originally developed because of their excellent activity against gram-negative aerobic bacteria; they had limited activity against gram-positive organisms. Several newer agents have improved activity against gram-positive cocci. This relative activity against gram-negative versus gram-positive species is useful for classification of these agents. Norfloxacin is the least active of the fluoroquinolones against both gram-negative and gram-positive organisms, with minimum inhibitory concentrations (MICs) fourfold to eightfold higher than those of ciprofloxacin.

Ciprofloxacin, enoxacin, lomefloxacin, levofloxacin, ofloxacin, and pefloxacin make up a second group of similar agents possessing excellent gram-negative activity and moderate to good activity against gram-positive bacteria. MICs for gram-negative cocci and bacilli, including Enterobacteriaceae, pseudomonas, neisseria, haemophilus, and campylobacter, are 1-2 mcg/mL and often less. Methicillin-susceptible strains of S aureus are generally susceptible to these fluoroquinolones, but methicillin-resistant strains of staphylococci are often resistant. Streptococci and enterococci tend to be less susceptible than staphylococci, and efficacy in infections caused by these organisms is limited. Ciprofloxacin is the most active agent of this group against gram-negatives, P aeruginosa in particular. Levofloxacin, the L-isomer of ofloxacin, has superior activity against gram-positive organisms, including S pneumoniae.

Gatifloxacin, gemifloxacin, and moxifloxacin make up a third group of fluoroquinolones with improved activity against gram-positive organisms, particularly S pneumoniae and some staphylococci. Gemifloxacin is active in vitro against ciprofloxacin-resistant strains of S pneumoniae, but in vivo efficacy is unproven. Although MICs of these agents for staphylococci are lower than those of ciprofloxacin (and the other compounds mentioned in the paragraph above) and may fall within the susceptible range, it is not known whether the enhanced activity is sufficient to permit use of these agents for treatment of infections caused by ciprofloxacin-resistant strains. In general, none of these agents is as active as ciprofloxacin against gram-negative organisms. Fluoroquinolones also are active against agents of atypical pneumonia (eg, mycoplasmas and chlamydiae) and against intracellular pathogens such as Legionella species and some mycobacteria, including Mycobacterium tuberculosis and M avium complex. Moxifloxacin also has good activity against anaerobic bacteria. Because of toxicity, gatifloxacin is no longer available in the USA.

Indications for Use

 

Fluoroquinolones are indicated for various infections caused by aerobic gram-negative and other microorganisms. Thus, they may be used to treat infections of the respiratory, genitourinary, and GI tracts as well as infections of bones, joints, skin, and soft tissues. Additional uses include treatment of gonorrhea, multidrug-resistant tuberculosis, Mycobacterium avium complex (MAC) infections in clients with AIDS, and fever in neutropenic cancer clients.

Contraindications to Use

 

Fluoroquinolones are contraindicated in clients who have experienced a hypersensitivity reaction and in children younger than 18 years of age, if other alternatives are available. Limited data are available on the safety of fluoroquinolones in pregnant or lactating women; they should not be used unless the benefits outweigh the potential risks.

 

The choice of fluoroquinolone is determined by local susceptibility patterns and specific organisms because individual drugs differ somewhat in their antimicrobial spectra. The drugs cause similar adverse effects.

Adverse Effects

Fluoroquinolones are extremely well tolerated. The most common effects are nausea, vomiting, and diarrhea. Occasionally, headache, dizziness, insomnia, skin rash, or abnormal liver function tests develop. Photosensitivity has been reported with lomefloxacin and pefloxacin. QTc prolongation may occur with gatifloxacin, levofloxacin, gemifloxacin, and moxifloxacin. Ideally, these agents should be avoided or used with caution in patients with known QTc interval prolongation or uncorrected hypokalemia; in those receiving class IA (eg, quinidine or procainamide) or class III antiarrhythmic agents (sotalol, ibutilide, amiodarone); and in patients receiving other agents known to increase the QTc interval (eg, erythromycin, tricyclic antidepressants). Gatifloxacin has been associated with hyperglycemia in diabetic patients and with hypoglycemia in patients also receiving oral hypoglycemic agents. Because of these serious effects (including some fatalities), gatifloxacin was withdrawn from sales in the USA in 2006; it may be available elsewhere.

Fluoroquinolones may damage growing cartilage and cause an arthropathy. Thus, these drugs are not routinely recommended for patients under 18 years of age. However, the arthropathy is reversible, and there is a growing consensus that fluoroquinolones may be used in children in some cases (eg, for treatment of pseudomonal infections in patients with cystic fibrosis). Tendinitis, a rare complication that has been reported in adults, is potentially more serious because of the risk of tendon rupture. They should be avoided during pregnancy in the absence of specific data documenting their safety.

ANTIVIRAL DRUGS

 

 

Drug therapy for viral infections is still limited, however, because drug development is difficult. Viruses use the metabolic and reproductive mechanisms of host cells for their own vital functions, and few drugs inhibit viruses without being excessively toxic to host tissues. Most of these agents inhibit viral reproduction but do not eliminate viruses from tissues. Available drugs are expensive, relatively toxic,

and effective in a limited number of infections. Some may be useful in treating an established infection if given promptly and in chemoprophylaxis if given before or soon after exposure. Protection conferred by chemoprophylaxis is immediate but lasts only while the drug is being taken.

Drugs for Herpesvirus Infections

Acyclovir, famciclovir, and valacyclovir penetrate virusinfected cells, become activated by an enzyme, and inhibit viral DNA reproduction. They are used in the treatment of herpes simplex and herpes zoster infections. Acyclovir is used to treat genital herpes, in which it decreases viral shedding and the duration of skin lesions and pain. It does not eliminate inactive virus in the body and thus does not prevent recurrence of the disease unless oral drug therapy is continued. Acyclovir is also used for treatment of herpes simplex infections in immunocompromised clients. Prolonged or repeated courses of acyclovir therapy may result in the emergence of acyclovirresistant viral strains, especially in immunocompromised clients. Acyclovir can be given orally, intravenously (IV), or applied topically to lesions. IV use is recommended for severe genital herpes in nonimmunocompromised patients and any herpes infections in immunocompromised patients. Oral and IV acyclovir are excreted mainly in urine, and dosage should be decreased in patients who are elderly or have renal impairment.

 

Famciclovir and valacyclovir are oral drugs for herpes zoster and recurrent genital herpes. Famciclovir is metabolized to penciclovir, its active form, and excreted mainly in the urine. Valacyclovir is metabolized to acyclovir by enzymes in the liver and/or intestine and is eventually excreted in the urine. As with acyclovir, dosage of these drugs must be reduced in the presence of renal impairment.

Cidofovir, foscarnet, ganciclovir, and valganciclovir also inhibit viral reproduction after activation by a viral enzyme found in virus-infected cells. The drugs are used to treat cytomegalovirus (CMV) retinitis most commonly in patients with AIDS. In addition, foscarnet is used to treat acyclovirresistant mucocutaneous herpes simplex infections in people with impaired immune functions. Valganciclovir and ganciclovir are used to prevent CMV disease, mainly in patients with organ transplants or HIV infection. Dosage of these drugs must be reduced with renal impairment. Ganciclovir causes granulocytopenia and thrombocytopenia in approximately 20% to 40% of recipients. These hematologic effects often occur during the first 2 weeks of therapy but may occur at any time. If severe bone marrow depression occurs, ganciclovir should be discontinued. Recovery usually occurs within a week of stopping the drug. Foscarnet and cidofovir should be used cautiously in patients with renal disease.

Trifluridine and vidarabine are applied topically to treat keratoconjunctivitis and corneal ulcers caused by the herpes simplex virus (herpetic keratitis). Trifluridine should not be used longer than 21 days because of possible ocular toxicity. Vidarabine also is given IV to treat herpes zoster infections in patients whose immune systems are impaired and encephalitis caused by herpes simplex viruses. IV dosage must be reduced with impaired renal function.

 

DRUGS FOR HIV INFECTION AND AIDS

(Antiretrovirals)

TREATMENT OF HIV-INFECTED INDIVIDUALS: IMPORTANCE OF PHARMACOKINETIC KNOWLEDGE

Concurrent use of many medications is necessary in most HIV-infected patients. These medications include combinations of antiretroviral agents, prophylaxis or treatment for opportunistic infections, antiemetics, neuropsychiatric drugs, and opioid pain medications. Such extreme polypharmacy necessitates awareness of pharmacokinetic and pharmacodynamic interactions.

Perhaps the most important of the pharmacokinetic complications results from the metabolism of the NNRTI and PI agents by the CYP450 enzyme system, primarily the 3A4 isoform. Because many are inducers or inhibitors of CYP3A4 as well as substrates, drug-drug interactions may have marked clinical ramifications. However, variable effects on different CYP450 isoforms may make interactions somewhat unpredictable. For example, in the treatment of tuberculosis, the use of rifampin, a standard antimycobacterial agent but also one of the most potent 3A4 inducers, may either decrease efficacy (eg, atazanavir, lopinavir) or increase toxicity (eg, saquinavir) of concurrent antiretroviral agents, owing to alteration of serum levels. Increased levels of rifabutin (associated with uveitis) or trazodone (causing hypotension, syncope), when co-administered with ritonavir, may markedly increase toxicity. Increased levels of clarithromycin used for treatment or prophylaxis of Mycobacterium avium infection or as an antibacterial agent, when co-administered with indinavir, ritonavir, and atazanavir, may increase the potential for QT interval prolongation. Conversely, decreased levels of clarithromycin with efavirenz may reduce antibacterial efficacy. Most recently, these types of interactions have been used to advantage in the form of dual protease inhibitor regimens (boosted regimens), based on resultant increased plasma concentrations of the substrate (eg, lopinavir, saquinavir) when co-administered with an inducer (most often ritonavir). Improved drug exposure, increased antiviral potency, more convenient dosing, and improved tolerability result, thus improving patient adherence.

Four classes of drugs currently exist for the management of HIV infection: nucleoside reverse transcriptase inhibitors (NRTIs), nucleotide reverse transcriptase inhibitors, nonnucleoside reverse transcriptase inhibitors (NNRTIs), and protease inhibitors. Each class inhibits enzymes required for viral replication in human host cells. To increase effectiveness and decrease viral mutations and emergence of drug-resistant viral strains, the drugs are used in combination. All of the drugs can cause serious adverse effects and require intensive monitoring.

Nucleoside Reverse Transcriptase Inhibitors

The NRTIs are structurally similar to specific DNA components (adenosine, cytosine, guanosine, or thymidine) and thus easily enter human cells and viruses in human cells. For example, zidovudine, the prototype, is able to substitute for thymidine. In infected cells, these drugs inhibit reverse transcriptase, an enzyme required by retroviruses to convert RNA to DNA and allow replication. The drugs are more active in preventing acute infection than in treating chronically infected cells. Thus, they slow progression but do not cure HIV infection or prevent transmission of the virus through sexual contact or blood contamination.

Zidovudine, the first NRTI to be developed, is still widely used. However, zidovudine-resistant viral strains are common. Other NRTIs are usually given in combination with zidovudine or as a substitute for zidovudine in patients who are unable to take or do not respond to zidovudine.

Nucleotide Reverse Transcriptase Inhibitors

This class of antiretroviral drugs is the newest and currently includes one agent. These drugs, like the NRTIs, inhibit the reverse transcriptase enzyme. However, they differ structurally from the NRTIs, and this difference helps them to circumvent acquired drug resistance. The drugs are partially activated and begin inhibiting HIV replication soon after ingestion. Tenofovir is the first available drug from this class; it can be dosed once daily. Tenofovir has also demonstrated efficacy in the treatment of hepatitis B.

ABACAVIR

Abacavir is a guanosine analog that is well absorbed following oral administration (83%) and unaffected by food. The elimination half-life is 1.5 hours, and the intracellular half-life ranges from 12 to 26 hours. Cerebrospinal fluid levels are approximately one third those of plasma.
High-level resistance to abacavir appears to require at least two or three concomitant mutations (eg, M184V, L74V, D67N) and thus tends to develop slowly. The K65R mutation is associated with reduced susceptibility to lamivudine, abacavir, tenofovir, and emtricitabine.

 

Hypersensitivity reactions, occasionally fatal, have been reported in approximately 5% of patients receiving abacavir. Symptoms, which generally occur within the first 6 weeks of therapy, include fever, malaise, nausea, vomiting, diarrhea, and anorexia. Respiratory symptoms such as dyspnea, pharyngitis, and cough may also be present, and skin rash occurs in about 50% of patients. Laboratory abnormalities such as mildly elevated serum aminotransferase or creatine kinase levels may be present but are not specific for the hypersensitivity reaction. Although the syndrome tends to resolve quickly with discontinuation of medication, rechallenge with abacavir results in return of symptoms within hours and may be fatal. Other potential adverse events are rash, fever, nausea, vomiting, diarrhea, headache, dyspnea, fatigue, and pancreatitis (rare).

 

DIDANOSINE

Didanosine (ddI) is a synthetic analog of deoxyadenosine. Oral bioavailability is 30-40%; dosing on an empty stomach is required. Cerebrospinal fluid concentrations of the drug are approximately 20% of serum concentrations. The elimination half-life is 1.5 hours, but the intracellular half-life of the activated compound is as long as 20-24 hours. The drug is eliminated by glomerular filtration and tubular secretion. Dosage reduction is therefore required for low creatinine clearance and for low body weight.

Buffered powder for oral solution and chewable tablets are taken twice daily; enteric-coated capsules can be taken once daily because of greater bioavailability. The buffer in the tablets and powder interferes with absorption of indinavir, delavirdine, dapsone, and itraconazole; therefore, concurrent administration is to be avoided. Because the tablets contain both phenylalanine (36.5 mg) and sodium (1380 mg), caution should be exercised in patients with phenylketonuria and those on sodium-restricted diets.

Resistance to didanosine is typically associated with the L74V mutation, although decreased susceptibility may also occur in the presence of K65R and multiple thymidine analog mutations (TAMs). These may partially restore susceptibility to zidovudine but may confer cross-resistance to abacavir, zalcitabine, and lamivudine. The M184V mutation is found in a significant proportion of isolates selected by didanosine and may confer resistance to lamivudine.

The major clinical toxicity associated with didanosine therapy is dose-dependent pancreatitis. Other risk factors for pancreatitis (eg, alcoholism, hypertriglyceridemia) are relative contraindications to administration of didanosine, and other drugs with the potential to cause pancreatitis, including zalcitabine and stavudine, should be avoided. Other reported adverse effects include painful peripheral distal neuropathy, diarrhea (particularly with tablets and powder), hepatitis, esophageal ulceration, cardiomyopathy, and central nervous system toxicity (headache, irritability, insomnia). Asymptomatic hyperuricemia may precipitate attacks of gout in susceptible individuals. Reports of retinal changes and optic neuritis in patients receiving didanosine, particularly in adults receiving high doses and in children, mandate periodic retinal examinations.

Fluoroquinolones and tetracyclines should be administered at least 2 hours before or after didanosine to avoid decreased antibiotic plasma concentrations due to chelation. Serum levels of didanosine are increased when co-administered with tenofovir and ganciclovir, thus increasing the risk of toxicity; they are decreased by atazanavir, delavirdine, ritonavir, tipranavir, and methadone

 

LAMIVUDINE

Lamivudine (3TC) is a cytosine analog with in vitro activity against HIV-1 that is synergistic with a variety of antiretroviral nucleoside analogs¾including zidovudine and stavudine¾against both zidovudine-sensitive and zidovudine-resistant HIV-1 strains. Activity against HBV is described below.

Oral bioavailability exceeds 80% and is not food-dependent. In children, the mean cerebrospinal fluid: plasma ratio of lamivudine was 0.2. Mean elimination half-life is 2.5 hours, whereas the intracellular half-life of the active 5'-triphosphate metabolite in HIV-1-infected cell lines is 10.5-15.5 hours. The majority of lamivudine is eliminated unchanged in the urine, and the dose should be reduced in patients with renal insufficiency or low body weight.

Lamivudine therapy rapidly selects for the M184V mutation in regimens that are not fully suppressive; this mutation confers high-level resistance as well as a reduction in susceptibility to abacavir, didanosine, and zalcitabine. Conversely, the M184V mutation may restore phenotypic susceptibility to zidovudine, indicating that this two-drug combination regimen may be particularly beneficial. However, HIV-1 strains resistant to both lamivudine and zidovudine have been isolated. The K65R mutation is associated with reduced susceptibility to lamivudine, abacavir, tenofovir, and emtricitabine.

Potential adverse effects are headache, insomnia, fatigue, and gastrointestinal discomfort, although these are typically mild. Lamivudine's bioavailability increases when it is co-administered with trimethoprim-sulfamethoxazole. Lamivudine and zalcitabine may inhibit the intracellular phosphorylation of one another in vitro, thus decreasing potency; therefore, their concurrent use should be avoided if possible.

ZIDOVUDINE

Zidovudine (azidothymidine; AZT) is a deoxythymidine analog that is well absorbed from the gut and distributed to most body tissues and fluids, including the cerebrospinal fluid, where drug levels are 60-65% of those in serum. The serum half-life averages 1 hour, and the intracellular half-life of the phosphorylated compound is 3-7 hours. Zidovudine is eliminated primarily by renal excretion following glucuronidation in the liver. Clearance of zidovudine is reduced by approximately 50% in uremic patients, and toxicity may increase in patients with advanced hepatic insufficiency.

Zidovudine was the first antiretroviral agent to be approved and has been well studied. The drug has been shown to decrease the rate of clinical disease progression and prolong survival in HIV-infected individuals. Efficacy has also been demonstrated in the treatment of HIV-associated dementia and thrombocytopenia. In pregnancy, a regimen of oral zidovudine beginning between 14 and 34 weeks of gestation (100 mg five times a day), intravenous zidovudine during labor (2 mg/kg over 1 hour, then 1 mg/kg/h by continuous infusion), and zidovudine syrup to the neonate from birth through 6 weeks of age (2 mg/kg every 6 hours) has been shown to reduce the rate of vertical (mother-to-newborn) transmission of HIV by up to 23%.

As with other NRTI agents, resistance may limit clinical efficacy. High-level zidovudine resistance is generally seen in strains with three or more of the five most common mutations: M41L, D67N, K70R, T215F, and K219Q. However, the emergence of certain mutations that confer decreased susceptibility to one drug (eg, L74V for didanosine and M184V for lamivudine) seems to enhance zidovudine susceptibility in previously zidovudine-resistant strains. Withdrawal of zidovudine exposure may permit the reversion of zidovudine-resistant HIV-1 isolates to the susceptible wild-type phenotype.

The most common adverse effect of zidovudine is myelosuppression, resulting in macrocytic anemia (1-4%) or neutropenia (2-8%). Gastrointestinal intolerance, headaches, and insomnia may occur but tend to resolve during therapy. Less frequent toxicities include thrombocytopenia, hyperpigmentation of the nails, and myopathy. Very high doses can cause anxiety, confusion, and tremulousness. Zidovudine causes vaginal neoplasms in mice; however, no human cases of genital neoplasms have been reported to date.

Increased serum levels of zidovudine may occur with concomitant administration of probenecid, phenytoin, methadone, fluconazole, atovaquone, valproic acid, and lamivudine, either through inhibition of first-pass metabolism or through decreased clearance. Zidovudine may decrease phenytoin levels, and this warrants monitoring of serum phenytoin levels in epileptic patients taking both agents. Hematologic toxicity may be increased during co-administration of other myelosuppressive drugs such as ganciclovir, ribavirin, and cytotoxic agents. Combination regimens containing zidovudine and stavudine should be avoided; antagonism has been demonstrated in vitro.

Non-nucleoside Reverse Transcriptase Inhibitors

The NNRTIs inhibit viral replication in infected cells by directly binding to reverse transcriptase and preventing its function. They are used in combination with NRTIs to treat patients with advanced HIV infection. Because the two types of drugs inhibit reverse transcriptase by different mechanisms, they have synergistic antiviral effects. NNRTIs are also used with other antiretroviral drugs because drug-resistant strains emerge rapidly when the drugs are used alone.

 

Protease Inhibitors

Protease inhibitors exert their effects against HIV at a different phase of its life cycle than reverse transcriptase inhibitors. Protease is an HIV enzyme required to process viral protein precursors into mature viral particles that are capable of infecting other cells. The drugs inhibit the enzyme by binding to the protease-active site. This inhibition causes the production of immature, noninfectious viral particles. These drugs are active in both acutely and chronically infected cells because they block viral maturation.

Most protease inhibitors are metabolized in the liver by the cytochrome P450 enzyme system and should be used cautiously in patients with impaired liver function. They should be used cautiously in pregnant women because few data exist. It is unknown whether the drugs are excreted in breast milk, but this may be irrelevant because the Centers for Disease Control and Prevention (CDC) advise women with HIV infection to avoid breast-feeding because HIV may be transmitted to an uninfected infant. Safety and efficacy of protease inhibitors in children have not been established.

Indinavir, ritonavir, and saquinavir are the oldest and best known protease inhibitors, but their long-term effects are unknown. Two major concerns are viral resistance and drug interactions. Viral resistance develops fairly rapidly, with resistant strains developing in approximately half of the recipients within a year of drug therapy. In relation to drug interactions, protease inhibitors interfere with metabolism, increase plasma concentrations, and increase risks of toxicity of numerous other drugs metabolized by the cytochrome P450 (CYP450) enzymes in the liver.

AMPRENAVIR

Amprenavir is rapidly absorbed from the gastrointestinal tract and can be taken with or without food. However, high-fat meals decrease absorption and thus should be avoided. The plasma half-life is relatively long (7-10.6 hours). Amprenavir is metabolized in the liver by CYP3A4 and should be used with caution in the setting of hepatic insufficiency.

The key mutation conferring resistance to amprenavir appears to be I50V. Evidence to date suggests that cross-resistance to other members of the PI class of drugs may be less prevalent with amprenavir than with previously available compounds.

The most common adverse effects of amprenavir are nausea, diarrhea, vomiting, perioral paresthesias, depression, and rash. Up to 3% of patients in clinical trials to date have had rashes (including Stevens-Johnson syndrome) severe enough to warrant drug discontinuation.

Amprenavir is both an inducer and an inhibitor of CYP3A4 and is contraindicated with numerous other drugs. The oral solution, which contains propylene glycol, is contraindicated in young children, pregnant women, patients with renal or hepatic failure, and those using metronidazole or disulfiram. Also, the oral solutions of amprenavir and ritonavir should not be co-administered because the propylene glycol in one and the ethanol in the other may compete for the same metabolic pathway, leading to accumulation of either. Because the oral solution also contains vitamin E at several times the recommended daily dosage, supplemental vitamin E should be avoided. Amprenavir is contraindicated in patients with a history of sulfa allergy because it is itself a sulfonamide. Lopinavir/ritonavir should not be co-administered with amprenavir owing to decreased amprenavir and increased lopinavir exposures. An increased dosage of amprenavir is recommended when co-administered with efavirenz (with or without the addition of ritonavir to boost levels).

ATAZANAVIR

Atazanavir is a newer azapeptide PI with a pharmacokinetic profile that allows once-daily dosing. Its oral bioavailability is approximately 60-68%; the drug should be taken with food. Atazanavir requires an acidic medium for absorption and exhibits pH-dependent aqueous solubility; therefore, separation of ingestion from acid-reducing agents by at least 12 hours is recommended. Atazanavir is able to penetrate both the cerebrospinal and seminal fluids. The plasma half-life is 6-7 hours, which increases to approximately 11 hours when co-administered with ritonavir. The primary route of elimination is biliary; atazanavir should not be given to patients with severe hepatic insufficiency.

Resistance to atazanavir has been associated with various known PI mutations including the novel I50L substitution, which has been associated with increased susceptibility to other PIs.

The most common adverse effects in patients receiving atazanavir in clinical trials were nausea, vomiting, diarrhea, abdominal pain, headache, peripheral neuropathy, and skin rash. As with indinavir, indirect hyperbilirubinemia with overt jaundice may occur, in all likelihood owing to inhibition of the UGT1A1 enzyme. Although bilirubinemia is not regularly associated with hepatic injury, elevation of hepatic enzymes has also been observed, usually in patients with underlying hepatitis B or C infection. In contrast to the other PIs, atazanavir does not appear to be associated with dyslipidemias, fat redistribution, or the metabolic syndrome. Atazanavir may be associated with electrocardiographic PR interval prolongation, which is usually inconsequential but may be exacerbated by other causative agents such as calcium channel blockers. Also, a possible concentration-dependent increase in the QTc interval may occur in patients receiving atazanavir in dosages greater than 400 mg/d or in conjunction with the CYP3A4 inhibitor clarithromycin.

As an inhibitor of CYP3A4 and CYP2C9, the potential for drug-drug interactions with atazanavir is great. Atazanavir AUC is reduced by 76% on average when combined with omeprazole; thus, the combination is to be avoided. In addition, co-administration of atazanavir with other drugs that inhibit the glucuronidation enzyme UGT1A1, such as indinavir and irinotecan, is contraindicated because of enhanced toxicity. Tenofovir and efavirenz should not be co-administered with atazanavir unless ritonavir is added to boost levels.

FOSAMPRENAVIR

Fosamprenavir is a prodrug of amprenavir that is rapidly hydrolyzed by enzymes in the intestinal epithelium. Tablets may be taken with or without food. Because of its significantly lower daily pill burden, fosamprenavir tablets have replaced amprenavir capsules for adults. All pharmacokinetic and pharmacodynamic attributes are those of amprenavir (see above).

INDINAVIR

Indinavir must be consumed on an empty stomach for maximal absorption; however, if co-administered with ritonavir, it may be taken without regard to food. Oral bioavailability is about 65%, and the drug has a high level of cerebrospinal fluid penetration (up to 76% of serum levels). Serum half-life is 1.5-2 hours. Excretion is primarily fecal. An increase in AUC by 60% and in half-life to 2.8 hours in the setting of hepatic insufficiency necessitates dose reduction.

Resistance may be associated with multiple mutations, particularly at positions 46 and 82, and the number of codon alterations (typically substitutions) tends to predict the level of phenotypic resistance. Resistance to indinavir is associated with a loss of susceptibility to ritonavir.

The most common adverse effects are indirect hyperbilirubinemia and nephrolithiasis due to crystallization of the drug. Nephrolithiasis can occur within days after initiating therapy, with an estimated incidence of 10-20%, and it may be associated with renal failure. Consumption of at least 48 ounces of water daily is important to maintain adequate hydration and prevent nephrolithiasis. Thrombocytopenia, elevations of serum aminotransferase levels, nausea, diarrhea, and irritability have also been reported. Insulin resistance may be more common with indinavir than with the other PI agents, occurring in 3-5% of patients. There have also been rare cases of acute hemolytic anemia. In rats, high doses of indinavir are associated with development of thyroid adenomas.

Since indinavir is an inhibitor of CYP3A4, numerous and complex drug interactions can occur. Combination with ritonavir (boosting) allows for twice-daily rather than thrice-daily dosing and eliminates the food restriction associated with use of indinavir. However, there is potential for an increase in nephrolithiasis with this combination compared with indinavir alone; thus, a high fluid intake (1.5-2 L/d) is advised.

ANTI-INFLUENZA AGENTS

Influenza virus strains are classified by their core proteins (ie, A, B, or C), species of origin (eg, avian, swine), and geographic site of isolation. Influenza A, the only strain that causes pandemics, is classified into 16 H (hemagglutinin) and 9 N (neuraminidase) known subtypes based on surface proteins. Although influenza B viruses usually infect only people, influenza A viruses can infect a variety of animal hosts. Current influenza A subtypes that are circulating among people worldwide include H1N1, H1N2, and H3N2. Fifteen subtypes are known to infect birds, providing an extensive reservoir. Although avian influenza subtypes are typically highly species-specific, they have on rare occasions crossed the species barrier to infect humans and cats. Viruses of the H5 and H7 subtypes (eg, H5N1, H7N7, and H7N3) may rapidly mutate within poultry flocks from a low to high pathogenic form and have recently expanded their host range to cause both avian and human disease. Of particular concern is the H5N1 virus, which first caused human infection (including severe disease and death) in 1997 and has become endemic in Southeast Asia poultry since 2003. It is feared that the virus will become transmissible from person to person rather than solely from poultry to human, thus initiating the potential for a global outbreak (ie, pandemic).

Although both classes of antiviral drugs available for influenza have activity against influenza A, many or most of the circulating strains of avian H5N1, as well as the H1 and H3 strains causing seasonal influenza in the United States, are resistant to the adamantanamine agents.

AMANTADINE
& RIMANTADINE

Amantadine (1-aminoadamantane hydrochloride) and its
a-methyl derivative, rimantadine, are cyclic amines of the adamantine family that block the M2 proton ion channel of the virus particle and inhibit uncoating of the viral RNA within infected host cells, thus preventing its replication. They are active against influenza A only. Rimantadine is four to ten times more active than amantadine in vitro. Amantadine is excreted unchanged in the urine, whereas rimantadine undergoes extensive metabolism by hydroxylation, conjugation, and glucuronidation before urinary excretion. Dose reductions are required for both agents in the elderly and in patients with renal insufficiency and for rimantadine in patients with marked hepatic insufficiency.

In the absence of resistance, both amantadine and rimantadine, at 100 mg twice daily or 200 mg once daily, are 70-90% protective in the prevention of clinical illness when initiated before exposure. When begun within 1-2 days after the onset of illness, the duration of fever and systemic symptoms is reduced by 1-2 days.

The primary target for both agents is the M2 protein within the viral membrane, incurring both influenza A specificity and a mutation-prone site that results in the rapid development of resistance in up to 50% of treated individuals. Resistant isolates with single-point mutation are genetically stable, retain pathogenicity, can be transmitted to close contacts, and may be shed chronically by immunocompromised patients. The prevalence of resistance to both agents in clinical isolates in the United States increased from 2% in the 2003-2004 influenza season, to 12% in 2004-2005, to an alarming 91% in 2005-2006 (99% in H3N2, 1% in H1N1). Cross-resistance to zanamivir and oseltamivir does not occur.

The most common adverse effects are gastrointestinal (nausea, anorexia) and central nervous system (nervousness, difficulty in concentrating, insomnia, light-headedness). Central nervous system toxicity may be due to alteration of dopamine neurotransmission, is less frequent with rimantadine than with amantadine, tends to diminish after the first week of use, and may increase with concomitant antihistamines, anticholinergic drugs, hydrochlorothiazide, and trimethoprim-sulfamethoxazole. Serious neurotoxic reactions, occasionally fatal, may occur in association with high amantadine plasma concentrations and are more likely in the elderly or with renal insufficiency. Peripheral edema is another potential adverse effect. Both agents are teratogenic in rodents, and birth defects have been reported after exposure during pregnancy.

ZANAMIVIR
& OSELTAMIVIR

The neuraminidase inhibitors zanamivir and oseltamivir, analogs of sialic acid, interfere with release of progeny influenza virus from infected to new host cells, thus halting the spread of infection within the respiratory tract. Unlike amantadine and rimantadine, zanamivir and oseltamivir have activity against both influenza A and influenza B viruses. Early administration is crucial because replication of influenza virus peaks at 24-72 hours after the onset of illness. When a 5-day course of therapy is initiated within 36-48 hours after the onset of symptoms, the duration of illness is decreased by 1-2 days compared with those on placebo, severity is diminished, and the incidence of secondary complications in children and adults decreases. Once-daily prophylaxis is 70-90% effective in preventing disease after exposure. Oseltamivir is FDA-approved for patients 1 year and older, whereas zanamivir is approved in patients 7 years or older.

Zanamivir is delivered directly to the respiratory tract via inhalation. Ten to twenty percent of the active compound reaches the lungs, and the remainder is deposited in the oropharynx. The concentration of the drug in the respiratory tract is estimated to be more than 1000 times the 50% inhibitory concentration for neuraminidase. Five to fifteen percent of the total dose (10 mg twice daily for treatment and 10 mg once daily for prevention) is absorbed and excreted in the urine with minimal metabolism. Potential side effects include cough, bronchospasm (occasionally severe), reversible decrease in pulmonary function, and transient nasal and throat discomfort.

Oseltamivir is an orally administered prodrug that is activated by hepatic esterases and widely distributed throughout the body. The dosage is 75 mg twice daily for treatment and 75 mg once daily for prevention; dosage must be modified in patients with renal insufficiency. The half-life of oseltamivir is 6-10 hours, and excretion is primarily in the urine. Potential side effects include nausea, vomiting, and abdominal pain, which occur in 5-10% of patients early in therapy but tend to resolve spontaneously. Taking oseltamivir with food does not interfere with absorption and may decrease nausea and vomiting. Headache, fatigue, and diarrhea have also been reported and appear to be more common with prophylactic use.

In adults, resistance during therapy is rare but may cause fatal disease. It is unknown whether resistant mutants retain pathogenicity or are spread between people. Worldwide resistance is rare and has not been documented in any clinical isolate from the 2005-2006 influenza season to date in the USA. Avian influenza is expected to retain susceptibility to the neuraminidase inhibitors.

 

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Keating GM, Scott LJ: Moxifloxacin: A review of its use in the management of bacterial infections. Drugs 2004;64:2347.

Mandell LA et al: Update of practice guidelines for the management of community-acquired pneumonia in immunocompetent adults. Clin Infect Dis 2003;37:1405.

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