For more than 60 years, the main trends in the management of infectious diseases have been the evolution and refinement of antibiotic therapy. Factors that have stimulated the development of new antibiotics include the continuous emergence of resistant bacteria, economics, and the desire to eliminate adverse effects. During the past 25 years, emphasis has gradually shifted from aminoglycosides to β-lactams and the development of new classes of antibiotics such as carbapenems and monobactams. In addition, vancomycin, TMP-SMX, erythromycin, and rifampin have enjoyed a resurgence in popularity and new applications. Quinolones offer the possibility of treating serious infections on an outpatient basis.
Antibacterial agents can be separated into groups according to their specific targets on or within bacteria:
β-Lactams and glycopeptides inhibit cell-wall synthesis.
Polymyxins distort cytoplasmic membrane function.
Quinolones and rifampicins inhibit nucleic acid synthesis.
Macrolides, aminoglycosides, and tetracyclines inhibit ribosome function.
Trimethoprim and sulfonamides inhibit folate metabolism.
All antibiotics facilitate the growth of resistant bacteria consequent to the destruction of susceptible bacteria. Although the wide use of antimicrobial agents for veterinary and agricultural purposes has contributed to the emergence of multiresistant microorganisms, the excessive use of antibiotics, especially in hospitals, has been the most significant catalyst for resistance. Bacteria resist antibiotics by inactivation of the antibiotic, decreased accumulation of the antibiotic within the microorganism, or alteration of the target site on the microbe. For example, resistance to penicillins and cephalosporins is initiated by β-lactamase enzymes that hydrolyze the β-lactam ring, thus destroying the antibiotic’s effectiveness. Resistance can be mediated by chromosomal mutations or by the presence of extrachromosomal DNA, also known as plasmid resistance. Plasmid resistance is important from an epidemiologic point of view because it is transmissible and usually highly stable, confers resistance to many different classes of antibiotics simultaneously, and is often associated with other characteristics that enable a microorganism to colonize and invade a susceptible host.
Resistance-conferring plasmids have been identified in virtually all bacteria. Plasmids can pick up chromosomal genes for resistance and transfer them to species that are not currently resistant. Bacteria that have acquired chromosomal and plasmid-mediated resistance can neutralize or destroy antibiotics in 3 different ways (they can use 1 or more of these mechanisms simultaneously):
by preventing the antibacterial agent from reaching its receptor site
by modifying or duplicating the target enzyme so that it is insensitive to the antibacterial agent
by synthesizing enzymes that destroy the antibacterial agent or modify the agent to alter its entry or receptor binding
Antimicrobial susceptibility testing permits a rational choice of antibiotics, although correlation of in vivo and in vitro susceptibility is not always precise. Disk-diffusion susceptibility testing has provided qualitative data about the inhibitory activity of commonly used antimicrobials against an isolated pathogen, and these data are usually sufficient. For serious infections, it is useful to quantify the drug concentrations that inhibit and kill the pathogen. The lowest drug concentration that prevents the growth of a defined inoculum of the isolated pathogen is the minimal inhibitory concentration (MIC); the lowest concentration that kills 99.9% of an inoculum is the minimal lethal concentration (MLC). For bactericidal drugs, the MIC and MLC are usually similar.
The β-lactam group includes the penicillins, cephalosporins, and monobactams, all of which possess a β-lactam ring that binds to specific microbial binding sites and interferes with cell-wall synthesis. Although the carbapenems and carbacephems are often grouped with β-lactams, they have a slightly different ring structure. Most new agents have been created by side-chain manipulation of the β-lactam ring, which has improved resistance to enzymatic degradation. However, some of the newer antibiotics (such as third-generation cephalosporins) show diminished potency against gram-positive cocci, especially staphylococci.
Penicillins The first natural penicillins, types G and V, were degraded by the enzyme penicillinase. The penicillinase-resistant penicillins, such as methicillin, nafcillin, oxacillin, and cloxacillin, were developed for treating resistant Staphylococcus species and were effective except against strains of methicillin-resistant S epidermidis. The next generation of penicillins included the aminopenicillins, ampicillin and amoxicillin, which were created by placing an amino group on the acyl side chain of the penicillin nucleus. This change broadened their effectiveness to include activity against H influenzae, Escherichia coli, and Proteus mirabilis. The next advance was development of the carboxypenicillins, carbenicillin and ticarcillin, which are active against aerobic gram-negative rods such as P aeruginosa, Enterobacter species, and indole-positive strains of Proteus. The fourth-generation penicillins, known as acyl ureidopenicillins, include azlocillin, mezlocillin, and piperacillin. Because of the possibility of emergence of resistance, the newer penicillins are usually administered in combination with an aminoglycoside.
Allergic reactions are the chief adverse effects encountered in using the penicillins. Among antimicrobial agents, the penicillins are the leading cause of allergy; symptoms range from mild rashes to anaphylaxis.
Cephalosporins The cephalosporins also belong to the β-lactam group of antibiotics, and cross-allergenicity may occur in 3%–5% of patients with penicillin allergies. The cephalosporins and their characteristics are outlined in Table 14-2.
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Monobactams are a monocyclic class of antibiotics that use only the β-lactam ring as their core structure. Aztreonam, the first approved monobactam antibiotic, has an excellent safety profile and good success rate in the treatment of infections caused by aerobic gram-negative bacilli, but has poor activity against gram-positive and anaerobic organisms. Aztreonam has the spectrum of an aminoglycoside antibiotic without the ototoxicity or nephrotoxicity.
Table 14-2 Cephalosporins
Carbapenems are a class of antibiotics with a basic ring structure similar to that of penicillins. The antibacterial spectrum of the carbapenems is broader than that of any other existing antibiotic and includes S aureus, Enterobacter species, and P aeruginosa, although carbapenem resistance is an ongoing global public health problem. Carbapenems produce a postantibiotic killing effect against some organisms, with a delay in regrowth of damaged organisms similar to that observed with aminoglycosides.
Imipenem/cilastatin combines a carbapenem, imipenem, with an inhibitor of renal dehydropeptidase, cilastatin. Cilastatin has no antimicrobial activity and is present solely to prevent degradation of imipenem by dehydropeptidase. Imipenem/cilastatin is an appropriate compound for monotherapy for mixed infections. Up to 50% of patients who are allergic to penicillin are also allergic to imipenem.
Meropenem, biapenem, panipenem, ertapenem, faropenem, tomopenem, and ritipenem are newer penems that have increased stability against degradation by dehydropeptidases. Doripenem is a newer agent that appears to be most effective in treating carbapenem-resistant gram-negative bacilli and penicillin-resistant streptococci.
Loracarbef is an oral carbacephem, a type of antibiotic that is structurally similar to cephalosporins but possesses a broader spectrum due to higher stability against both plasmid and chromosomally mediated β-lactamases. Loracarbef provides good coverage for most gram-positive and gram-negative aerobic bacteria.
Clavulanic acid, sulbactam, and tazobactam are β-lactam molecules that possess little intrinsic antibacterial activity but are potent inhibitors of many plasmid-mediated class A β-lactamases. Currently, there are 4 combinations of β-lactam antibiotics plus β-lactamase inhibitors available in the United States: Augmentin (oral amoxicillin and clavulanic acid), Timentin (intravenous ticarcillin and clavulanic acid), Unasyn (intravenous ampicillin and sulbactam), and Zosyn (intravenous piperacillin and tazobactam). These drugs have excellent activity against β-lactamase–producing gram-positive and gram-negative bacteria as well as many anaerobes.
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Vancomycin has regained popularity because of the emergence of methicillin-resistant staphylococci and the recognition that C difficile is a cause of pseudomembranous colitis. This drug has excellent activity against Clostridium and against most gram-positive bacteria, including methicillin-resistant staphylococci, Corynebacterium species, and other diphtheroids. Vancomycin has been used alone to treat serious infections caused by methicillin-resistant staphylococci.
Vancomycin-resistant enterococcal infections have recently become more common. The CDC has issued recommendations regarding appropriate use of vancomycin to help counteract the problem of bacterial drug resistance.
Teicoplanin has several advantages over vancomycin, including longer half-life, lower nephrotoxicity, and no requirement for monitoring drug levels. Teicoplanin is effective for treatment of staphylococcal infections, including endocarditis, bacteremia, osteomyelitis, and septic arthritis. Teicoplanin may be preferable to vancomycin for surgical prophylaxis because of its excellent tissue penetration, lower toxicity, and long half-life, allowing single-dose administration in several surgical procedures. The antibacterial activity of teicoplanin is similar to that of vancomycin but with increased potency, particularly against Streptococcus and Enterococcus. Teicoplanin is active against many vancomycin-resistant organisms. The newer agents oritavancin and dalbavancin are also highly active against vancomycin-resistant infections.
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The introduction of a fluorine into the basic quinolone nucleus of nalidixic acid has produced compounds known as fluoroquinolones, which have excellent activity against gram-positive bacteria. The subsequent addition of piperazine produced compounds such as norfloxacin and ciprofloxacin, which have a broad spectrum of activity, encompassing staphylococci and most of the significant gram-negative bacilli, including Pseudomonas. Ciprofloxacin is available in both oral and parenteral forms and can be used to treat urinary tract infections, gonorrhea, and diarrheal diseases, as well as respiratory, skin, and bone infections. Other fluoroquinolones in the US market include ofloxacin, temafloxacin, lomefloxacin, enoxacin, levofloxacin, moxifloxacin, gemifloxacin, and besifloxacin.
The newer fluoroquinolones possess even greater activity against gram-positive and gram-negative bacteria. Either moxifloxacin or levofloxacin appears to be a good treatment choice for pneumococcal infections that are resistant to penicillin and the macrolides. Oral quinolones are an alternative form of therapy to β-lactams and aminoglycosides and have allowed physicians to treat more patients outside the hospital setting. Reported adverse effects include tendon rupture (especially in elderly patients), retinal detachment, and peripheral neuropathy. Of the quinolones, moxifloxacin carries the highest risk of dysglycemia.
The macrolide erythromycin is often employed for the initial treatment of community-acquired pneumonia. This agent is effective against infections caused by pneumococci, group A streptococci, M pneumoniae, Chlamydia, and Legionella. Erythromycin is used to treat upper respiratory tract infections and sexually transmitted infections in patients who are allergic to penicillin.
Clarithromycin and azithromycin are macrolide antibiotics that are chemically related to erythromycin. Both are well-tolerated alternatives to erythromycin and may offer advantages in treating gonococcal and chlamydial infections and in treating Mycobacterium avium and other recalcitrant infections associated with AIDS and HIV infection. Clarithromycin and ethambutol are used to treat Mycobacterium avium-intracellulare complex (MAC) in an HIV-infected patient, and prophylactic therapy with azithromycin, clarithromycin, rifabutin, or combined therapy may help prevent disseminated MAC in AIDS patients. Azithromycin is subclassified as an azalide, and it causes far fewer drug interactions than erythromycin. There is increasing cross-resistance among the macrolides.
Clindamycin has a gram-positive spectrum similar to that of erythromycin and is also active against most anaerobes, including Bacteroides fragilis. Except for treating anaerobic infection, clindamycin is rarely the drug of choice, although it is well absorbed orally, and parenteral formulations are available. Its major adverse effect is diarrhea, which may progress to pseudomembranous enterocolitis in some patients. Macrolides, especially azithromycin, can increase the risk of cardiac arrhythmias.
The aminoglycoside antibiotics inhibit protein synthesis by binding to bacterial ribosomes. Gentamicin, tobramycin, amikacin, kanamycin, streptomycin, and netilmicin possess similar activity, pharmacology, and toxicity. Because of poor gastrointestinal absorption, parenteral administration is necessary to produce therapeutic levels.
Aminoglycosides are used to treat serious infections caused by gram-negative bacilli. They do not cross the blood–brain barrier. Aminoglycosides are not used for most gram-positive infections because the β-lactams are less toxic.
The major adverse effects of the aminoglycosides are nephrotoxicity and ototoxicity. Blood urea nitrogen, creatinine, and aminoglycoside peak and trough serum levels should be monitored, especially in patients with known renal disease. Combined administration of a loop diuretic such as furosemide with aminoglycosides has a synergistic ototoxic effect, potentially leading to permanent loss of cochlear function. Penicillins may decrease the antimicrobial effectiveness of parenteral aminoglycosides, particularly in patients with impaired renal function.
The tetracyclines are bacteriostatic agents that reversibly inhibit ribosomal protein synthesis. Although they are active against a wide range of organisms (including Staphylococcus, Rickettsia, Chlamydia, Nocardia, and Actinomyces), resistance is widespread, especially among S aureus and gram-negative bacilli. The principal clinical uses of tetracyclines are in the treatment of nongonococcal urethritis, Rocky Mountain spotted fever, chronic bronchitis, and sebaceous disorders such as acne rosacea. In addition, tetracyclines are an alternative for the penicillin-allergic patient with syphilis. Tetracyclines are well absorbed when taken on an empty stomach; however, their absorption is decreased when taken with milk, antacids, calcium, or iron. Tetracyclines are distributed throughout the extracellular fluid, but cerebrospinal fluid penetration is unreliable. Adverse effects include oral or vaginal candidiasis with prolonged use, gastrointestinal upset, photosensitivity, elevation of the blood urea nitrogen level, and idiopathic intracranial hypertension. Tetracyclines can prolong the international normalized ratio (INR) in patients taking warfarin, and they should not be administered to pregnant women or to children younger than 10 years because of the potential for harm to developing bone and teeth.
Miscellaneous antibacterial agents
Rifampin was originally developed as an anti-TB agent, but it is also used to treat several intractable bacterial infections. The drug is usually employed adjunctively because bacteria develop resistance to the drug when it is used as a single agent. It is effective in eradicating the carrier state of nasal S aureus. The drug is also effective prophylactically against Neisseria meningitidis and may be useful for treating oropharyngeal carriers of H influenzae type b.
Another oral antibiotic with potential for treating deep-seated infections is TMP-SMX. After a single oral dose, the mean serum levels of TMP-SMX are approximately 75% of the concentration that would be achieved via intravenous administration. In addition to its excellent pharmacokinetics, TMP-SMX has an extremely broad spectrum of activity, including effectiveness against Enterobacteriaceae and some organisms that are resistant to cephalosporins. Although there is a misconception that TMP-SMX has limited activity against gram-positive bacteria, in fact, most streptococci, staphylococci, and Listeria monocytogenes are susceptible to it. Beyond the broad-spectrum effect of TMP-SMX, the concomitant use of metronidazole creates an antibiotic combination with activity against microorganisms that surpasses that of a third-generation cephalosporin. TMP-SMX has been increasingly used in the treatment and prophylaxis of Pneumocystis infection and toxoplasmosis.
Chloramphenicol is a bacteriostatic agent that reversibly inhibits ribosomal protein synthesis. This drug is active against a wide variety of gram-negative and gram-positive organisms, including anaerobes. The major concern with this agent is hematopoietic toxicity, including reversible bone marrow suppression and irreversible aplasia. Aplastic anemia is an idiosyncratic late reaction to the drug and is usually fatal. Other adverse effects include hemolysis, allergy, and peripheral neuritis.
Excerpted from BCSC 2020-2021 series: Section 1 - Update on General Medicine. For more information and to purchase the entire series, please visit https://www.aao.org/bcsc.