BACK TO BASICS: Antibiotics: Mechanisms of Action Kathleen A. Woodin and Susan H. Morrison Pediatr. Rev. 1994;15;440-447 DOI: 10.1542/pir.15-11-440 The online version of this article, along with updated information and services, is located on the World Wide Web at: http://pedsinreview.aappublications.org Pediatrics in Review is the official journal of the American Academy of Pediatrics. A monthly publication, it has been published continuously since 1979. Pediatrics in Review is owned, published, and trademarked by the American Academy of Pediatrics, 141 Northwest Point Boulevard, Elk Grove Village, Illinois, 60007. Copyright © 1994 by the American Academy of Pediatrics. All rights reserved. Print ISSN: 0191-9601. Online ISSN: 1526-3347. Downloaded from http://pedsinreview.aappublications.org at Univ Of Calgary LIB-MLB 425A on September 25, 2008 Antibiotics: Kathleen A. Woodin, Mechanisms MD* and Susan of Action H. Morrison, MDt Medical practice rests on the foundation of science. Clinicians are constantly making practical decisions and dealing with immediate situations that demand solutions. Time should be taken to focus on those scientific principles that underlie our diagnostic and therapeutic maneuvers. This section of Pediatrics in Review presents selected topics that are relevant to practice from the areas of physiology, pharmacology, biochemistry, and other disciplines; clarification of these will augment the pediatrician ‘s understanding of clinical procedures. Introduction Unlike physicians practicing in the 1940s, who had only sulfonamides and penicillin to treat infections, practitioners now choose from a broad (and sometimes overwhelming) number of antibiotics. However, trends in emerging antimicrobial resistance may force us to take a giant step backward to that frightening situation of the past of having bacteria that are essentially “untreatable” by any of our available antibiotics. This article is an overview of some of the microbiology, pharmacology, and physiology critical to the rational use of antibiotics in today’s practice. It summarizes the basic mechanisms of action of some commonly used antibiotics and briefly discusses the emergence of resistance to several common pathogens. Structures Important of Bacteria to Antibiotic Action The outermost component of most bacteria is the cell wall, a multilayered structure located external to the cytoplasmic membrane. The cell wall is composed of an inner layer of peptidoglycan, a complex interwoven lattice of linear sugars (glycan) that are 440 cross-linked tidoglycan by which acteristic by peptide chains. Pepprovides the rigid support the cell maintains its charshape. Gram-positive and Gram-negative bacteria differ in their cell wall structures (Figure). In Gram-positive organisms, the peptidoglycan layer is a thick (15 to 80 nm) multilayer and may have a thin layer of teichoic acid outside the peptidoglycan. In contrast, Gram-negative organisms have a thin (2 nm) single layer of peptidoglycan covered by a complex outer membrane layer composed of lipopolysaccharides, lipoproteins, and phospholipids. The outer membrane of Gram-negative bacteria contains porn proteins that act as channels to transport small molecules such as sugars, metals, vitamins, and antibiotics into the bacterial cell. The cytoplasm of bacteria contains an inner nucleoid region composed of single-stranded circular DNA and matrix that contains ribosomes, nutrient granules, metabolites, and plasmids. Plasmids are double-stranded circular DNA molecules that can replicate independently of the bacterial chromosomes. Most plasmids are extrachromosomal, but some are integrated into the bacterial chromosome. Pediatrics Plasmids occur in both Gram-negative and Gram-positive organisms and are an important source of genetic information that can convey resistance to various antibiotics. Selective Toxicity An ideal antimicrobial agent would exhibit selective toxicity; that is, the drug would be harmful to the infecting microorganism without harming the host. Because peptidoglycan is present in bacteria but not in human cells, it is an excellent target for antibiotics. Similarly, antibiotics that affect protein synthesis take advantage of the differences in size and chemical composition of ribosomes from bacteria and eukaryotic organisms (ie, those having a true nucleus surrounded by a nuclear membrane and multiple chromosomes, as in human cells). Other metabolic steps that occur in bacteria but not humans (eg, synthesis of folic acid for nucleotides) also can be inhibited selectively by antibiotics. BactericIdal Bacterlostatlc Antibiotics Versus Properties A favorable therapeutic lowing the administration in Review VoL 15 No. of outcome folof a spe11 November Downloaded from http://pedsinreview.aappublications.org at Univ Of Calgary LIB-MLB 425A on September 25, 2008 1994 I cific antibiotic depends on multiple factors, including those related to the bacteria (eg, resistance mechanisms), the antibiotic (eg, mechanism of action, ability to penetrate to the infected site, and spectrum of activity), and the host defenses (eg, phagocytosis, opsonization, complement production). When host defenses are maximally effective, the contribution of the antibiotic may be less important. For example, a bacteriostatic agent (eg, chloramphenicol, erythromycin, clindamycin, tetracycline) that slows or inhibits protein synthesis may be adequate when combined with the host’s ability to opsonize and phagocytize bacteria. In contrast, a patient whose host defenses are impaired may require a bactericidal agent (eg, penicillin, cephalosporin, aminoglycoside) that actually will kill or lyse the bacteria. Bactericidal agents (Table 1) generally are used to treat bacterial endocarditis, meningitis, and osteomyelitis as well as any bacterial infections in neutropenic patients. Antibiotic Susceptibility If the concentration of an antibiotic required to inhibit or kill the organism can be achieved safely in the affected tissue or fluid, a microorganism is considered sensitive to a particular antibiotic. However, if the concentration required is greater than what can be achieved safely, the microorganism is considered to be resistant to that antibiotic. Most in vitro sensitivity tests are standardized on the basis of drug concentrations that can be achieved safely in plasma and may not take into account increased drug concentrations that may occur at specific sites (eg, bladder) or any local conditions that may affect the activity of the antimicrobial agent. Mechanisms Antibiotics of Action of For many antibiotics, the mechanism of action is not understood fully. However, it is known that antibiotics can act in the following ways: 1) inhibit cell wall synthesis, 2) alter the permeability of the cell membrane, 3) inhibit protein synthesis, and 4) inhibit nucleic acid synthesis (Table 1). Pediatrics in Review VoL 15 No. Ii November WEAKEN CELL WALL BY INHIBITING CROSS-LINKING PEPTIDOGLYCAN Penicillins and OF Cephalosporins Penicillins and cephalosporins (betalactam antibiotics) are among the most widely prescribed antibiotics because of their safety profiles. The basic structure of penicillin consists of a five-member thiazolidine ring connected to a beta-lactam ring to which a side chain is attached. In contrast, the cephalosporins have a six-membered hydrothiazine ring connected to the beta-lactam ring. An intact betalactam ring structure is an essential requirement for the biologic and antibacterial activity of both penicillins and cephalosporins. New derivatives of the basic penicillin nuclei continue to be produced; each has unique advantages. Modification of the various side chains on these structures affects the specific antibacterial spectrum as well as the pharmacokinetic profile of these drugs. Beta-lactam antibiotics kill susceptible bacteria by interfering with cell wall synthesis. They are bactericidal, but only kill organisms undergoing active cell wall synthesis. The biosynthesis of peptidoglycan in the cell wall occurs in three stages and involves about 30 different enzymes. Beta-lactam antibiotics inhibit transpeptidases, the enzymes that catalyze the final cross-linking step of peptidoglycan synthesis. There also are receptors called penicillin binding proteins (PBPs) in the bacterial cell membrane and cell wall for the beta-lactam antibiotics. Each bacterium has several types of 1994 PBPs that vary in their affinity for different penicillins and cephalosporins. Some PBPs are transpeptidases responsible for peptidoglycan crosslinking and necessary for bacterial shape; the function of others is unknown. Inhibition of PBPs causes abnormal cell shape, division, and eventual lysis. Altering the PBPs is one mechanism by which bacteria can develop resistance to penicillin. This resistance may be intrinsic because of structural differences in PBPs or a previously sensitive strain may acquire resistance following a mutation of PBPs. Resistance of Streptococcus pneumoniae to penicillin and cephalosporins, which has been reported around the world as well as in the United States, is due to alterations in PBPs (Table 2). Activation of cell wall autolytic enzymes (ie, autolysins) is another factor that is important in the degradation of the cell wall. The relationship between the inhibition of PBP activity and the activation of autolysis is unclear and very complex. Tolerance to penicillin occurs when the organism is inhibited but not killed by an antibiotic that usually is bactericidal. For example, the growth of certain tolerant strains of Staphylococcus aureus can be arrested by beta-lactam antibiotics, but autolytic enzymes are not activated. Production of beta-lactamases, enzymes that can cleave the beta-lactam ring, is an important mechanism for the inactivation of beta-lactam antibiotics and development of resistance by many bacteria (eg, S aureus, Neisseria gonorrhoeae, Pseudomonas sp, Bacteroides fragilis, and some enteric Downloaded from http://pedsinreview.aappublications.org at Univ Of Calgary LIB-MLB 425A on September 25, 2008 441 IT. I MECHANISM DRUGS Weaken bacterial cell wall and cause cell death . Inhibit cross-linking of peptidoglycan . Activate autolytic enzymes (ie, autolysins) . Inhibit other steps in peptidoglycan synthesis Penicillins, Increase cell membrane permeability . Cause leakage of cell contents Inhibit protein synthesis . Bind to 505 ribosome . Bind to 305 subunit ribosome subunit Inhibit nucleic acid synthesis . Inhibit nucleotide synthesis . Inhibit DNA-dependent RNA polymerase . Inhibit DNA supercoiling and DNA synthesis *Note: Bacteriostatic agents ORGANISM Streptococcus Enterococcus Enterococcus Neisseria 442 pneumoniae fecalis faecium gonorrhoeae may be bactericidal against some cephalosporins Bactericidal Vancomycin Bactericidal Polymyxin NA Chloramphenicol Erythromycin Clarithromycin Clindamycin Aminoglycosides Tetracyclines Bacteriostatic Bacteriostatic Bacteriostatic Bacteriostatic Bactericidal Bacteriostatic Sulfonamides, Rifampin Quinolones organisms ACT1ON at high trimethoprim Bacteriostatic Bactericidal Bactericidal concentrations. DRUGS FOR WHICH RESISTANCE HAS BEEN REPORTED RECOMMENDATiONS #{149} Penicillin Intermediate-level resistance is increasing High-level resistance has been reported in various areas worldwide and is increasing in the United States Clusters of cases may occur (eg, childcare contacts) #{149} Cephalosporins Treatment failures have prompted susceptibility testing #{149} Conduct oxacillin disk susceptibility all isolates #{149} If resistant, check MICs to penicillin, cefotaxime, ceftriaxone, vancomyin, or others #{149} If sensitive, susceptible to all betalactams #{149} If meningitis, treat with vancomycin PLUS third-generation cephalosporin OR chloramphenicol OR imipenem pending susceptibility testing on #{149} Ampicillin #{149} Vancomyin Resistant identified #{149} If invasive disease, check MICs and with ampicillin PLUS vancomycin PLUS aminoglycoside (gentamicin) pending susceptibility testing treat strains have been #{149} Penicillinase-producing strains common #{149} Tetracycline High-level plasmid-mediated resistance reported #{149} Fluoroquinolones Decreased susceptibility reported #{149} Penicillin or doxycycline are not recommended empiric therapies #{149} Monitor fluoroquinolone susceptibility pattern and clinical response #{149} Third-generation cephalosporins (eg, ceftriaxone) still seem effective Pediatrics in Review VoL 15 No. 11 November Downloaded from http://pedsinreview.aappublications.org at Univ Of Calgary LIB-MLB 425A on September 25, 2008 1994 I Gram-negative bacilli). The information for producing beta-lactamases can be coded in chromosomes or on a plasmid. The beta-lactamases can be constitutive (produced all the time) or inducible (only produced at certain times). In the case of inducible resistance, the organism initially will be susceptible to a certain antibiotic, but after a short period of therapy, the organism will become resistant because of the beta-lactamases that have been induced. Frequently, this is signaled by only limited improvement or clinical deterioration of the patient after an initial improvement. Inducible beta-lactamase production is a particular problem with some Gramnegative bacteria (eg, Pseudomonas, Enterobacter, Citrobacter, Acinetobacter, Serratia sp) treated with broad-spectrum cephalosporins. Beta-lactamase production by bacteria can be inhibited by the addition of certain chemical structures that are similar in structure to penicillin (eg, clavulanic acid, sulbactam). The inhibitors bind strongly to the beta-lactamases and prevent the subsequent inactivation of the penicillin nucleus. Penicillins have good activity against Gram-positive bacteria and oral anaerobes and variable activity against Gram-negative bacilli. They are the treatment of choice for syphilis, leptospirosis, or Listeria infections. Penicillins generally are classified according to their spectrum of activity as determined by changes in their side chains relative to penicillin: penicillinase-resistant penicillin (eg, methicillin, nafcillin, oxacillin, cloxacillin, and dicloxacillin); aminopenicillins (ampicillin, amoxicillin); antipseudomonal penicillins (eg, carbenicillin, ticarcillin, and azlocillin); and extended-spectrum penicillins (eg, mezlocillin, piperacillin). The cephalosporins are divided into “generations” based on their antimicrobial activity. First-generation cephalosporins (eg, cephalexin, cefadroxil, and cefazolin) have good activity against Gram-positive bacteria, including penicillinase-producing S aureus, group A beta-hemolytic streptococci, group B streptococci, and S pneumoniae, and modest activity against some Gram-negative organisms. The second-generation Pediatrics in Review VoL iS No. ii November cephalosporins (eg, cefaclor, cefuroxime, cefuroxime axetil, cefprozil, cefamandole, cefoxitin, and cefotetan) retain activity against Gram-positive organisms but have more activity against Gram-negative organisms, including most strains of Haemophilus influenzae and some strains of enteric bacteria. The third-generation cephalosporins (eg, cefixime, cefoperazone, cefotaxime, cefpodoxime proxetil, ceftazidime, ceftizoxime, and ceftriaxone) are more active against Gramnegative organisms (including Enterobacteriaceae and beta-lactamaseproducing strains of H infiuenzae, Moraxella catarrhalLi, and N gonorrhoeae), but they are less active than first-generation cephalosporins against Gram-positive organisms. Ceftazidime is active against Pseudomonas sp and has superior central nervous system penetration compared with aminoglycosides. Ceftriaxone has a prolonged half-life that allows for once-a-day dosing. None of the cephalosporins is effective against anaerobes, enterococci, or L monocytogenes. Because of the structural similarity between penicillin and first- and second-generation cephalosporins, patients may manifest cross-reactivity when a member of the other class is administered. Immunologic studies demonstrate a 20% cross-reactivity; more recent clinical studies indicate a frequency as low as 1%. Cross-reactivity between penicillins and cephalosporins generally occurs in about 8% of patients who have a history of an allergic reaction to penicillin. Although side chains do not seem to be a factor in allergic reactions to penicillins, they may be important in cephalosporin allergy. The patient who is allergic to cephalosporins may have an allergy to the beta-lactam ring, the bulky side chain, or both. The risk of allergic reaction with the newer third-generation cephalosporins is not known. WEAKEN CELL WALL BY INHIBITING PEPFIDOGLYCAN SYNTHESIS Vancomycin Vancomycin is a complex and unusual tricyclic glycopeptide that inhibits cell synthesis in sensitive bacteria by binding tightly to precursor subunits of the cell wall and preventing 1994 their incorporation into the growing peptidoglycan. The drug is rapidly bactericidal for dividing microorganisms. Because vancomycin may be only bacteriostatic for some enterococci, an aminoglycoside is added to vancomycin therapy in serious infections known to be caused by this organism (eg, infective endocarditis). Early preparations of vancomycin contained impurities that probably contributed significantly to the toxicity associated with its early use; this no longer is a problem. In recent years, there has been renewed interest in the use of vancomycin for several reasons. First, it is structurally unrelated to other antibiotics, so it is useful in the patient who is allergic to penicillin and cephalosporins. Second, it is active primarily against Gram-positive bacteria and forms the mainstay of therapy for the treatment of infections caused by methicillinresistant S aureus (MRSA), coagulase-negative staphylococci that are resistant to other penicillins, and S pneumoniae strains that are resistant to penicillin and cephalosporins (Table 2). Vancomycin is an important antibiotic for use in immunocompromised patients who have evidence of catheter-related infections. Because oral vancomycin is absorbed poorly, high concentrations occur in the stool. Thus, it can be used as a more expensive alternative to metronidazole for the treatment of Clostridium difficile infections; metronidazole is not approved by the Food and Drug Administration for use in children. Reports of vancomycin-resistant strains of enterococci and S aureus have caused extreme concern in the medical community. Prudent use of this drug is essential to minimize the development of further resistance. Measurement of serum levels of vancomycin is recommended to avoid potential ototoxicity and nephrotoxicity. The incidence of both toxicities is increased when vancomycin is administered simultaneously with an aminoglycoside. INCREASE Polymyxin CELL PERMEABILITY B Polymyxin B is a basic orated by various strains peptide elabof Bacillus Downloaded from http://pedsinreview.aappublications.org at Univ Of Calgary LIB-MLB 425A on September 25, 2008 443 sp. It is a surface-active agent contaming both lipophilic and lipophobic groups within the molecule that interact strongly with phospholipids and disrupt the integrity of cell membranes. The permeability of the bacterial membrane changes immediately after contact with the drug. Polymyxin B is prescribed primarily for ophthalmic, otic, or topical use in combination with a variety of other compounds (eg, bacitracin, neomycin, hydrocortisone). INHIBIT PROTEIN SYNTHESIS Ribosomes are the site of protein synthesis in both bacterial and eukaryotic cells, but bacterial and eukaryotic ribosomes differ in both size and chemical composition. Bacterial ribosomes are 70S in size (with 50S and 30S subunits) compared with 80S (with 60S and 40S subunits) in eukaryotic cells. Thus, antibiotics that phenicol usually is caused by a plasmid acquired by conjugation. Other plasmids may transfer resistance to multiple antibiotics (eg, chloramphenicol, tetracycline, and beta-lactams). Once acetylated, choramphenicol cannot attach to the bacterial ribosome. Use of chloramphenicol must be limited to infections for which the benefits of the drug outweigh the risk of the potential toxicities (eg, reversible, dose-related bone marrow suppression, potentially fatal idiosyncratic aplastic anemia, and “gray baby” syndrome). When antimicrobials that have equivalent activity but are potentially less toxic are available, they should be used. In addition, it is necessary to monitor serum levels when treating a patient with chloramphenicol. Chloramphenicol is a broad-spectrum antibiotic that is active against Gram-positive and Gram-negative bacteria differ in their cell wall structures; the peptidoglycan layer is thick in Gram-positive organisms and thin in Gram-negative organisms. Resistance to erythromycin can occur by at least three plasmid-mediated mechanisms: failure of the drug to penetrate the cell, modification of the target sites on the 505 ribosome so that the drug fails to bind, and production of an esterase by the bacteria to hydrolyze the drug. Gram-positive bacteria accumulate about 100 times more erythromycin than do Gram-negative organisms. Although erythromycin generally is classified as a bacteriostatic agent, it can have bactericidal activity against a small number of rapidly dividing bacteria, especially in an alkaline environment. In patients who have penicillin allergy, erythromycin is an effective alternative agent against Gram-positive bacteria such as group A streptococci, S pneumoniae, and S aureus. However, the emergence of resistant strains must be monitored. Erythromycin also has good antimicrobial activity against Bordetella pertussis, Borrelia sp, Campylobacter sp, Chlamydia trachomatis, C pneumoniae (TWAR strain), Mycoplasma pneumoniae, and Legionella pneumophila. Clanthromycin affect protein synthesis can have a selective effect on sensitive bacteria without affecting human cells. Chloramphenicol Chloramphenicol, a nitrobenzene moiety, penetrates bacterial cells by facilitated diffusion and binds reversibly to the bacterial 505 ribosomal subunit. This drug (like tetracycline’s effect on the 305 ribosome subunit) blocks the binding of the aminoacyl transfer RNA (tRNA) to the acceptor site on the ribosome. Chloramphenicol has less of an effect on protein synthesis in eukaryotic cells than in bacterial cells. Chloramphenicol is primarily a bacteriostatic agent, but it may be bactericidal to certain species (eg, H influenzae, S pneumoniae, N meningiditis). Mechanisms of resistance to chloramphenicol include production of an acetyltransferase by the bacteria that inactivates chloramphenicol and inability of chloramphenicol to enter selected bacteria. Resistance of Gram-negative bacteria to chloram444 many Gram-positive and -negative bacteria as well as against rickettsiae. In particular, it is effective against most anaerobic bacteria, including B fragilis, and the majority of Salmonella sp and H influenzae strains. It is a recommended alternative therapy for infections caused by Brucella and Pasteurella sp as well as for Rocky Mountain spotted fever. Chloramphenicol has been effective in some S pneumoniae infections resistant to penicillins and cephalosporins. Erythromycin Erythromycin has a macrolide structure composed of a large 13-carbon ring to which two sugars are attached by glycosidic linkages. Erythromycin and other macrolides inhibit protein synthesis by reversibly binding to the 50S ribosome subunit of sensitive microorganisms. It blocks the translocation step in protein synthesis by preventing the release of the tRNA from the acceptor to the donor site on the ribosome after the peptide bond is formed. Pediatrics Clarithromycin, recently approved for pediatric use, differs chemically from erythromycin by having a methyl substitution on the macrolide ring. Its spectrum of activity is similar to that of erythromycin except for enhanced H influenzae activity (including betalactamase-producing strains), and its longer half-life allows for twice-a-day dosing. Clarithromycin and its active metabolite penetrate well into body fluids and tissues (eg, lung tissue, tonsils), resulting in intracellular and tissue concentrations that are higher than serum concentrations. Gastrointestinal side effects occur less frequently in patients receiving clarithromycin (8% to 16%) than in those treated with erythromycin (20% to 40%). Because it reaches excellent levels in serum, alveoli, macrophages, and lung tissue, other important uses of clarithromycin will be in the therapy of Mycobacterium avium and C pnewnoniae (TWAR) infections. Clindamycin Clindamycin, amino acid in Review a derivative of an attached to a sulfur-conVol. 15 No. 11 November Downloaded from http://pedsinreview.aappublications.org at Univ Of Calgary LIB-MLB 425A on September 25, 2008 1994 I taming sugar, has replaced its parent drug lincomycin in clinical use. Clindamycin inhibits protein synthesis by reversibly binding to the 505 ribosome subunit of sensitive microrganisms. Although bactericidal for some organisms, clindamycin generally is bacteriostatic. Mechanisms of resistance are similar to those outlined for erythromycin. Clindamycin is active against pneumococci and group A streptococci. It has excellent activity against S aureus and many anaerobic bacteria, particularly B fragilis. Clindamycin is an important antibiotic for the treatment of intra-abdominal or pelvic infections and as an alternative therapy in patients who are allergic to penicillin. Bacterial strains that are resistant to clindamycin generally are resistant to erythromycin. Clindamycin penetrates well into most body fluids, including sputum, pleural fluid, and bone. However, it should not be used for central nervous system infections because of its poor penetration into cerebrospinal fluid. the inner cytoplasmic membrane can be reduced by acidic or anaerobic conditions, such as those present in an abscess. Inactivation by microbial enzymes is an important cause of the acquired resistance to aminoglycosides that occurs frequently. The genetic information for these enzymes is acquired primarily by conjugation and the transfer of DNA as plasmids or resistance factors. Such plasmids are widespread and may disseminate resistance to other antibiotics simultaneously. Amikacin may be less vulnerable to these inactivating enzymes than kanamycin, gentimicin, and tobramycin because of protective molecular side chains. The antibacterial activity of aminoglycosides is directed primarily against aerobic Gram-negative bacilli; there is little activity against anaerobes or Gram-positive bacteria. Streptomycin has been used in the In patients who have penicillin effective alternative agent. outer membrane of bacteria. Then it is transported into the inner cytoplasmic membranes where it is bound mainly to the 30S subunits of the bacterial ribosomes. The tetracyclines inhibit protein synthesis by blocking aminoacyl tRNA from entering the acceptor site on the mRNA ribosome complex. Tetracycline’s selective action on bacterial cells is based on its greatly increased uptake in susceptible bacterial cells compared with human cells; the host cells lack the active transport system present in bacteria. Resistance to the tetracyclines frequently is mediated by plasmids and is an inducible trait; that is, the bacteria become resistant following exposure to the drug. A number of transferable resistance determinants for tetracycline have been identified. Microrganisms that develop resistance to one tetracycline usually are allergy, erythromycin is an Aminoglycosides The aminoglycosides (eg, amikacin, gentamicin, tobramycin, and streptomycin) contain amino sugars linked to an aminocyclitol ring by glycosidic bonds. Aminoglycosides diffuse through channels formed by porin proteins in the outer membrane of Gram-negative bacteria and into the periplasmic space (Figure). There the aminoglycosides bind irreversibly to polysomes, especially the 305 ribosomal subunits, and prevent protein synthesis by inhibiting the ‘initiation complex.” In addition, aminoglycosides cause misreading of the messenger RNA (mRNA) template, which results in the incorporation of incorrect amino acids into the growing protein chain. As a result, the membrane is damaged and the bacteria die. Unlike the other inhibitors of microbial protein synthesis, the aminoglycosides are bactericidal rather than bacteriostatic. Bacteria may be resistant to the antimicrobial activity of aminoglycosides if the drug fails to penetrate the cell, has a low affinity for the bacterial ribosome, or is inactivated by microbial enzymes. Transport across ‘ Pediatrics in Review VoL 15 No. ii November multiple drug therapy of resistant pulmonary tuberculosis or disseminated mycobacterial disease. Gentamicin has been used in combination with other antibiotics for its synergistic effects against certain bacteria (eg, with penicillin against enterococci, with nafcillin against S aureus, with penicillin against group B streptococci, with ampicillin against L monocytogenes, and with other drugs effective against Pseudomonas sp). The clinical usefulness of aminoglycosides is limited by the potential for ototoxicity and nephrotoxicity, poor central nervous system penetration, and the need for monitoring serum levels. Tetracycline The structure of tetracycline consists of four cyclic rings with different substituents in three regions; the latter substitutions result in different pharmacologic properties but similar antibacterial activity. Initially, the tetracycline moiety passively diffuses through the porn proteins in the 1994 resistant to the congeners as well. High-level plasmid resistance to tetracycline has increased nationally among strains of N gonorrhoeae; consequently, monotherapy with tetracycline or doxycycline no longer is recommended to treat a patient who has both gonorrhea and chiamydial infections (Table 2). The tetracyclines have bacteriostatic activity against a variety of Gram-positive and Gram-negative bacteria. Tetracyclines are a recommended treatment for early Lyme disease, Rocky Mountain spotted fever, and infections caused by M pneumoniae, C trachomatis (including pelvic inflammatory disease), and C pneumoniae (TWAR strain). Because of its increased lipophilic properties, doxycycline attains higher central nervous system concentrations than other tetracyclines, which may be important in the treatment of early Lyme disease. Tetracyclines are not given routinely to children younger than 9 years of age because of toxicity to teeth and bones. However, cx- Downloaded from http://pedsinreview.aappublications.org at Univ Of Calgary LIB-MLB 425A on September 25, 2008 445 I I ceptions younger Mountain have been made to treat children who have Rocky spotted fever. INHIBIT NUCLEIC SYNTHESIS ACID Sulfonamides Sulfonamide is a generic name for the derivatives of para-aminobenzenesulfonamide. Sulfonamides are structural analogs and competitive inhibitors of the bacterial enzyme dihydropteroate synthase, which is responsible for incorporating para-aminobenzoic acid (PABA) into dihydropteroic acid, the precursor of folic acid. This results in a decreased pool of bacterial nucleotides, which are the building blocks for DNA synthesis. Mammalian cells are not affected by this mechanism because they require preformed folic acid from their diet. disrupted synergistically and less resistance develops. TMP-SMZ is used widely for the treatment of urinary tract infections, respiratory infections, sinusitus, otitis media, and gastrointestinal infections (eg, salmonellosis, shigellosis, traveler’s diarrhea). TMPSMZ also is the drug of choice for the treatment and prophylaxis of Pneumocystis carinii infections. Rifampin Rifampin inhibits DNA-dependent RNA polymerase at the B subunit of this enzyme, which prevents chain initiation but not elongation in RNA synthesis. Rifampin is bactericidal for both intracellular and extracellular microorganisms. Resistant strains of bacteria have altered RNA polymerase that is not inhibited by rifampin. Microorganisms may develop resistance to rifampin rapidly in vitro as a The clinical usefulness of aminoglycosides is limited by the potential for ototoxicity and nephrotoxicity, poor central nervous system penetration, and the need for monitoring serum levels. Sulfonamides are bacteriostatic agents; thus, the final eradication of the infection depends on the cellular and humoral defense mechanisms of the host. Sulfonamides have a wide range of antimicrobial activity against Grampositive and Gram-negative bacteria. They were the first effective chemotherapeutic agents used to cure bacterial diseases (eg, puerperal sepsis and meningococcal infections). Sulfonamides frequently are used as chemoprophylaxis and also are recommended for the treatment of Toxoplasma infections. Tnmethoprim Trimethoprim, an antimetabolite that affects folic acid synthesis, is a highly selective inhibitor of dihydrofolate reductase in lower organisms. It prevents the reduction of dihydrofolate to tetrahydrofolate, another critical precursor in purine synthesis. By combining trimethoprim with sulfamethoxazole (TMP-SMZ), two sequential steps of purine synthesis are 446 one-step mutation; this also occurs in vivo. For this reason, rifampin should not be administered alone, except for short-term chemoprophylaxis (eg, infections caused by N meningiditis or H influenzae type b). Rifampin is used in combination with other agents to treat tuberculosis and persistent group A streptococcal or staphylococcal infections. Quinolones Nalidixic acid has been available for the treatment of urinary tract infections for decades, but it has limited usefulness because bacterial resistance develops rapidly. Newer synthetic fluoroquinolones (eg, norfioxacm, ciprofloxacin, enoxacin, fleroxacm, lomefloxacin, and ofloxacin) have broad-spectrum antimicrobial activity and are a therapeutic advance. Their use in pediatrics has been limited by the potential risk of arthropathy that has been documented in several species of immature animals. The quinolones bind to the A subPediatrics units of DNA gyrase, which are responsible for cutting DNA strands, thus preventing supercoiling, unraveling the DNA, and halting DNA replication. Most quinolones are not as active against Gram-positive bacteria as they are against Gram-negative bacteria; they are only effective against streptococci and enterococci at levels that can be reached in the urine. The emergence of resistance to fluoroquinolones has been problematic for MRSA, methicillin-sensitive S aureus, P aeruginosa, and some Serratia infections. Decreased susceptibility of N gonorrhoeae to fluoroquinolones recently has been reported (Table 2). It is believed that widespread and often indiscriminate use of fluoroquinolones has contributed to this resistance problem. However, when used in selected patients, the quinolones can be life-saving, may allow the patient to avoid or shorten hospitalization, and can be very costeffective. Fluoroquinolones have been used to treat patients who have pyelonephritis or recurrent urinary tract infections, prostatitis, gonorrhea (single dose) and chlamydia (7-day course) infections, malignant external otitis, osteomyelitis caused by Gram-negative bacteria, respiratory infections including exacerbations of cystic fibrosis, and gastrointestinal infections (eg, Shigella, Salmonella, Campylobacter infections and traveler’s diarrhea). Quinolones are not approved by the Food and Drug Administration for use in patients younger than 18 years of age or in pregnant or nursing women. Children who have cystic fibrosis and are younger than 18 years old have been treated with quinolones without adverse effects because the benefits were believed to outweigh the risks. Implications Understanding the many different mechanisms of action for available antibiotics may help practitioners make better clinical decisions regarding the use of antibiotics. Although the increasing emergence of antibiotic-resistant pathogens is alarming, there are steps that each physician can take to slow this trend (Table 3). in Review VoL 15 No. 11 November Downloaded from http://pedsinreview.aappublications.org at Univ Of Calgary LIB-MLB 425A on September 25, 2008 1994 I Admittedly, some of these recommendations are not easy or popular. However, the alternative may be the emergence of resistant bacteria that cannot be treated with any of our many antibiotics. SUGGESTED READING General Brooks OF, Butel JS, Ornston LN, Ct al. Medical Microbiology. Norwalk, Conn: Appleton and Lange; 1991 Craft JC, Siepman N. Overview of the safety profile of clarithromycin suspension in pediatric patients. Pediatr Infect Dis J. 1993;12:S142-.S147 Oilman AG, Rail 1’W, Nies AS, et al. The Pharmacological Basis of Therapeutics. New York, NY: Pergamon Press; 1990 Kucers A, Bennett N. The Use of Antibiotics, 4th ed. Philadelphia, Penn: JB Lippincott Company; 1987 Mulligan Mi, Cobbs CO. Bacteriostatic versus bactericidal activity. Infect Dis Clin North Am. 1989;3:389-397 Petz LD. Immunological reactions between penicillins and cephalosporins: a review. J Infect Dis. 1978;137(suppl):S74-S79 Reese RE, Betts RF. Handbook of Antibiotics, 2nd ed. Boston, Mass: Little Brown and Company; 1993 Rodriequez Wi, Wiedermann VL. Role of newer oral cephalosporins, fluoroquinolones and macrolides in the treatment of pediatric infections. In: Aronoff SC, ed. Advances in Pediatric Infectious Diseases, vol 9. St. Louis, Mo: CV Mosby; 1994:125-151 Table 3. What Practftloners Can Do To Umft of Antibiotlcreslstant Pathogens the Emergence #{149} Wash hands thoroughly to avoid spreading resistant organisms to other patients. #{149} Stop and think. Is this a bacterial disease and is an antibiotic needed? #{149} Educate your patients that viral illnesses do not respond to antibiotics. #{149} Always use the narrowest-spectrum antibiotic possible. #{149} Try to limit the empiric use of broad-spectrum agents. #{149} Stay informed about your hospital’s antibiotic resistance patterns. #{149} Recognize that hospitaiwide antibiotic control programs may be implemented in some cases to limit access to certain antibiotics. AntIbiotic-resistant Pathogens Breiman RF, Butler JC, Tenover FC, Elliott JA, Facklam RR. Emergence of drugresistant pneumococcal infections in the US. JAMA. 1994;271:1831-1835 Centers for Disease Control. Decreased susceptibility of Neisseria gonorrhoeae to fluoroquinolones: Ohio and Hawaii, 19921994. MMWR. 1994;43:325-327 Leggiadro RJ. Penicillin and cephalosporinresistant Streptococcus pneumoniae: an emerging microbial threat. Pediatrics. 1994; 93:500-503 Sloas MM, Barrett FF, Chesney PJ, et at. Cephalosporin treatment failure in penicillinand cephalosporin-resistant Streptococcus pneumoniae meningitis. Pediatr Infect Dis J. 1992;! 1:662-666 Smith AL. Antibiotic resistance in pediatric pathogens. Infect Dis Clin North Am. 1992; 6:177-195 ASSiSOJU of Pediatric Pediatrics, NY. Private Diseases Pediatrics Professor Infectious University of Pediatrics, Divisions Diseases and General of Rochester, Rochester, Practice, Pediatric Infectious and Allergy, Bellevile, NJ. in Review VoL 15 No. ii November 1994 Downloaded from http://pedsinreview.aappublications.org at Univ Of Calgary LIB-MLB 425A on September 25, 2008 447 BACK TO BASICS: Antibiotics: Mechanisms of Action Kathleen A. Woodin and Susan H. Morrison Pediatr. Rev. 1994;15;440-447 DOI: 10.1542/pir.15-11-440 Updated Information & Services including high-resolution figures, can be found at: http://pedsinreview.aappublications.org Permissions & Licensing Information about reproducing this article in parts (figures, tables) or in its entirety can be found online at: http://pedsinreview.aappublications.org/misc/Permissions.shtml Reprints Information about ordering reprints can be found online: http://pedsinreview.aappublications.org/misc/reprints.shtml Downloaded from http://pedsinreview.aappublications.org at Univ Of Calgary LIB-MLB 425A on September 25, 2008