Chapter 27. Antibacterial Agents

Infectious diseases are among the most common forms of illness. Thus, many patients undergoing physical rehabilitation may be taking one or more antimicrobial drugs. Most agents (but not all) have little direct impact on the functional rehabilitation outcomes, but they will certainly have an impact on the overall health status of the patient.

The next four chapters address agents used to treat infections caused by various parasites including bacteria, viruses, fungi, protozoa, and helminths (worms). Once these pathogens gain access inside the human body, they can cause illnesses ranging from minor infections to life-threatening illnesses. Antimicrobial drugs are among the most dramatic examples of advances of modern medicine; many infectious diseases once considered incurable and lethal are now amenable to treatment. Antimicrobial drugs are classified and identified according to the primary type of infectious organism they are used to treat (e.g., antibacterial, antiviral, antifungal).

The remarkably powerful and specific activity of antimicrobial drugs is due to selective toxicity—that is, drugs are designed to target structures selectively that are either unique to microorganisms or much more important in them than in humans. Therefore, a general understanding of microbial structure and function is necessary to understand the mechanisms of action of antimicrobial agents. Notably, selective toxicity is not perfect, and antimicrobials may exert some adverse effects in humans.

Bacterial infections harm humans in several ways. Bacteria can directly damage or destroy human cells by releasing toxins, and they can compete with human cells for vital nutrients. In addition, in immunocompetent individuals, bacteria trigger a host immune response that may damage not only pathogenic bacteria but also human cells and tissues.

It is also important to understand that not all bacteria living in the human body are harmful. In fact, some bacteria normally coexist within humans and actually benefit their human hosts. For example, Escherichia coli microorganisms normally inhabit the gastrointestinal tract and are thus considered part of the normal flora. E coli assist in digestion of food, synthesize essential nutrients such as vitamin K, and inhibit the growth of other organisms. As an illustration of the latter function, antibiotic therapy often results in the eradication of normal gut flora. After antibiotic treatment is completed, overgrowth of other microorganisms (e.g., yeasts) often occurs.

The target site for antibacterial drugs, or antibiotics, is either the cell wall or structures involved in bacterial reproduction.

Bacteria are single-celled prokaryotes (cells without a distinct nucleus) that have a characteristic cellular organization. Fungi, protozoa, and multicellular organisms have nuclei containing their genetic material and are called eukaryotes. Viruses, on the other hand, are not strictly cellular at all and comprise a very different form of life. Bacterial deoxyribonucleic acid (DNA) forms a long circular molecule called a nucleoid. In addition, genetic information may be present in DNA molecules termed plasmids. Plasmids replicate independently of chromosomal DNA and may carry genes that affect resistance to antimicrobials (i.e., plasmid-mediated resistance). Both nucleoid DNA and plasmids are subject to mutations that can be passed on to daughter cells. In addition, bacteria can exchange genetic material by a process called conjugation, thus allowing passage of drug resistance genes without mutation. Both nucleoid and plasmid DNA are transcribed into messenger ribonucleic acid (RNA) by the enzyme RNA polymerase.

Ribosomal function is the same in prokaryotic and eukaryotic cells—that is, ribosomes translate messenger RNA into a new protein chain, the final product of the gene. However, ribosomal structure is characterized as 70S in prokaryotes and as 80S in eukaryotes. (The “S” unit refers to how a molecule sediments under centrifugal force in an ultracentrifuge.) The bacterial 70S ribosome is specifically targeted by certain antibacterials such as the aminoglycosides. Two major subunits comprise the ribosome: 30S and 50S in prokaryotes and 40S and 60S in eukaryotes.

In all bacteria except mycoplasmas, the cell is completely surrounded by a cell wall, a structure not found in eukaryotes. The cell wall lies external to a cytoplasmic membrane, which is similar to the cell membranes of eukaryotic cells. The cell wall’s rigidity maintains cell integrity, protecting bacteria from lysis due to high internal osmotic pressure.

Bacteria are classified as gram positive or gram negative according to their cell wall structure. The primary structural component of the cell wall is a peptidoglycan, a polymer of sugars and charged amino acids, which make the peptidoglycan highly polar. In gram-positive bacteria, the peptidoglycan forms a very thick hydrophilic layer external to the cell membrane. The thick hydrophilic surface of gram-positive bacteria can be digested by lysozyme, an enzyme present in body secretions and intracellular organelles, but provides protection against most other enzymes and bile in the intestine. Penicillin and cephalosporin antibiotics inhibit bacterial cell wall synthesis by disrupting peptidoglycan formation. In gram-negative bacteria, the peptidoglycan layer is thinner and anchored to an overlying outer membrane (Figure 27–1). The outer membrane is relatively hydrophobic. To enable hydrophilic nutrients to enter the cell, gram-negative bacteria have special pores formed by proteins called porins.

The cell wall is a primary determinant of the ultimate shape of the bacterium, which is an important characteristic for bacterial identification. In general, bacterial shapes are categorized as spherical (cocci), rods (bacilli), or helical (spirilla). Although each bacterium is named according to its genus and species (e.g., Staphylococcus aureus), bacteria are often categorized by common characteristics such as histologic staining properties and shape. For example, gram-positive cocci include bacteria that stain in a certain manner (determined by the gram-positive cell wall) and are spherical in shape (cocci). This group includes S aureus and Streptococcus pneumoniae.

The most common way to classify antibiotics is on the basis of their site of action: inhibitors of bacterial cell wall synthesis, inhibitors of bacterial protein synthesis, and inhibitors of bacterial DNA synthesis. Antimycobacterial drugs are discussed separately.

Some antibiotics are bactericidal (kill bacteria), while others are bacteriostatic (inhibit bacterial growth). Bacteriostatic antibiotics are successful in treating infections in patients with intact immune systems because they prevent the bacterial population from increasing, and allow host defense mechanisms to eradicate the remaining population. For bacteriostatic drugs (e.g., clindamycin, macrolides, sulfonamides, tetracyclines), the concentrations that inhibit growth are much lower than those that kill bacteria. Bactericidal drugs (e.g., aminoglycosides, β-lactams, fluoroquinolones, streptogramins, vancomycin, and most antimycobacterial agents) are preferred for treating infections in immunocompromised patients because they are able to eradicate an infection even in the absence of normal host defense mechanisms. For bactericidal drugs, there is little difference between concentrations that inhibit growth and those that kill bacteria.

Dosage regimens with antibiotics have traditionally used multiple daily doses to maintain serum concentrations above the minimal inhibitory concentration (MIC) for as long as possible. However, the in vivo effectiveness of some antibiotics (e.g., aminoglycosides) results from a concentration-dependent killing action. As the plasma level is increased above the MIC, these agents kill an increasing proportion of bacteria and do so at a more rapid rate. Many other antibiotics (e.g., penicillins and cephalosporins) cause time-dependent killing of bacteria, wherein their in vivo efficacy is directly related to time above MIC and becomes independent of concentration once the MIC has been reached.

Some agents exert a postantibiotic effect in which inhibition of bacterial growth continues after plasma levels have fallen to low levels. The mechanisms of the postantibiotic effect are unclear, but may reflect delayed time required by bacteria to synthesize new enzymes and cellular components, persistence of antibiotic at target sites, or enhanced susceptibility of bacteria to host defense mechanisms. The postantibiotic effect contributes to the efficacy of once-daily administration of aminoglycosides, and may also contribute to the efficacy of the fluoroquinolones.

The emergence of microbial resistance poses an increasing challenge to the use of all antimicrobial drugs. The mechanisms underlying microbial resistance to antibiotics include production of drug-inactivating enzymes, changes in the structure of target receptors, increased antibiotic efflux via drug transporters, and decreases in cell wall permeability to antibiotics. Strategies designed to combat microbial resistance include the use of additional agents that protect against enzymatic inactivation, the use of antibiotic combinations, the introduction of new (and often expensive) chemical derivatives of established antibiotics, and efforts to avoid indiscriminate use or misuse of antibiotics.

The most common cause of resistance is the use of inappropriate antibiotics for viral or other nonsusceptible infections. This presents resident and environmental organisms with selective pressure to develop resistance to the drug being used. A secondary cause of resistance is the use of inadequate dosage or duration of an appropriate drug. Such treatment eliminates only the most susceptible organisms, leaving the more resistant ones to proliferate.

The major antibiotics in this class are penicillins and cephalosporins. These agents only kill bacterial cells that are actively growing and synthesizing new cell walls. They are called β-lactams, or β-lactam antibiotics, because they share an unusual four-member ring structure called a β-lactam ring. The β-lactam antibiotics include some of the most effective, widely used, and well-tolerated antimicrobial agents. The selective toxicity of β-lactams and other cell wall synthesis inhibitors is due to specific actions on the synthesis of cell walls—structures that are unique to bacteria. More than 50 antibiotics that act as cell wall synthesis inhibitors are currently available, with individual spectra of activity that afford a wide range of clinical applications. Figure 27–2 outlines this broad class of cell wall synthesis inhibitors, and Table 27–1 lists the key drugs in this class.

Penicillins

All penicillins are derivatives of 6-aminopenicillanic acid and contain a β-lactam ring structure that is essential for antibacterial activity. Penicillin subclasses have additional chemical modifications that confer differences in antimicrobial activity, susceptibility to acid and enzymatic hydrolysis, and biodisposition. Penicillins vary in their resistance to gastric acid and, therefore, vary in their oral bioavailability. Except for amoxicillin, oral penicillins should generally not be given with food to minimize binding to food proteins and acid inactivation. Thus, patients should be advised to take penicillins 1 to 2 hours before or after meals. Penicillins are not metabolized extensively; they are usually excreted unchanged in the urine via glomerular filtration and tubular secretion. Ampicillin and nafcillin are excreted partly in the bile. The plasma half-lives of most penicillins vary from 30 to 60 minutes. Two forms of penicillin G, the prototype of a subclass of penicillins with a limited antibacterial spectrum, are administered intramuscularly and have long plasma half-lives because the active drug is released very slowly into the bloodstream. Most penicillins cross the blood-brain barrier only when the meninges are inflamed (e.g., in meningitis).

Mechanisms of Action and Resistance

The β-lactams exert bactericidal effects by inhibiting cell wall synthesis. Inhibition of cell wall synthesis occurs as follows (Figure 27–1): (1) binding of the β-lactam agent to specific receptor proteins called penicillin-binding proteins (PBPs) located in the bacterial cytoplasmic membrane, enzymes that cross-link linear peptidoglycan chains that form part of the cell wall; and (2) activation of [gx id=""]autolytic[/gx] enzymes that cause lesions in the bacterial cell wall.

Bacteria have developed several mechanisms to resist destruction by β-lactam drugs. The most common mechanism of resistance is the production of β-lactamases (penicillinases) by many bacteria (especially Staphylococcus species and many gram-negative organisms). β-Lactamases hydrolyze the β-lactam ring of these antibiotics, resulting in the loss of antibacterial activity. To prevent the inactivation of the β-lactam ring, pencillins are sometimes administered in combination with inhibitors of bacterial β-lactamases (e.g., clavulanic acid, sulbactam, tazobactam). Another mechanism of resistance is structural change in target PBPs. This is an important mechanism because altered PBPs are responsible for methicillin resistance (in staphylococci) and penicillin resistance (in pneumococci and enterococci). In some gram-negative bacteria, resistance may be due to impaired penetration of antibiotics to their target PBPs. To cross the outer membrane that distinguishes gram-negative from gram-positive bacteria, β-lactams must enter gram-negative bacteria via porins (Figure 27–1). Altered porin structures may contribute to resistance by impeding β-lactam access to PBPs. Finally, some gram-negative bacteria may produce efflux pumps that effectively expel some β-lactam agents that get past the outer membrane.

Clinical Uses

Penicillins can be divided into very narrow, narrow, and wider spectrum agents, with spectrum referring to the number of organisms against which they provide antibacterial activity. They may also be classified by whether the agents are susceptible to bacterial β-lactamase (penicillinase) (Figure 27–2).

Among the narrow-spectrum penicillinase–susceptible agents, penicillin G is the prototype. Clinical uses include treatment for infections caused by common streptococci, meningococci, gram-positive bacilli, and spirochetes. Many strains of pneumococci are now resistant to penicillins. Most strains of Staphylococcusaureus and a significant number of strains of Neisseria gonorrhoeae are resistant via production of β-lactamases. Penicillin V, the oral equivalent of penicillin G, is only used in minor oropharyngeal infections.

The very narrow-spectrum penicillinase–resistant subclass includes the prototype methicillin, nafcillin, and oxacillin. Their primary use is in the treatment of known or suspected staphylococcal infections. However, methicillin-resistant Staphylococcus aureus (MRSA) and methicillin-resistant Staphylococcus epidermidis (MRSE), two strains important in many hospital-acquired infections, are resistant to other members of this subgroup and are often resistant to multiple antimicrobial drugs.

Wider spectrum penicillinase–susceptible drugs are among the most commonly used penicillins. Ampicillin and amoxicillin are often used to treat urinary tract infections (UTIs), otitis media, pneumonia, and bacteremias resulting from infections with susceptible bacterial species. Piperacillin and ticarcillin have activity against several gram-negative bacteria, including Pseudomonas (e.g., UTI, pneumonia, bacteremia), Enterobacter (e.g., UTI), and in some cases Klebsiella species (e.g., UTI, pneumonia). For infections with penicillinase-producing bacteria, inhibitors of penicillinases (e.g., clavulanic acid) are co-administered to enhance the antibacterial activity of this subclass. Most drugs in this subclass have synergistic actions when used with aminoglycosides, inhibitors of protein synthesis discussed later in this chapter.

Adverse Effects

The penicillins are remarkably nontoxic. However, the potential for allergic reactions is a concern and allergic reactions account for most of the serious adverse effects. All penicillins are cross-sensitizing and cross-reacting, so cross-allergenicity among different penicillins is assumed. About 5 to 10% of individuals with a history of penicillin reaction have an allergic response when given a penicillin again. Allergic reactions include urticaria, severe pruritus, fever, joint swelling, hemolytic anemia, nephritis, and in rare cases anaphylaxis. Methicillin causes nephritis more often than other penicillins, and nafcillin is associated with neutropenia. Ampicillin frequently causes maculopapular skin rash that does not appear to be an allergic reaction.

Large oral doses of penicillins, especially ampicillin, may lead to gastrointestinal upset (e.g., nausea, vomiting, and diarrhea). Gastrointestinal upset may be caused by direct irritation or by overgrowth of gram-positive organisms or yeasts.

Problems Relating to the Use and Misuse of Penicillins

Penicillins are among the most misused antibiotics, having been used irrationally for nonsusceptible infections for over 50 years. As a result, 90% of all staphylococcal strains both in the hospital and in the community are β-lactamase producers, and the prevalence of methicillin-resistant strains of S aureus (MRSA) continues to increase. Broad-spectrum penicillins also eradicate normal flora, thereby predisposing the patient to colonization and superinfection with opportunistic, drug-resistant species present within the hospital environment.

Cephalosporins

The cephalosporins also contain the β-lactam ring structure, and are therefore classified as β-lactam antibiotics. They vary in their antibacterial activity and are designated first-, second-, third-, or fourth-generation drugs according to the order of their introduction into clinical use (Figure 27–2). Several cephalosporins are available for oral use (e.g., cephalexin, cefixime), but most are administered parenterally. Cephalosporins with side chains may undergo hepatic metabolism, but the major elimination mechanism is renal excretion via active tubular secretion. Cefoperazone and ceftriaxone are excreted mainly in the bile. Most first- and secondgeneration cephalosporins do not enter the cerebrospinal fluid even when the meninges are inflamed.

Mechanisms of Action

Cephalosporins have a broader spectrum of activity than the penicillins because they are less susceptible to many bacterial penicillinases. Cephalosporins’ bactericidal activity results from binding to PBPs in bacterial cell membranes and interfering with bacterial cell wall synthesis.

Bacterial resistance to cephalosporins can result from certain β-lactamases, decreases in membrane permeability to cephalosporins, and from altered PBP structures. Methicillin-resistant staphylococci (i.e., MRSA) are also resistant to cephalosporins.

Clinical Uses

Cefazolin (parenteral) and cephalexin (oral) are examples of first-generation cephalosporins. Although they are fairly broad-spectrum agents with very minimal toxicities, first-generation cephalosporins are rarely drugs of choice for any infection. Clinical uses include treatment of infections caused by gram-positive cocci, including susceptible staphylococci and common streptococci. Cefazolin may be the drug of choice in infections for which it is the least toxic drug (e.g., Klebsiella pneumoniae).

Second-generation agents include cefotetan, cefoxitin, cefamandole, cefuroxime, and cefaclor. Members of this subclass usually have less activity against gram-positive organisms than first-generation drugs, but have extended gram-negative coverage. Marked differences in activity, pharmacokinetics, and toxicity occur among second-generation agents. Examples of clinical uses include infections caused by Bacteroides fragilis (e.g., peritonitis, diverticulitis) andHaemophilus influenzae or Moraxella catarrhalis (e.g., sinusitis, otitis, lower respiratory infections).

Characteristic features of third-generation drugs (e.g., ceftazidime, cefoperazone, cefotaxime) include increased activity against gram-negative organisms resistant to other β-lactam drugs and ability to penetrate the blood-brain barrier (except cefoperazone and cefixime). Individual drugs have activity against Pseudomonas (cefoperazone, ceftazidime) and B fragilis (ceftizoxime). Drugs in this subclass are usually reserved for treatment of serious infections (e.g., bacterial meningitis). The exceptions are ceftriaxone (parenteral) and cefixime (oral), which are currently drugs of choice to treat gonorrhea. Likewise, in acute otitis media, a single injection of ceftriaxone is usually as effective as a 10-day treatment course with amoxicillin.

The fourth-generation agents have the widest antibacterial spectrum of the cephalosporins. They are more resistant to β-lactamases produced by gram-negative organisms, including Enterobacter, Haemophilus, Neisseria, and some penicillin-resistant pneumococci. Cefepime, the prototypic fourth-generation agent, combines the gram-positive activity of first-generation agents with the wider gram-negative spectrum of third-generation cephalosporins.

Adverse Effects

Cephalosporins may elicit a variety of hypersensitivity reactions that are identical to those of penicillins, including fever, skin rashes, nephritis, granulocytopenia, hemolytic anemia, and anaphylaxis. However, the chemical nucleus of cephalosporins is sufficiently different from that of penicillins so that some individuals with a history of penicillin allergy may sometimes be treated successfully with a cephalosporin. However, patients with a history of anaphylaxis to penicillins should not receive cephalosporins. Complete cross-hypersensitivity among different cephalosporins should be assumed.

Cephalosporins may cause pain at intramuscular injection sites and phlebitis after intravenous administration. They may increase the nephrotoxicity of aminoglycosides when the two are administered together. Drugs containing a methylthiotetrazole group (e.g., cefamandole, cefoperazone, cefotetan) may cause hypoprothrombinemia and disulfiram-like reactions with ethanol.

Other β-Lactam Drugs

Several other β-lactam drugs are of clinical importance. Aztreonam is neither a penicillin nor a cephalosporin. It is a monobactam, named for its chemical structure that contains one β-lactam ring. Aztreonam is resistant to β-lactamases produced by certain gram-negative rods, but has no activity against gram-positive bacteria or anaerobes. It inhibits cell wall synthesis by preferentially binding to a specific penicillin-binding protein (PBP3). It is synergistic with aminoglycosides. Aztreonam is administered intravenously, and is eliminated via renal tubular secretion. Penicillin-allergic patients tolerate aztreonam without reaction. Adverse effects include gastrointestinal upset with possible superinfection, vertigo, headache, and rare hepatotoxicity.

Imipenem, meropenem, and ertapenem are carbapenems and are chemically different from pencillins. While they retain the β-lactam ring structure, they have low susceptibility to β-lactamases. Carbapenems have wide activity against gram-positive cocci (including some penicillin-resistant pneumococci), gram-negative rods, and anaerobes. The carbapenems are administered parenterally, and are especially useful for infections caused by organisms resistant to other antibiotics.

Because imipenem is inactivated by a renal enzyme, it is administered in combination with cilastatin, an inhibitor of this enzyme. Adverse effects of imipenem-cilastatin include gastrointestinal distress, skin rash, and, at very high plasma levels, central nervous system (CNS) toxicity (confusion, encephalopathy, seizures). There is partial cross-allergenicity with the penicillins. Meropenem is similar to imipenem except that it is not metabolized by renal enzymes and is less likely to cause seizures. Ertapenem has a long half-life, and its intramuscular injection causes pain and irritation.

β-Lactamase Inhibitors

An obvious problem with using β-lactam antibiotics such as pencillins and cephalosporins is that many bacteria produce β-lactamases that inactivate these agents. Clavulanic acid, sulbactam, and tazobactam are β-lactamase inhibitors that have little or no antibacterial action themselves. They are administered in fixed combinations with certain penicillins to treat infections caused by bacteria that produce β-lactamases. Adverse effects of these drug combinations are caused primarily by the penicillin agent.

Other Inhibitors of Cell Wall Synthesis

Vancomycin is a glycopeptide antibiotic produced by a strain of Streptococcus. It binds to a unique set of amino acids used in cross-linking the peptidoglycan cell wall. As a result, chains of the peptidoglycan cannot be cross-linked and the cell wall is disrupted, making the bacterial cell susceptible to lysis. Vancomycin has a narrow spectrum of activity and is used for serious infections caused by drug-resistant gram-positive organisms, including MRSA, penicillin-resistant pneumococci, and Clostridium difficile.Teicoplanin, another glycopeptide, has similar characteristics.

Some strains of enterococci and staphylococci have become resistant to vancomycin (i.e., vancomycin-resistant enterococci [VRE] and vancomycin-resistant S aureus [VRSA]). Resistance to vancomycin is due to a single amino acid change in the bacterial binding site for vancomycin, which significantly decreases its binding affinity. The prevalence of VRE is increasing and poses a serious clinical problem because such organisms usually exhibit multiple-drug resistance. Likewise, strains of MRSA have been reported with intermediate resistance to vancomycin, leading to treatment failures.

Vancomycin is not absorbed from the gastrointestinal tract, but may be given orally to treat bacterial enterocolitis. When given parenterally, vancomycin penetrates most tissues and is eliminated unchanged in the urine. Dosage modification is mandatory in patients with renal impairment. Toxic effects of vancomycin include chills, fever, phlebitis, ototoxicity, and nephrotoxicity. Rapid intravenous infusion may cause diffuse flushing (“red man syndrome”).

Daptomycin, a new lipopeptide agent, is chemically different from vancomycin and has a different mechanism of action, but a similar spectrum of activity and indications. It is active against several strains of VRE and VRSA. Daptomycin is described in Chapter 30.

Other inhibitors of cell wall synthesis include bacitracin and cycloserine. Bacitracin is a peptide antibiotic that interferes with a late stage in cell wall synthesis in gram-positive organisms. Because of its marked nephrotoxicity, this antibiotic is limited to topical use for skin lesions. Bacitracin solutions in saline can also be used for irrigation of joints, wounds, or the pleural cavity. Cycloserine prevents formation of a functional bacterial peptidoglycan. Because of its potential neurotoxicity (tremors, seizures, psychosis), cycloserine is only used to treat strains of Mycobacteriumtuberculosis (the causative agent of tuberculosis) that are resistant to first-line antituberculous drugs.

The basic process by which mammalian and bacterial cells make proteins is similar. In both mammalian and bacterial cells, the specific genetic information contained within DNA is transcribed into messenger RNA (mRNA). Next, mRNA is translated into a new polypeptide or protein chain. The role of ribosomes in this process is to move along the mRNA chain, recruit transfer RNA (tRNA) molecules that carry different amino acids, and join incoming amino acids to the growing polypeptide chain. One critical difference between protein synthesis in mammalian and bacterial cells is the structure of their ribosomes.

Differences in ribosomal subunits, chemical composition, and functional specificities of component nucleic acids and proteins form the basis of selective toxicity of certain antibiotics against bacterial protein synthesis with much less effect on mammalian cells.

Although drugs in this class vary dramatically in their structure and spectrum of antimicrobial efficacy (Figure 27–3), each agent inhibits bacterial protein synthesis by acting at the level of the bacterial ribosome. Chloramphenicol, tetracyclines, and aminoglycosides were the first inhibitors of bacterial protein synthesis to be discovered. Because they had a broad spectrum of antibacterial activity and were thought to have low toxicities, they were overused. As a result, many once highly susceptible bacterial species have become resistant, and these drugs are now only used for more selected targets. Erythromycin, an older macrolide antibiotic, has a narrower spectrum of action but continues to be active against several important pathogens. Newer drugs (e.g., streptogramins, linezolid, telithromycin) have activity against certain gram-positive bacteria that have developed resistance to older antibiotics.

Mechanisms of Action

Most antibiotics in this subclass are bacteriostatic. Figure 27–4 illustrates the specific binding sites on the 70S bacterial ribosomal complex for chloramphenicol, tetracyclines, and the macrolides. With the exception of tetracyclines and aminoglycosides, the binding sites for these antibiotics are on the 50S ribosomal subunit. Chloramphenicol, clindamycin, and the macrolides prevent a step called transpeptidation, in which the next new amino acid is added to the nascent peptide chain. Tetracyclines bind to the 30S ribosomal subunit at a site that blocks the binding of amino acid–carrying tRNA (charged tRNA) to the acceptor site of the ribosome-mRNA complex.

The streptogramins are bactericidal for most susceptible organisms. They bind to the 50S ribosomal subunit, and prevent extrusion of the nascent polypeptide chain. In addition, streptogramins inhibit the activity of enzymes that synthesize tRNA, leading to a decrease in free tRNA within the cell. Linezolid also binds to the 50S subunit. It blocks formation of the tRNA-ribosome-mRNA complex. The action of the aminoglycosides is described below.

Chloramphenicol

Chloramphenicol has a simple and distinctive structure, and no other antimicrobials have been discovered in this chemical class. It is effective orally as well as parenterally and is distributed throughout all tissues. It readily crosses the placental and blood-brain barriers. The drug undergoes enterohepatic cycling, and is mostly inactivated by the liver. Chloramphenicol has a wide spectrum of antimicrobial activity and is usually bacteriostatic. It is not active against Chlamydia. Although chloramphenicol does not bind to ribosomal RNA of mammalian cells, it can inhibit the functions of mammalian mitochondrial ribosomes, which are more similar to bacterial ribosomes. Clinically significant resistance to chloramphenicol occurs through the formation of plasmid-encoded enzymes that inactivate the drug.

Clinical Uses

Because of its toxicity and bacterial resistance, chloramphenicol has very few uses as a systemic drug. It is a back-up drug for severe infections caused by Salmonella species and for the treatment of penicillin-resistant pneumococcal or meningococcal meningitis, or in patients who have major hypersensitivity reactions to penicillin. Chloramphenicol is commonly used as a topical agent for eye infections because of its broad spectrum and ability to penetrate ocular tissue.

Adverse Effects

Patients taking chloramphenicol occasionally develop nausea, vomiting, and diarrhea. Oral or vaginal candidiasis may occur as a result of alteration of normal microbial flora. Chloramphenicol commonly causes dose-related reversible suppression of red blood cell production. Idiosyncratic aplastic anemia, which involves suppression of production of all blood cells, can also occur, but is rare and unrelated to dose. Unfortunately, it occurs more frequently with prolonged use and is usually irreversible.

If newborn infants are given high dosages, chloramphenicol may accumulate because infants lack effective mechanisms for metabolism of the drug. The resulting gray baby syndrome includes vomiting, flaccidity, hypothermia, gray color, cyanosis, and cardiovascular collapse.

Because chloramphenicol inhibits hepatic enzymes that metabolize several drugs, it has significant interactions when taken with other drugs. Half-lives are prolonged, and 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.

Tetracyclines

Tetracyclines (tetracycline, doxycycline, minocycline, demeclocycline) are broad-spectrum bacteriostatic antibiotics that inhibit protein synthesis in gram-positive and gram-negative bacteria, Rickettsia (the cause of Rocky Mountain spotted fever and some other difficult to treat infections), Chlamydia, Mycoplasma,Borrelia (the cause of Lyme disease), and some protozoa. Drugs in this class have only minor differences in their activities against specific organisms. Susceptible organisms accumulate tetracyclines intracellularly via energy-dependent transport systems in their cell membranes. Tetracyclines have little effect on mammalian protein synthesis because an active efflux mechanism prevents their intracellular accumulation.

Oral absorption is variable, especially for the older drugs, and may be impaired by foods and multivalent cations (calcium, iron, aluminum). Tetracyclines have a wide tissue distribution and cross the placental barrier. All of the tetracyclines undergo enterohepatic cycling. Doxycycline is excreted mainly in feces; the other tetracyclines are eliminated primarily in the urine. The half-lives of doxycycline and minocycline are longer than those of other tetracyclines.

Plasmid-mediated resistance to tetracyclines is widespread. Resistance mechanisms include decreased activity of the uptake systems and, most importantly, the development of mechanisms such as efflux pumps for active extrusion of tetracyclines. Plasmids that include genes involved in producing efflux pumps for tetracyclines commonly include resistance genes for multiple antibiotics.

Clinical Uses

A tetracycline is the drug of choice in infections caused by Mycoplasma pneumoniae (in adults), Chlamydia, Rickettsia, and Vibrio (e.g., cholera). Specific tetracyclines are used in the treatment of gastrointestinal ulcers caused by Helicobacter pylori (tetracycline), in Lyme disease (doxycycline), and in the meningococcal carrier state (minocycline). Doxycycline is also used for the prevention of malaria and in the treatment of amebiasis. Demeclocycline inhibits the renal actions of antidiuretic hormone (ADH) and is used in the management of patients with ADH-secreting tumors.

Tetracyclines are alternative drugs in the treatment of syphilis. They are also used in the treatment of respiratory infections caused by susceptible organisms, for prophylaxis against infection in chronic bronchitis, in the treatment of leptospirosis, and in the treatment of acne.

Adverse Effects

Hypersensitivity reactions (i.e., fever, rashes) to tetracyclines are uncommon. Most of the adverse reactions are due to direct toxicity of the tetracycline agent or due to alterations in microbial flora.

Effects on the gastrointestinal system range from mild nausea and diarrhea to severe, possibly life-threatening colitis. Disturbances in the normal flora are due to suppression of tetracycline-susceptible organisms and overgrowth of resistant organisms, especially pseudomonas, staphylococci, and candida. This can result in intestinal disturbances, anal pruritus, vaginal or oral candidiasis, or enterocolitis.

Tetracyclines bind to calcium deposited in newly formed bone or teeth in young children. Thus, fetal exposure to tetracyclines may lead to tooth enamel dysplasia and discoloration and irregularities in bone growth. Although usually contraindicated in pregnancy, there may be situations in which the benefit of administering tetracyclines outweighs the risk. If taken for long periods of time in children under 8 years of age, tetracyclines may cause similar changes in teeth and bone.

High doses of tetracyclines, especially in pregnant patients and those with preexisting hepatic disease, may impair liver function and lead to hepatic necrosis. Likewise, in patients with kidney disease, tetracyclines may exacerbate renal dysfunction.

Systemic tetracyclines (especially demeclocycline) may enhance skin sensitivity to ultraviolet light, particularly in fair-skinned individuals.

Dose-dependent reversible dizziness and vertigo have been reported with doxycycline and minocycline.

Macrolides

The macrolide antibiotics are large cyclic lactone ring structures with attached sugars. The macrolides include the prototypic drugs erythromycin, azithromycin, and clarithromycin. The macrolides have good oral bioavailability, but azithromycin absorption is impeded by food. Macrolides distribute to most body tissues, but azithromycin is unique in that the levels achieved in tissues and in phagocytes are considerably higher than those in the plasma. The elimination of erythromycin (via biliary excretion) and clarithromycin (via hepatic metabolism and urinary excretion of intact drug) is fairly rapid (half-life 2 to 5 hours). Azithromycin is eliminated slowly (half-life 2 to 4 days), mainly in urine as unchanged drug.

Clinical Uses

Erythromycin has activity against many species of Campylobacter, Chlamydia, Mycoplasma, Legionella, gram-positive cocci (including β-lactamase–producing staphylococci), and some gram-negative organisms. The antibacterial action may be bacteriostatic or bactericidal; the latter effect occurring more commonly at higher concentrations for susceptible organisms. Erythromycin does not have activity against penicillin-resistant Streptococcus pneumoniae or methicillin-resistant S aureus (MRSA).

The spectra of activity of azithromycin and clarithromycin are similar to erythromycin, but include greater activity against Chlamydia,Mycobacterium avium complex, and Toxoplasma species. Because of its long half-life, a 4-day course of treatment with azithromycin has been effective in community-acquired pneumonia. Clarithromycin is approved for prophylaxis against and treatment of M avium complex and as a component of drug regimens for ulcers caused by Helicobacter pylori.

Resistance to macrolide antibiotics in gram-positive organisms involves efflux pump mechanisms and the production of an enzyme (methylase) that alters the drugs’ ribosomal binding site. Cross-resistance among individual macrolides is complete; that is, if an organism is resistant to one macrolide agent, it will be resistant to all other macrolides. In the case of methylase-producing bacterial strains, there is partial cross-resistance with other drugs that bind to the same ribosomal site as macrolides, including clindamycin and streptogramins. Resistance in Enterobacteriaceae is due to formation of drug-metabolizing esterases.

Adverse Effects

Gastrointestinal irritation (anorexia, nausea, vomiting) is often associated with oral administration. Stimulation of gut motility is the most common reason for discontinuing erythromycin and choosing another antibiotic. This action is sometimes exploited therapeutically in patients with inadequate gastrointestinal motility. A hypersensitivity-based acute cholestatic hepatitis (fever, jaundice, impaired liver function) may occur with erythromycin estolate. This condition usually resolves. Hepatitis is rare in children, but there is an increased risk with erythromycin estolate in pregnant patients. Because erythromycin inhibits several forms of hepatic cytochrome P450, it increases the plasma levels of anticoagulants, carbamazepine, cisapride, digoxin, and theophylline. Similar drug interactions have also occurred with clarithromycin. Drug interactions are uncommon with azithromycin because this agent does not inhibit hepatic cytochrome P450.

Telithromycin

Telithromycin is a ketolide structurally related to macrolides. It has the same mechanism of action as erythromycin and a similar moderate spectrum of antimicrobial activity. However, some macrolide-resistant microbial strains are susceptible to telithromycin because it binds more tightly to ribosomes and is a poor substrate for bacterial efflux pumps that mediate resistance. Clinical uses include community-acquired bacterial pneumonia and other upper respiratory tract infections. Telithromycin is given orally once daily and is eliminated in the bile and the urine.

Clindamycin

Clindamycin inhibits bacterial protein synthesis via a mechanism similar to that of the macrolides, although it is not chemically related. Mechanisms of resistance include alteration of the drug’s ribosomal binding site and enzymatic inactivation of the drug. Cross-resistance between clindamycin and the macrolides is common. Good tissue penetration occurs after oral absorption. Clindamycin is eliminated partly by metabolism and partly by biliary and renal excretion.

Clinical Uses

The main use of clindamycin is in the treatment of severe infections caused by certain anaerobes such as Bacteroides (most common bacteria in the colon) 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 (e.g., septic abortion and pelvic abscesses), or aspiration pneumonia. Clindamycin has been used as a back-up drug against gram-positive cocci, and is currently recommended for prophylaxis of endocarditis in patients with cardiac valve disease who are allergic to penicillin. 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

Adverse effects of clindamycin include gastrointestinal irritation, skin rashes, neutropenia, and hepatic dysfunction. Severe diarrhea and enterocolitis have followed clindamycin administration. Antibiotic-associated colitis due to superinfection with C difficile is a potentially fatal complication and must be recognized promptly and treated.

Streptogramins

Quinupristin-dalfopristin is a combination of two streptogramins. The combination has rapid bactericidal activity that lasts longer than the half-lives of the individual compounds. Antibacterial activity includes penicillin-resistant pneumococci, methicillin-resistant and vancomycin-resistant staphylococci (MRSA and VRSA, respectively), and resistant Enterococcus faecium. Administered intravenously, the combination product may cause pain at the infusion site and an arthralgia-myalgia syndrome. Streptogramins are potent inhibitors of CYP3A4 and increase plasma levels of many drugs, including cisapride, cyclosporine, diazepam, nonnucleoside reverse transcriptase inhibitors, and warfarin.

Linezolid

Linezolid is the first of a new class of antibiotics called oxazolidinones. Linezolid is mainly bacteriostatic, and is active against gram-positive cocci, including strains resistant to β-lactams and vancomycin (e.g., vancomycin-resistant E faecium). Linezolid binds to a unique site on one of the ribosomal subunits, and there is currently no cross-resistance with other protein synthesis inhibitors. Although rare to date, resistance can occur with a decreased affinity of linezolid for its binding site. Linezolid is available in both oral and parenteral formulations. The primary adverse effect is hematologic; thrombocytopenia and neutropenia occur, most commonly in immunosuppressed patients.

Aminoglycosides

Aminoglycosides exert bactericidal activity and are useful mainly against aerobic gram-negative microorganisms. One of the primary advantages of aminoglycosides is that they can often be used in a once-daily dosing protocol, which can save time and lends itself to outpatient therapy with these agents. In addition, once-daily dosing can be more effective and less toxic than traditional dosing regimens. Aminoglycosides have greater efficacy when administered as a single large dose because their bactericidal effectiveness is concentration dependent. That is, as the plasma level is increased above the MIC, aminoglycosides kill an increasing proportion of bacteria and do so more rapidly. Aminoglycosides can also exert a postantibiotic effect, so that that their killing action continues when plasma levels have declined below measurable levels. The single large daily dose of an aminoglycoside generally results in fewer adverse effects because toxicity depends both on a critical plasma concentration and on the time that such a level is exceeded. With single large doses, the time above such a threshold is shorter than with administration of multiple smaller doses.

The aminoglycosides include gentamicin, amikacin, neomycin, tobramycin, and others. They are structurally related amino sugars attached by glycosidic linkages. All of the aminoglycosides are polar compounds, so they are not absorbed after oral administration. Therefore, they must be given intramuscularly or intravenously for systemic effect. They have limited tissue penetration and do not readily cross the blood-brain barrier. The major mode of excretion is via the kidney, and plasma levels of these drugs are greatly affected by changes in renal function. With normal renal function, the elimination half-life of aminoglycosides is 2 to 3 hours. Patients receiving aminoglycosides for more than 1 day must have plasma levels of the drug monitored for safe and effective dosage selection and adjustment. Even with once-daily dosing, plasma levels may be monitored, especially in patients with decreased kidney function.

Mechanism of Action

To kill susceptible bacteria, aminoglycosides must penetrate the bacterial cell envelope. This process is partly dependent on oxygen-dependent active transport; therefore, these agents have minimal activity against strict anaerobes. To assist entry of aminoglycosides into bacterial cells, aminoglycosides may be co-administered with a cell wall synthesis inhibitor such as a β-lactam agent. Once inside the bacterial cell, aminoglycosides bind to the 30S ribosomal subunit and interfere with protein synthesis in at least three ways: (1) they block formation of the initiation complex; (2) they cause misreading of mRNA; and (3) they inhibit translocation (Figure 27–5).

Clinical Uses

Aminoglycosides are mostly used against gram-negative enteric (i.e., intestinal) bacteria. The main differences among the individual aminoglycosides lie in their activities against specific organisms, particularly gram-negative rods. Gentamicin, tobramycin, and amikacin are important drugs for the treatment of serious infections caused by aerobic gram-negative bacteria, including E coli and Enterobacter, Klebsiella (especially important in respiratory infections and urinary tract infections), Proteus, Providencia, Pseudomonas, and Serratia (important in septicemia and pulmonary infections) species. These aminoglycosides also have activity against other species (e.g., H influenzae, Moraxella catarrhalis,Shigella), although they are not drugs of choice for infections caused by these organisms. When used alone, aminoglycosides are not reliably effective for treating infections caused by gram-positive cocci. Antibacterial synergy may occur when aminoglycosides are used in combination with cell wall synthesis inhibitors. For example, aminoglycosides may be combined with penicillins to treat pseudomonal, listerial (important in some cases of meningitis), and enterococcal infections.

Streptomycin is an aminoglycoside that is often used in the treatment of tuberculosis, plague, and tularemia (rabbit fever). Because of the risk of irreversible ototoxicity, streptomycin should not be used when other drugs will serve. Owing to its toxic potential, neomycin is only used topically or locally (e.g., in the gastrointestinal tract to eliminate bowel flora). Netilmicin is usually reserved for treatment of serious infections caused by organisms resistant to the other aminoglycosides.

Adverse Effects

All aminoglycosides are ototoxic and nephrotoxic. Auditory or vestibular damage (or both) may occur and may be irreversible. Auditory impairment, which may manifest as tinnitus and high-frequency hearing loss initially, is more likely with amikacin and kanamycin. Vestibular dysfunction, which may manifest as vertigo, ataxia, and loss of balance, is more likely with gentamicin and tobramycin. These toxic risks are proportionate to plasma levels of the drug. Precautions taken to reduce these risks include once-daily dosing (versus traditional dosing regimens), monitoring plasma levels of aminoglycosides with appropriate dose modification, and avoiding the additive ototoxicity of loop diuretics during dosing. Because ototoxicity has been reported after fetal exposure, aminoglycosides are contraindicated in pregnancy unless their potential benefits are judged to outweigh risk.

Renal toxicity usually takes the form of acute tubular necrosis, which is often reversible. It is more common in elderly patients and in those concurrently receiving amphotericin B, cephalosporins, or vancomycin. Gentamicin and tobramycin are the most nephrotoxic aminoglycosides.

Allergic skin reactions may occur in patients, and contact dermatitis may occur in personnel handling these drugs. Neomycin is the most likely culprit.

Although rare, respiratory paralysis may occur at high doses. It is usually reversible by prompt treatment with calcium and neostigmine, but ventilatory support may be required.

The sulfonamides, trimethoprim, and fluoroquinolones make up the group of drugs that exert antibacterial effects by interfering with bacterial DNA synthesis (Figure 27–6). Individual key drugs in this class of drugs are listed in Table 27–2.

Sulfonamides and Trimethoprim

Mechanism of Action and Pharmacokinetics

Sulfonamides and trimethoprim are called antifolate drugs because they interfere with folic acid synthesis. Folic acid and folate are the names of forms of vitamin B9. Folic acid is the synthetic form found in fortified foods and supplements, and folate is the anionic form found naturally in foods. Folic acid is necessary for DNA replication; thus, it is necessary for production and maintenance of new cells. While mammals can use exogenous (i.e., dietary) folate, many bacteria cannot and rely on enzymes to synthesize folate from its precursor, para-aminobenzoic acid (PABA). Antifolate drugs inhibit folic acid synthesis at different stages (Figure 27–7). The selective toxicity of antifolate drugs results from the fact that mammalian cells utilize dietary folic acid, so inhibition of folic acid synthesis will primarily affect bacteria.

Used as single agents, sulfonamides are bacteriostatic inhibitors of folic acid synthesis (Figure 27–7). They competitively inhibit dihydropteroate synthase and can also act as substrates for this enzyme, resulting in the synthesis of nonfunctional forms of folic acid. Trimethoprim selectively inhibits bacterial dihydrofolate reductase, which prevents formation of the active form of folic acid. Bacterial dihydrofolate reductase is 4 to 5 orders of magnitude more sensitive to trimethoprim inhibition than the mammalian form of dihydrofolate reductase. Because microbial resistance is common if sulfonamides are used as single antimicrobial agents, a sulfonamide is frequently used in combination with trimethoprim, with the combination being known as TMP-SMZ or TMP-SMX. This combination causes a sequential blockade of folic acid synthesis in which both drugs inhibit sequential steps in bacterial metabolism. This results in a synergistic, often bactericidal, action against a wide spectrum of microorganisms. Resistance to the combination occurs but has been relatively slow in development.

The sulfonamides are weakly acidic compounds that have a chemical nucleus resembling PABA, the substrate with which they compete. Members of this group differ mainly in their pharmacokinetic properties and clinical uses. Shared pharmacokinetic features include modest tissue penetration, hepatic metabolism, and excretion of both intact drug and acetylated metabolites in the urine. They 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-acting (e.g., sulfisoxazole), intermediate-acting (e.g., sulfamethoxazole), or long-acting (e.g., sulfadoxine) on the basis of their half-lives. Sulfonamides bind to plasma proteins at sites shared by bilirubin and by other drugs.

Trimethoprim is structurally similar to folic acid. It is a weak base and is trapped in acidic environments, reaching high concentrations in prostatic and vaginal fluids. A large fraction of trimethoprim is excreted unchanged in the urine.

Clinical Uses

Among the oral absorbable sulfonamides, sulfisoxazole and sulfamethoxazole are used almost exclusively for treating urinary tract infections. Oral sulfadiazine plus pyrimethamine (a dihydrofolate reductase inhibitor) work synergistically as a first-line treatment for toxoplasmosis. As topical agents, several sulfonamides are used to treat bacterial ophthalmic and wound infections. Sodium sulfacetamide ophthalmic solution or ointment is effective for treating bacterial conjunctivitis. In the prevention of infection of burn wounds, mafenide acetate can be used to treat topical infections. However, silver sulfadiazine is the preferred agent because mafenide acetate can cause metabolic acidosis.

The combination of trimethoprim-sulfamethoxazole is the drug regimen of choice for infections such as Pneumocystis jiroveci pneumonia, toxoplasmosis, and nocardiosis (Chapter 29). TMP-SMX is also a possible back-up drug for cholera, typhoid fever, and shigellosis, and has been used in the treatment of infections caused by MRSA and Listeria monocytogenes.

Adverse Effects

Adverse effects of the sulfonamides include hypersensitivity reactions, hepatotoxicity, nephrotoxicity, and gastrointestinal discomfort such as nausea, vomiting, and diarrhea. Allergic reactions, including skin rashes and fever, are common. Cross-allergenicity among the individual sulfonamides should be assumed and may rarely occur with chemically related drugs (e.g., oral hypoglycemics, thiazides). Common drug interactions include competition with warfarin and methotrexate for plasma protein binding, which transiently increases the plasma levels of these drugs. Sulfonamides can displace bilirubin from plasma proteins, with the risk of severe newborn jaundice and kernicterus if used in the third trimester of pregnancy. Persons with glucose-6-phosphate dehydrogenase (G6PD) deficiency may suffer hemolysis if sulfonamides are given.

Trimethoprim may cause the predictable adverse effects of an antifolate drug, including megaloblastic anemia, leukopenia, and granulocytopenia. These effects are usually ameliorated by supplementary folinic acid. The combination of TMP-SMX may also cause any of the adverse effects associated with sulfonamides. AIDS patients given TMP-SMX have a high incidence of adverse effects, including fever, rashes, leukopenia, and diarrhea.

Fluoroquinolones

Mechanism of Action and Pharmacokinetics

Fluoroquinolones selectively inhibit two enzymes critical for bacterial DNA synthesis: topoisomerase II(DNA gyrase) and topoisomerase IV. Inhibition of DNA gyrase prevents relaxation of positively supercoiled DNA; uncoiling is required for normal transcription, whereas inhibition of topoisomerase IV interferes with the separation of replicated chromo-somal DNA during cell division.

Fluoroquinolones are usually bactericidal against susceptible organisms. Like aminoglycosides, the fluoroquinolines also exhibit postantibiotic effects.

Resistance has emerged to the older fluoroquinolones, but has been offset to some extent by the introduction of newer generations with expanded activity against common pathogenic organisms.

All of the fluoroquinolones have good oral bioavailability (although some antacids may interfere) and penetrate most body tissues. Elimination of most fluoroquinolones is through the kidneys; dosage reductions are usually needed in renal dysfunction. Moxifloxacin is eliminated partly by hepatic metabolism and also by biliary excretion. Half-lives of fluoroquinolones are usually 3 to 8 hours, but the agents eliminated by nonrenal routes have half-lives from 10 to 20 hours.

Fluoroquinolines are classified by “generation” based on their antimicrobial spectrum of activity (Table 27–2). Norfloxacin, a first-generation agent, is the least active fluoroquinolone against both gram-negative and gram-positive organisms. Ciprofloxacin and ofloxacin (second-generation fluoroquinolones) have excellent activity against gram-negative bacteria and moderate to good activity against gram-positive cocci. Third-generation fluoroquinolones (e.g., levofloxacin) are slightly less active against gram-negative bacteria, but have greater activity against gram-positive cocci, including S pneumoniae and some strains of enterococci and MRSA. The most recently introduced fourth-generation drugs (e.g., moxifloxacin) are the broadest spectrum fluoroquinolones to date, with enhanced activity against anaerobes.

Clinical Uses

Fluoroquinolones are effective in the treatment of urogenital and gastrointestinal tract infections even when caused by multidrug-resistant bacteria. Fluoroquinolones (except norfloxacin, which does not achieve adequate systemic concentrations) have been used widely for respiratory tract, skin, bone, joint, and soft tissue infections. However, their effectiveness may be variable because of the emergence of resistance. Ciprofloxacin and ofloxacin are alternatives to third-generation cephalosporins in gonorrhea, and are administered in single oral doses. Ofloxacin will eradicate accompanying organisms such as Chlamydia. Levofloxacin has good activity against organisms associated with community-acquired pneumonia. Fluoroquinolones have also been used in the meningococcal carrier state, in the treatment of tuberculosis, and in prophylactic management of neutropenic patients.

Adverse Effects

Overall, fluoroquinolones are very well tolerated. Gastrointestinal distress is the most common side effect. In addition, they may cause skin rashes, headache, dizziness, insomnia, abnormal liver function tests, and phototoxicity. Although rare, tendonitis has been reported, which may be serious because of the risk of tendon rupture. They are not recommended for use in children or in pregnancy because they have caused cartilage problems in developing animals. Fluoroquinolones may increase plasma levels of theophylline and other methylxanthines, enhancing their toxicity.

Mycobacteria are slow-growing aerobic gram-positive bacteria that are widespread in the environment and in animals. The peptidoglycan layer has a different chemical basis than gram-positive or gram-negative bacteria. The outer envelope contains a variety of complex lipids called mycolic acids, which create a waxy layer that provides resistance to drying and other environmental factors. Thus, mycobacteria can survive for prolonged periods in the environment and are effectively transmitted by airborne droplets. After entering host cells, mycobacteria survive as intracellular parasites in macrophages.

Major human pathogens include Mycobacterium tuberculosis and M leprae, the causative agents of tuberculosis and leprosy, respectively. Mycobacteria other than tuberculosis are associated with several other conditions, usually in immunocompromised individuals. In AIDS patients in the United States, M avium complex is an increasingly important pathogen.

Mycobacterial infections are generally slowly developing chronic conditions. Because mycobacterial cell wall components promote immunologic reactions, a significant portion of the pathology is attributable to the host immune response rather than to direct bacterial toxicity. For all mycobacterial infections, social and environmental factors as well as genetic predisposition play a role.

Chemotherapy for tuberculosis, leprosy, and other atypical mycobacteria is complicated by numerous factors, including (1) limited information about the mechanisms of antimycobacterial drug actions; (2) the rapid development of resistance; (3) the intracellular location of mycobacteria; (4) the chronic nature of mycobacterial disease, which requires protracted drug treatment and is associated with drug toxicities; and (5) patient compliance. Chemotherapy of mycobacterial infections almost always involves prolonged use of drug combinations to delay the emergence of resistance and to enhance antimycobacterial efficacy.

Drugs Used in Tuberculosis

The major drugs used in tuberculosis are isoniazid (INH), rifampin, ethambutol, pyrazinamide, and streptomycin (Table 27–3). Actions of these agents on M tuberculosis are bactericidal or bacteriostatic, depending on drug concentration and strain susceptibility. Treatment of pulmonary tuberculosis usually begins with a three- or four-drug combination regimen depending on the known or anticipated rate of resistance to INH. Directly observed therapy (DOT) regimens, in which a health-care provider witnesses ingestion of the antituberculosis agents, are recommended in noncompliant patients and in drug-resistant tuberculosis.

Isoniazid

Isoniazid is structurally similar to pyridoxine (vitamin B6). The drug is well absorbed orally and penetrates cells to act on intracellular mycobacteria. It is metabolized by the liver and the rate of metabolism varies among ethnic groups. Fast metabolizers may require higher dosage than slow metabolizers for equivalent therapeutic effects.

Mechanism of Action

Antitubercular action involves inhibition of an acyl carrier protein reductase involved in synthesis of mycolic acid required for the outer envelope of the peptidoglycan layer. Because resistance can emerge rapidly if the drug is used alone, INH is always used together with other antituberculosis drugs in active infections.

Clinical Use

INH is the single most important drug used in tuberculosis and is a component of most drug combination regimens for this disease (Table 27–3). INH is given as the sole drug in the treatment of latent infection (formerly known as prophylaxis) including purified protein derivative (PPD) skin test converters, and for individuals who have close contact with patients with active disease.

Adverse Effects

Neurotoxic effects are common and include peripheral neuritis, restlessness, muscle twitching, and insomnia. Pyridoxine can be given to reduce this toxicity without impairing the antibacterial action. INH is hepatotoxic and may cause abnormal liver function tests, jaundice, and hepatitis. Fortunately, hepatotoxicity is rare in children. INH may inhibit the hepatic metabolism of drugs (e.g., phenytoin). Hemolysis and a lupus-like syndrome have been reported.

Rifampin

Rifampin is bactericidal against susceptible M tuberculosis organisms. When given orally, it is well absorbed and distributed to most body tissues, including the CNS. The drug undergoes enterohepatic cycling and is partially metabolized in the liver. Both free drug and metabolites are eliminated mainly in the feces.

Mechanism of Action

Rifampin inhibits DNA-dependent RNA polymerase (encoded by the rpo gene) in M tuberculosis and many other microorganisms. If rifampin is used alone, changes in drug sensitivity of the polymerase emerges rapidly, leading to resistance.

Clinical Use

In tuberculosis, rifampin is always used in combination with other drugs (Table 27–3) because resistance develops rapidly when it is used alone in active infections. Rifampin can be used as the sole drug in treatment of latent tuberculosis in INH-intolerant patients or in individuals who have close contact with patients carrying INH-resistant strains. Other uses of rifampin include the meningococcal and staphylococcal carrier states. In leprosy, rifampin given monthly delays the emergence of resistance to dapsone.

Adverse Effects

Rifampin imparts a harmless orange color to urine, sweat, tears, and contact lenses (soft lenses may be permanently stained). Occasional adverse effects include rashes, thrombocytopenia, nephritis, and liver dysfunction.

Rifampin commonly causes light-chain proteinuria and may impair antibody responses. If given less often than twice weekly, rifampin may cause a flu-like syndrome (chills, fever, myalgias) and anemia.

Rifampin strongly induces liver drug-metabolizing enzymes and enhances the elimination rate of many drugs, including anticonvulsants, contraceptive steroids, cyclosporine, ketoconazole, methadone, terbinafine, and warfarin. Rifabutin is less likely to cause drug interactions than rifampin and is equally effective as an antimycobacterial agent. Rifabutin is usually preferred over rifampin in treating tuberculosis in AIDS patients.

Ethambutol

This antituberculous drug is well absorbed orally and distributed to most tissues, including the CNS when the meninges are inflamed. A large fraction is eliminated unchanged in the urine. Dose reduction is necessary in renal failure.

Mechanism of Action

Ethambutol interferes with mycobacterial cell wall synthesis by inhibiting arabinosyl transferases involved in the synthesis of arabinogalactan, a component of the organisms’ cell walls. Resistance occurs rapidly via mutations in the emb gene if the drug is used alone.

Clinical Use

The main use of ethambutol is in tuberculosis, including tubercular meningitis. To avoid resistance, ethambutol is always given in combination with other antituberculous drugs (Table 27–3).

Adverse Effects

The most common adverse effects are dose-dependent visual disturbances, including decreased visual acuity, red-green color blindness, optic neuritis, and possible retinal damage (from prolonged use at high doses). Most of these effects regress if the drug is stopped promptly. Other neurotoxic effects include headache, confusion, and peripheral neuritis. Ethambutol is relatively contraindicated in children too young to permit assessment of visual acuity and red-green color discrimination.

Pyrazinamide

Pyrazinamide is well absorbed orally and penetrates most body tissues, including inflamed meninges. The drug is partly metabolized to pyrazinoic acid, and both parent molecule and metabolite are excreted in the urine. Plasma half-life of pyrazinamide is increased in hepatic or renal failure.

Mechanism of Action

The mechanism of action of pyrazinamide is unknown; however, its bacteriostatic action appears to require metabolic conversion via pyrazinamidases (encoded by the pncA gene) present in M tuberculosis. Resistant mycobacteria lack these enzymes, and resistance develops rapidly if the drug is used alone. There is minimal cross-resistance with other antimycobacterial drugs.

Clinical Use

Pyrazinamide, when combined with other antituberculous drugs (INH and rifampin), is an important front-line drug used in “short-course” (i.e., 6 months) treatment regimens as a “sterilizing” agent active against residual intracellular organisms that may cause relapse.

Adverse Effects

Approximately 40% of patients develop nongouty polyarthralgia (i.e., pain at multiple joints). Hyperuricemia occurs commonly but is usually asymptomatic. Other adverse effects include myalgia, gastrointestinal irritation, maculopapular rash, hepatic dysfunction, porphyria, and photosensitivity reactions.

Streptomycin

This aminoglycoside is now used more frequently than before because of the growing prevalence of strains of M tuberculosis resistant to other drugs. Streptomycin is used principally in drug combinations for the treatment of life-threatening tuberculous disease, including meningitis, miliary dissemination (mycobacterial invasion of multiple organs via the bloodstream), and severe organ tuberculosis. The pharmacodynamic and pharmacokinetic properties of streptomycin are similar to those of other aminoglycosides.

Alternative Drugs

Several drugs with antimycobacterial activity are used in cases that are resistant to first-line agents; they are considered second-line drugs because they are no more effective, and their toxicities are often more serious than those of the major drugs. Second-line agents include amikacin, ciprofloxacin, ofloxacin, ethionamide, para-aminosalicylic acid (PAS), capreomycin, and cycloserine. As with first-line agents, these drugs are always used in combinations.

Drugs Used in Leprosy

Mycobacterium leprae is the causative agent of leprosy (Hansen’s disease). M leprae grows intracellularly, typically within skin and endothelial cells and Schwann cells of peripheral nerves. Onset of leprosy is gradual and the spectrum of disease is broad, depending on the host’s immune response. Leprosy requires close and prolonged contact for transmission. Transmission is directly related to overcrowding and poor hygiene, and occurs by direct contact and aerosol inhalation. Although rare in the United States, the worldwide prevalence of cases is estimated at over 1 million, with highest concentration being in Southeast Asia, Africa, and Central and South America.

Several drugs closely related to the sulfonamides have been used effectively in long-term treatment of leprosy. Dapsone (diaminodiphenylsulfone) remains the most active drug against M leprae. Like the sulfonamides, its mechanism of action involves inhibition of folic acid synthesis. Resistance can develop, especially if low doses are given. Dapsone can be given orally, penetrates tissues well, undergoes enterohepatic cycling, and is eliminated in the urine, partly as acetylated metabolites. It is usually well tolerated. Common adverse effects include gastrointestinal irritation, fever, skin rashes, and methemoglobinemia. Hemolysis may occur, especially in patients with G6PD deficiency.

Dapsone is rarely used alone in leprosy. Drug regimens usually include combinations of dapsone with rifampin (or rifabutin, see discussion above) with or without clofazimine. Clofazimine causes gastrointestinal irritation and pinkish brown skin discoloration.

Acedapsone is a repository form of dapsone that provides inhibitory plasma concentrations for several months. In addition to its use in leprosy, dapsone is an alternative drug for the treatment of P jiroveci pneumonia in AIDS patients.

Drugs for Atypical Mycobacterial Infections

Infections resulting from atypical mycobacteria (e.g., M marinum, M avium-intracellulare, M ulcerans), although sometimes asymptomatic, may be treated with the described antimycobacterial drugs (e.g., ethambutol, rifampin) or other antibiotics (e.g., erythromycin, amikacin).

M avium complex (MAC) is a cause of disseminated infections in AIDS patients. Currently, clarithromycin or azithromycin is recommended for primary prophylaxis in patients with CD4 counts less than 50/μL. Treatment of MAC infections requires a combination of drugs; one favored regimen consists of azithromycin or clarithromycin with ethambutol and rifabutin.

A large number of antibacterial agents are currently in clinical use. Many factors are considered in the choice of a particular drug. These include the species of bacterium (if known), the bacterium’s drug susceptibility (if known), the location of the infection (which often points to the most likely organism), the severity of infection, and the adverse effects of the drug under consideration in a patient with impaired elimination mechanisms (e.g., renal or liver dysfunction).

One serious problem of antibacterial therapy is the potential for increasing the prevalence of resistant strains. The number of resistant bacterial strains continues to increase and mechanisms for the development of bacterial resistance are complex. As health-care professionals, physical therapists should educate patients about the role each individual plays in limiting the development of drug-resistant bacteria. Specifically, patients can be reminded that (1) antibacterial drugs should be used cautiously and not overused, and (2) once a drug regimen has been initiated, it should be completed in its entirety.

Physical therapists routinely treat patients receiving antibacterial agents for conditions either directly or indirectly related to their need for rehabilitative intervention. For example, therapists often treat patients with infections directly related to rehabilitation, such as burns, open wounds, and surgery. Other infections not directly related to rehabilitation include pneumonia and urinary tract infections. These infections are common in both hospitalized patients and patients receiving outpatient or home health care.

Because such a large proportion of patients receiving rehabilitation services will be taking antibacterial agents, physical therapists should have a general understanding of the various types of antibacterial agents, their type of action (e.g., bactericidal or bacteriostatic), and their adverse effects.

Finally, physical therapists must understand their role in preventing the spread of infections. Handwashing between patients, adequately cleaning or sterilizing rehabilitation equipment (e.g., walkers, whirlpools) between patients, and maintaining appropriate sterile technique when working with open infections can limit therapists’ transferring infection among patients.

Adverse Drug Reactions

The most common adverse effects associated with many of the antibacterial agents include hypersensitivity and allergic reactions and gastrointestinal disturbances.

• • Hypersensitivity or allergic reactions: skin rashes, itching, wheezing, ultraviolet sensitivity, fever, anaphylaxis
• • Gastrointestinal problems: nausea, vomiting, diarrhea, superinfection with resistant organisms, colitis
• • Many antibiotics (especially chloramphenicol, erythromycin, clarithromycin, fluoroquinolones, and rifampin) have significant drug interactions, increasing or decreasing plasma levels of other drugs.
• • IV infusions of cephalosporins and vancomycin may cause phlebitis.
• • Some antibiotics inhibit production of red blood cells (e.g., chloramphenicol), white blood cells (e.g., clindamycin, linezolid, trimethoprim) or platelets (e.g., linezolid).
• • Doxycycline and minocycline may cause dizziness and vertigo.
• • Vancomycin and aminoglycosides are ototoxic.
• • Fluoroquinolones may cause tendonitis.
• • Antimycobacterial drugs commonly cause neurotoxic effects (e.g., isoniazid, ethambutol), visual changes (e.g., ethambutol, pyrazinamide), and nongouty polyarthralgia (e.g., pyrazinamide).

Effects Interfering with Rehabilitation

• • Hypersensitivity reactions and gastrointestinal problems may hinder rehabilitation intervention.
• • If plasma levels of other drugs increase, patients may experience increased adverse effects. If plasma levels of other drugs decrease, their efficacy may be decreased.
• • Phlebitis causing pain, tenderness, and edema in the affected extremity may limit mobility.
• • Anemia limits exercise tolerance. Leukocytopenia increases patients’ susceptibility to infection. Thrombocytopenia increases patients’ susceptibility to bleeding and bruising.
• • Dizziness and vertigo may limit mobility and balance, increasing the risk of falling.
• • High-frequency hearing loss, more common with amikacin and kanamycin, may limit patients’ ability to follow directions of therapist. Vertigo, ataxia, and loss of balance, more common with gentamicin and tobramycin, may limit mobility and increase risk of falling.
• • Tendonitis may limit range of motion and strengthening of involved joints.
• • Neurotoxic and visual disturbances may hinder participation in rehabilitation programs.

Possible Therapy Solutions

• • Alter therapy times around gastrointestinal problems if symptoms occur routinely with continued therapy.
• • The physical therapist should know all of the drugs the patient is taking, be aware of the agents with high potential to cause significant drug interactions, and recognize adverse effects, or decreases in drug efficacy.
• • Phlebitis after parenteral antibiotic administration should be reported to the primary health-care provider. Weight bearing on the affected extremity should be as tolerated, following any restrictions set by the primary health-care provider.
• • Aerobic exercise goals should be lowered in patients with anemia. Oxygen saturation should be monitored by pulse oximetry during exercise to ensure adequate oxygenation.
• • Physical therapists should take extra infection control precautions when working with patients with leukocytopenia: sanitizing all equipment prior to patient use, treating patient in his/her own room in preference to areas with larger pathogenic exposures (e.g., therapy gym), and avoiding patient contact if the therapist is ill.
• • In patients with thrombocytopenia, sharp wound debridement, deep tissue massage, and resistive exercise that puts significant pressure on bony or small surface areas (e.g., resistive tubing around ankle, resisted seated knee extension) should be avoided.
• • For dizziness, increase the assistance provided or the stability of the assistive device and caution patients to move slowly, especially when transitioning between positions.
• • If the patient reports (or the therapist observes) decreased hearing acuity or vestibular function, these symptoms should be reported to the primary health-care provider immediately.
• • Tendonitis as a result of fluoroquinolones should be reported to the primary health-care provider. Strengthening exercises around involved joints should be avoided to avoid risk of tendon rupture.
• • Neurotoxic and visual disturbances consequent to antimycobacterial drugs should be reported to the primary health-care provider. In the absence of serious toxicity, the patient should be strongly encouraged to continue with the drug regimen because compliance is required for eradication of the infectious agent. If symptoms are limiting activity, rehabilitation goals may need to be postponed until the drug regimen has been completed.

Brief History: The patient is a 53-year-old white female with a 40-year history of insulin-dependent type 1 diabetes mellitus. Two weeks ago, she suffered a myocardial infarction (MI) for which she was hospitalized for several days. In addition to her insulin, she has been taking the anticoagulant warfarin since her MI. Prior to her MI, the patient had been referred to an outpatient wound clinic for evaluation and treatment of neuropathic ulcers on both feet.

Current Medical Status and Drugs: The patient attends the wound clinic for her first treatment, 2.5 weeks after her MI. When the patient takes off her shoes and socks, the physical therapist notes that the ulcer on her right foot has increased in size since the evaluation and that the right lower extremity is edematous. The therapist contacts the primary health-care provider with the patient’s change in status. The wound is cultured and is positive for S aureus. The patient is given oral erythromycin to treat the wound infection and resulting phlebitis.

Rehabilitation Setting: After another week, the patient returns to the wound clinic. The physical therapist notes that the wound circumference on the right foot is back to the baseline measurements taken prior to her MI. However, the wound bed appears to have an increased amount of necrotic tissue. The physician working at the wound clinic writes an order for whirlpool cleansing and wet-to-dry dressings for debridement. After discussion between the physician and the physical therapist of the proposed treatment plan, changes are made to the treatment plan to include enzymatic debridement instead of wet-to-dry dressings and modification of orthotics to inhibit wound progression.

Problem/Clinical Options: The patient was prescribed an anticoagulant after her MI to lessen the likelihood of thrombus formation. Subsequently, she was given erythromycin to treat the bacterial infection in her right lower extremity. Erythromycin inhibits several hepatic cytochrome P450 isoforms, and therefore has significant drug interactions. Specifically, erythromycin increases the plasma level of anticoagulants, leading to an increased risk of bleeding. The proposed treatment plan of wet-to-dry dressings for wound debridement would result in significant tissue tearing, with resultant bleeding that may be increased with the patient’s current medications. In contrast, enzymatic debridement of necrotic tissue would make bleeding almost negligible.

β-Lactam Antibiotics and Other Cell Wall Synthesis Inhibitors

Penicillins

Amoxicillin (Generic, Amoxil, Others)

Oral: 125-, 200-, 250-, 400-mg chewable tablets; 500-, 875-mg tablets; 250-, 500-mg capsules;

powder to reconstitute for 50, 125, 200, 250, 400 mg/mL solution

Amoxicillin/Potassium Clavulanate (Generic, Augmentin)1

Oral: 250-, 500-, 875-mg tablets; 125-, 200-, 250-, 400-mg chewable tablets; 1000-mg

extended-release tablet powder to reconstitute for 125, 200, 250 mg/5 mL suspension

Ampicillin (Generic)

Oral: 250-, 500-mg capsules; powder to reconstitute for 125-, 250-mg suspensions

Parenteral: powder to reconstitute for injection (125, 250, 500 mg, 1, 2 g per vial)

Ampicillin/Sulbactam Sodium (Generic, Unasyn)2

Parenteral: 1, 2 g ampicillin powder to reconstitute for IV or IM injection

Carbenicillin (Geocillin)

Oral: 382-mg tablets

Dicloxacillin (Generic)

Oral: 250-, 500-mg capsules

Mezlocillin (Mezlin)

Parenteral: powder to reconstitute for injection (in 1-, 2-, 3-, 4-g vials)

Nafcillin (Generic)

Oral: 250-mg capsules

Parenteral: 1, 2 g per IV piggyback units

Oxacillin (Generic)

Oral: 250-, 500-mg capsules; powder to reconstitute for 250 mg/5 mL solution

Parenteral: powder to reconstitute for injection (0.5, 1, 2, 10 g per vial)

Penicillin G (Generic, Pentids, Pfizerpen)

Oral: 0.2-, 0.25-, 0.4-, 0.5-, 0.8-million unit tablets; powder to reconstitute 400,000 units/5 mL suspension

Parenteral: powder to reconstitute for injection (1-, 2-, 3-, 5-, 10-, 20-million units)

Penicillin G Benzathine (Permapen, Bicillin)

Parenteral: 0.6-, 1.2-, 2.4-million units per dose

Penicillin G Procaine (Generic)

Parenteral: 0.6-, 1.2-million units/mL for IM injection only

Penicillin V (Generic, V-Cillin, Pen-Vee K, Others)

Oral: 250-, 500-mg tablets; powder to reconstitute for 125 , 250 mg/5 mL solution

Piperacillin (Pipracil)

Parenteral: powder to reconstitute for injection(2, 3, 4 g per vial)

Piperacillin and Tazobactam Sodium (Zosyn)3

Parenteral: 2-, 3-, 4-g powder to reconstitute for IV injection

Ticarcillin (Ticar)

Parenteral: powder to reconstitute for injection (1, 3, 6 g per vial)

Ticarcillin/Clavulanate Potassium (Timentin)4

Parenteral: 3 g powder to reconstitute for injection

Cephalosporins and Other β-Lactam Drugs

Narrow Spectrum (First-Generation) Cephalosporins

Cefadroxil (Generic, Duricef)

Oral: 500-mg capsules; 1-g tablets; 125, 250, 500 mg/5 mL suspension

Cefazolin (Generic, Ancef, Kefzol)

Parenteral: powder to reconstitute for injection (0.25, 0.5, 1 g per vial or IV piggyback unit)

Cephalexin (Generic, Keflex, Others)

Oral: 250-, 500-mg capsules and tablets; 1-g tablets; 125, 250 mg/5 mL suspension

Cephalothin (Generic, Keflin)5

Parenteral: powder to reconstitute for injection and solution for injection (1 g per vial or infusion pack)

Cephapirin (Cefadyl)

Parenteral: powder to reconstitute for injection (1 g per vial or IV piggyback unit)

Cephradine (Generic, Velosef)

Oral: 250-, 500-mg capsules; 125, 250 mg/5 mL suspension

Parenteral: powder to reconstitute for injection (0.25, 0.5, 1, 2 g per vial)

Intermediate Spectrum (Second-Generation) Cephalosporins

Cefaclor (Generic, Ceclor)

Oral: 250-, 500-mg capsules; 375-, 500-mg extended-release tablets; powder to reconstitute for 125, 187, 250, 375 mg/5 mL suspension

Cefamandole (Mandol)

Parenteral: 1, 2 g (in vials) for IM, IV injection

Cefmetazole (Zefazone)

Parenteral: 1-, 2-g powder for IV injection

Cefonicid (Monocid)

Parenteral: powder to reconstitute for injection (1, 10 g per vial)

Cefotetan (Cefotan)

Parenteral: powder to reconstitute for injection (1, 2, 10 g per vial)

Cefoxitin (Mefoxin)

Parenteral: powder to reconstitute for injection (1, 2, 10 g per vial)

Cefprozil (Cefzil)

Oral: 250-, 500-mg tablets; powder to reconstitute 125, 250 mg/5mL suspension

Cefuroxime (Generic, Ceftin, Kefurox, Zinacef)

Oral: 125-, 250-, 500-mg tablets; 125, 250 mg/5 mL suspension

Parenteral: powder to reconstitute for injection (0.75, 1.5, 7.5 g per vial or infusion pack)

Loracarbef (Lorabid)

Oral: 200-, 400-mg capsules; powder for 100, 200 mg/5 mL suspension

Broad-Spectrum (Third- and Fourth-Generation) Cephalosporins

Cefdinir (Omnicef)

Oral: 300-mg capsules; 125 mg/5 mL suspension

Cefditoren (Spectracef)

Oral: 200-mg tablets

Cefepime (Maxipime)

Parenteral: powder for injection 0.5, 1, 2 g

Cefixime (Suprax)

Oral: 200-, 400-mg tablets; powder for oral suspension, 100 mg/5 mL

Cefoperazone (Cefobid)

Parenteral: powder to reconstitute for injection (1, 2 g per vial, 10 g bulk)

Cefotaxime (Claforan)

Parenteral: powder to reconstitute for injection (0.5, 1, 2 g per vial)

Cefpodoxime Proxetil (Vantin)

Oral: 100-, 200-mg tablets; 50-, 100-mg granules for suspension in 5 mL

Ceftazidime (Generic, Fortaz, Tazidime)

Parenteral: powder to reconstitute for injection (0.5, 1, 2 g per vial)

Ceftibuten (Cedax)

Oral: 400-mg capsules; 90, 180 mg/5 mL powder for oral suspension

Ceftizoxime (Cefizox)

Parenteral: powder to reconstitute for injection and solution for injection (0.5, 1, 2 g per vial)

Ceftriaxone (Rocephin)

Parenteral: powder to reconstitute for injection (0.25, 0.5, 1, 2, 10 g per vial)

Carbapenems and Monobactam

Aztreonam (Azactam)

Parenteral: powder to reconstitute for injection (0.5, 1, 2 g)

Ertapenem (Invanz)

Parenteral: 1 g powder to reconstitute for intravenous (0.9% NaCl diluent) or intramuscular (1% lidocaine diluent) injection

Imipenem/Cilastatin (Primaxin)

Parenteral: powder to reconstitute for injection (250, 500, 750 mg imipenem per vial)

Meropenem (Merrem IV)

Parenteral: powder for injection (0.5, 1 g per vial)

Other Drugs Discussed in This Chapter

Cycloserine (Seromycin Pulvules)

Oral: 250-mg capsules

Fosfomycin (Monurol)

Oral: 3-g packet

Vancomycin (Generic, Vancocin, Vancoled)

Oral: 125-, 250-mg Pulvules; powder to reconstitute for 250 mg/5 mL, 500 mg/6 mL solution

Parenteral: 0.5-, 1-, 5-, 10-g powder to reconstitute for IV injection

Inhibitors of Bacterial Protein Synthesis

Chloramphenicol

Chloramphenicol (Generic, Chloromycetin)

Oral: 250-mg capsules; 150 mg/5 mL suspension

Parenteral: 100-mg powder to reconstitute for injection

Tetracyclines

Demeclocycline (Declomycin)

Oral: 150-, 300-mg tablets; 150-mg capsules

Doxycycline (Generic, Vibramycin, Others)

Oral: 50-, 100-mg tablets and capsules; powder to reconstitute for 25 mg/5 mL suspension; 50 mg/5 mL syrup

Parenteral: 100-, 200-mg powder to reconstitute for injection

Methacycline (Rondomycin)

Oral: 150-, 300-mg capsules

Minocycline (Minocin)

Oral: 50-, 100-mg tablets and capsules; 50 mg/5 mL suspension

Tetracycline (Generic, Achromycin V, Others)

Oral: 100-, 250-, 500-mg capsules; 250-, 500-mg tablets; 125 mg/5 mL suspension

Parenteral: 100-, 250-mg powder to reconstitute for IM injection; 250-, 500-mg powder to reconstitute for IV injection

Macrolides

Azithromycin (Zithromax)

Oral: 250-mg capsules; powder for 100, 200 mg/5 mL oral suspension

Clarithromycin (Biaxin)

Oral: 250-, 500-mg tablets, 500-mg extended- release tablets; granules for 125, 250 mg/5 mL oral suspension

Erythromycin (Generic, Ilotycin, Ilosone, E-Mycin, Erythrocin, Others)

Oral (base): 250-, 333-, 500-mg enteric-coated tablets

Oral (base) delayed-release: 333-mg tablets, 250-mg capsules

Oral (estolate): 500-mg tablets; 250-mg capsules; 125, 250 mg/5 mL suspension

Oral (ethylsuccinate): 200-, 400-mg film-coated tablets; 200, 400 mg/5 mL suspension

Oral (stearate): 250-, 500-mg film-coated tablets

Parenteral: lactobionate, 0.5-, 1-g powder to reconstitute for IV injection

Ketolides

Telithromycin (Proteck)

Oral: 800-mg tablets

Lincomycins

Clindamycin (Generic, Cleocin)

Oral: 75-, 150-, 300-mg capsules; 75 mg/5 mL granules to reconstitute for solution

Parenteral: 150 mg/mL in 2-, 4-, 6-, 60-mL vials for injection

Streptogramins

Quinupristin and Dalfopristin (Synercid)

Parenteral: 30:70 formulation in 500 mg vial for reconstitution for IV injection

Oxazolidinones

Linezolid (Zyvox)

Oral: 400-, 600-mg tablets; 100-mg powder for solution

Parenteral: 2 mg/mL for IV infusion

Aminoglycosides and Spectinomycin

Amikacin (Generic, Amikin)

Parenteral: 50, 250 mg (in vials) for IM, IV injection

Gentamicin (Generic, Garamycin)

Parenteral: 10, 40 mg/mL vials for IM, IV injection

Kanamycin (Kantrex)

Oral: 500-mg capsules

Parenteral: 500, 1000 mg for IM, IV injection; 75 mg for pediatric injection

Neomycin (Generic, Mycifradin)

Oral: 500-mg tablets; 125 mg/5 mL solution

Netilmicin (Netromycin)

Parenteral: 100 mg/mL for IM, IV injection

Paromomycin (Humatin)

Oral: 250-mg capsules

Spectinomycin (Trobicin)

Parenteral: 2 g powder to reconstitute for IM injection

Streptomycin (Generic)

Parenteral: 400 mg/mL for IM injection

Tobramycin (Generic, Nebcin)

Parenteral: 10, 40 mg/mL for IM, IV injection; powder to reconstitute for injection

Inhibitors of Bacterial DNA Synthesis

Sulfonamides, Trimethoprim, and Fluoroquinolones

General-Purpose Sulfonamides

Sulfadiazine (Generic)

Oral: 500-mg tablets

Sulfamethizole (Thiosulfil Forte)

Oral: 500-mg tablets

Sulfamethoxazole (Generic, Gantanol, Others)

Oral: 500-mg tablets; 500 mg/5 mL suspension

Sulfanilamide (AVC)

Vaginal cream: 15%

Sulfisoxazole (Generic, Gantrisin)

Oral: 500-mg tablets; 500 mg/5 mL syrup

Ophthalmic: 4% solution

Sulfonamides for Special Applications

Mafenide (Sulfamylon)

Topical: 85 mg/g cream; 5% solution

Silver Sulfadiazine (Generic, Silvadene)

Topical: 10-mg/g cream

Sulfacetamide Sodium (Generic)

Ophthalmic: 1, 10, 15, 30% solutions; 10% ointment

Trimethoprim

Trimethoprim (Generic, Proloprim, Trimpex)

Oral: 100-, 200-mg tablets

Trimethoprim-Sulfamethoxazole Co-Trimoxazole, TMP-SMZ (Generic, Bactrim, Septra, Others)

Oral: 80 mg trimethoprim + 400 mg sulfamethoxazole per single-strength tablet; 160 mg trimethoprim

+ 800 mg sulfamethoxazole per double-strength tablet; 40 mg trimethoprim + 200 mg sulfamethoxazole per 5 mL suspension

Parenteral: 80 mg trimethoprim + 400 mg sulfamethoxazole per 5 mL for infusion (in 5 mL ampules and 5-, 10-, 20-, 30-, 50-mL vials)

Quinolones and Fluoroquinolones

Cinoxacin (Generic, Cinobac)

Oral: 250-, 500-mg capsules

Ciprofloxacin (Cipro, Cipro I.V.)

Oral: 250-, 500-, 750-mg tablets; 50, 100 mg/mL suspension

Parenteral: 2, 10 mg/mL for IV infusion

Ophthalmic (Ciloxan): 3 mg/mL solution; 3.3 mg/g ointment

Enoxacin (Penetrex)

Oral: 200-, 400-mg tablets

Levofloxacin (Levaquin)

Oral: 250, 500, 750 mg for injection

Parenteral: 250, 500 mg for IV injection

Ophthalmic (Quixin): 5 mg/mL solution

Lomefloxacin (Maxaquin)

Oral: 400-mg tablets

Moxifloxacin (Avelox, Avelox I.V.)

Oral: 400-mg tablets

Parenteral: 400 mg in IV bag

Nalidixic Acid (NegGram)

Oral: 250-, 500-, 1000-mg caplets; 250 mg/5 mL suspension

Norfloxacin (Noroxin)

Oral: 400-mg tablets

Ofloxacin (Floxin)

Oral: 200-, 300-, 400-mg tablets

Parenteral: 200 mg in 50 mL 5% D/W for IV administration; 20, 40 mg/mL for IV injection

Ophthalmic (Ocuflox): 3 mg/mL solution

Antimycobacterial Drugs

Drugs Used in Tuberculosis

Aminosalicylate Sodium (Paser)

Oral: 4 g delayed-release granules

Capreomycin (Capastat Sulfate)

Parenteral: 1-g powder to reconstitute for injection

Cycloserine (Seromycin Pulvules)

Oral: 250-mg capsules

Ethambutol (Myambutol)

Oral: 100-, 400-mg tablets

Ethionamide (Trecator-SC)

Oral: 250-mg tablets

Isoniazid (Generic)

Oral: 50-, 100-, 300-mg tablets; syrup, 50 mg/5 mL

Parenteral: 100 mg/mL for injection

Pyrazinamide (Generic)

Oral: 500-mg tablets

Rifabutin (Mycobutin)

Oral: 150-mg capsules

Rifampin (Generic, Rifadin, Rimactane)

Oral: 150-, 300-mg capsules

Parenteral: 600-mg powder for IV injection

Rifapentine (Priftin)

Oral: 150-mg tablets

Streptomycin (Generic)

Parenteral: 1 g lyophilized for IM injection

Drugs Used in Leprosy

Clofazimine (Lamprene)

Oral: 50-mg capsules

Dapsone (Generic)

Oral: 25-, 100-mg tablets

1Clavulanate content varies with the formulation; see package insert.

2Sulbactam content is half the ampicillin content.

3Tazobactam content is 12.5% of the piperacillin content.

4Clavulanate content 0.1 g.

5Not available in the United States.