Key Clinical Questions
What resistance patterns are associated with major nosocomial pathogens?
When should empiric antibiotic therapy be initiated? When is it permissible to delay empiric antibiotic therapy, if ever?
What impact do pharmacokinetics and pharmacodynamics have on antibiotic choice?
In what circumstances is combination antibiotic therapy appropriate?
What are the major adverse effects of antibiotics?
Introduction
In this chapter, we will use the terms antibacterial agents and antibiotics interchangeably. The term antibiotic has sometimes been defined as a substance produced by microbes that inhibits the growth of other microbes, especially bacteria. More broadly, it is used to characterize any agent with antibacterial properties, whether found in nature or synthesized artificially. Antibiotics are prescribed to approximately one-third of all hospitalized patients, and account for greater than 10% of hospital pharmacy expenditures. Up to one-half of antibiotic orders may be unnecessary, poorly chosen, or dosed incorrectly. Indiscriminant use of broad-spectrum agents is also believed to be a key contributor to emerging worldwide antimicrobial resistance. The estimated additional hospital costs associated with drug-resistant hospital-acquired bacterial infections in the United States is estimated to several billions of dollars. Hospitalists should be familiar with the currently available antibiotics, their penetration into various tissues, their major adverse effects, and their spectrum of activity relative to local patterns of antibacterial resistance. Antimicrobial prescribing should also take into account issues of cost and potential for the emergence of resistance.
Antibiotic Categories and Spectrum of Activity
Major categories, subdivisions, and some individual antibacterial agents are summarized in Table 185-1 according to their mode of action, and side effects and drug-drug interactions are listed in Table 185-2. Antibacterial spectrum often overlaps between different antibiotic groups. However, few antibiotics are active against multidrug- or highly resistant bacteria. Thus, the clinician may sometimes have several choices of potentially appropriate antibiotics, but at other times may only have only one, or even none.
Table 185-1 The Main Categories, Subdivisions, and Individual Antibacterial Agents, with Spectrum of Activity and Main Modes of Action
Table 185-1 The Main Categories, Subdivisions, and Individual Antibacterial Agents, with Spectrum of Activity and Main Modes of Action
| Antibiotic Category | Subdivisions (Individual Substances) | Spectrum of Antibacterial Activity |
|---|---|---|
| Antibiotics acting on bacterial cell wall | ||
| A. Beta-lactams | ||
| 1. Penicillins | Naturally occurring (penicillin G, penicillin V) | Gram-positive cocci, excluding staphylococci and most enterococci. Gram-positive rods, including anaerobes. Spirochetes. |
| Penicillinase-resistant antistaphylococcal (methicillin, oxacillin, nafcillin, dicloxacillin) | Methicillin-susceptible staphylococci (MSS). Gram-positive cocci, but not many enterococci. | |
| Aminopenicillins (ampicillin, amoxicillin) | All the above plus enterococci, Listeria monocytogenes, Hemophilus influenzae, Moraxella catarrhalis, and some enteric Gram-negative rods. | |
| Carboxy-penicillins and ureido- penicillins (ticarcillin, piperacillin) | All the above plus Enterobacter, Klebsiella, Pseudomonas, Acinetobacter species, and anaerobes. | |
| 2. Cephalosporins | First generation (cefadroxil, cefazolin, cephalexine, cephradine) | Gram-positive cocci including MSS, excluding enterococci. Some strains of Escherichia coli, Klebsiella, Proteus mirabilis. Not active against indole-positive Proteus and Serratia. |
| Second generation (cefamandole, cefaclor, cefprozil, cefuroxime, cefotetan, cefoxitin, loracarbef) | Similar to first generation, plus Hemophilus influenzae, Enterobacter species, indole-positive Proteus and Serratia, Neisseriae. Cephamycins (cefotetan, cefoxitin) have good anaerobic activity against Bacteroides fragilis but poor against Gram-positive cocci and Enterobacter species. | |
| Third generation (cefotaxime, ceftriaxone, ceftazidime, cefoperazone, cefixime) | Enhanced activity against Gram-negative rods. Ceftazidime has good, cefoperazone moderate, and the rest poor activity against Pseudomonas aeruginosa. Good against Gram-negative cocci. Variable activity against Gram-positive cocci, cefotaxime and ceftriaxone being excellent for pneumococci. Poor anaerobic activity. | |
| Fourth generation (cefepime, cefpirome) | Good activity against Gram-positive cocci, with enhanced activitiy against Pseudomonas aeruginosa and other Gram-negative rods. | |
| 3. Monobactams | (aztreonam) | Gram-negative rods including Pseudomonas aeruginosa and some strains of Acinetobacter baumannii. Poor against Gram-positive bacteria and anaerobes. |
| 4. Carbapenems | (meropenem, imipenem/ cilastatin, ertapenem) | Excellent activity against Gram-negative rods, including Enterobacter species, as well as multidrug-resistant Klebsiella pneumoniae, Pseudomonas aeruginosa, and Acinetobacter baumannii (not ertapenem). Good Gram-positive activity. No advantage over ampicillin for enterococci. Compared to imipenem, meropenem has better Gram-negative but worse Gram-positive activity. Ertapenem has narrower spectrum than the other two. |
| B. Glycopeptides | (vancomycin, teicoplanin) | Excellent activity against Gram-positive cocci, including MRS, highly resistant pneumococci, and enterococci. |
| Antibiotics acting on bacterial cell membrane | ||
| C. Polypeptides | ||
| 1. Bacitracin | Used only topically against Gram-positive bacteria. | |
| 2. Polymyxins | (polymyxin B and polymyxin E also known as colistin) | Gram-negative microbes including multidrug-resistant Klebsiella pneumoniae, Pseudomonas aeruginosa, and Acinetobacter baumannii. Naturally inactive against Proteus. Poor Gram-positive activity. |
| D. Lipopeptides | (daptomycin) | Similar activity to glycopeptides. Good against vancomycin-resistant enterococci. |
| Antibiotics acting on bacterial protein synthesis | ||
| E. Macrolides | (erythromycin, clarithromycin, azithromycin) | Good against Gram-positive cocci (excluding many staphylococci and most enterococci), Mycoplasma and Chlamydia species, Legionella pneumoniae, and nontuberculous mycobacteria. |
| F. Tetracyclines | (tetracycline, minocycline, doxycycline) | Similar to macrolides plus rickettsiae, Brucella species and spirochetes. |
| G. Glycylcyclines | (tigecycline) | Gram-positive cocci, including MRS, highly resistant pneumococci, and enterococci. Gram-negative bacteria, including multidrug-resistant Klebsiella pneumoniae and Acinetobacter baumanii, but not Pseudomonas aeruginosa. Good anaerobic activity |
| H. Aminoglycosides | (streptomycin, gentamicin, tobramycin, amikacin, netilmicin, kanamycin) | Gram-negative bacteria including multidrug-resistant Klebsiella pneumoniae,Acinetobacter baumannii and Pseudomonas aeruginosa. Moderate activity against Gram-positive cocci. Poor anaerobic activity. |
| I. Chloramphenicol | Gram-positive and negative cocci including MRS and Neisseria meningitidis. Enterobacteriaceae. Not active against Pseudomonas aeruginosa and Enterobacter species. Good anaerobic activity. | |
| J. Lincosamides | (clindamycin) | Activity against Gram-positive cocci, including some MRS. Excellent anaerobic activity. |
| K. Mupirocin | Topical antistaphylococcal agent active against MRS. | |
| L. Oxazolidinones | (linezolid) | Similar activity to glycopeptides. Good against vancomycin-resistant enterococci (VRE). |
| M. Streptogramins | (quinupristin/dalfopristin, pristinamycin) | Similar activity to glycopeptides. Good against vancomycin-resistant Enterococcus faecium but not Enterococcus faecalis. Good activity against Gram-positive anaerobes. |
| N. Fusidic acid | Gram-positive cocci, active against many MRS but not enterococci. Gram-negative cocci. Poor activity against Gram-negative rods except Moraxella and Legionella species. | |
| Antibiotics acting against cell metabolism | ||
| O. Sulfonamides | (sulfomethoxazole, sulfacetamide, sulfasalazine, sulfadiazine) | Moderate antistaphylococcal activity, also against some MRS. Poor against streptococci and enterococci. Good Gram-negative activity, including Haemophilus influenza, Moraxella, enteric Gram-negative rods, Stenotrophomonas maltophilia and Acinetobacter species. Poor anaerobic activity. Good against nocardiosis, Pneumocystis jiroveci, toxoplasmosis. |
| Antibiotics acting on DNA synthesis | ||
| P. Quinolones | ||
| 1. First generation quinolones (nonfluorinated) | (nalidixic acid, cinoxacin,† enoxacin,† norfloxacin) | Gram-negative activity, mainly Enterobacteriaceae. |
| 2. Second generation, fluoroquinolones | (ofloxacin, ciprofloxacin, levofloxacin*) | Wide Gram-negative activity. Additional activity against intracellular microbes. Ciprofloxacin and (to a lesser degree) levofloxacin have good anti-pseudomonal activity. Moderate activity against Gram-positive cocci. |
| 3. Third generation, respiratory quinolones | (levofloxacin,* moxifloxacin, sparfloxacin,† gatifloxacin†) | Added good activity against streptococci, especially pneumococcus. |
| 4. Fourth generation | (clinafloxacin,§ trovafloxacin,† prulifloxacin) | Wide spectrum of activity with additional Gram-positive (including MRS, highly resistant pneumococci, and enterococci) and anaerobic activity to the previous categories. |
| Q. Rifampin | Specific Gram-positive and Gram-negative microbes (staphylococci including MRS, neisseriae, brucella). First line antimycobacterial. Always used combined with other antibiotics. | |
| R. Nitroimidazoles | (metronidazole, tinidazole) | Excellent antianaerobic activity. |
| Various mechanisms of action | ||
| S. Beta-lactamase inhibitors | (clavulanic acid, sulbactam, tazobactam) | Enhance the spectrum and activity of aminopenicillins and carboxypenicillins. Sulbactam used as monotherapy against highly-resistant Acinetobacter baumannii in ICUs. |
Table 185-2 Major Adverse Effects and Partial List of Drug-Drug Interactions of Antibiotics
Table 185-2 Major Adverse Effects and Partial List of Drug-Drug Interactions of Antibiotics
| Antibiotics | Major Adverse Effects | Interactions |
|---|---|---|
| Penicillins | Allergic and hypersensitivity reactions, including fever, rash, anaphylaxis; high intravenous doses may be associated with sodium load and edema, as well as central nervous system toxicity in patients with renal insufficiency; hepatitis (especially oxacillin) | Nafcillin decreases the effect of warfarin and cyclosporine; the combination of ampicillin and allopurinol is associated with a higher risk of rash; oral absorption of beta-blockers is diminished in patients taking amoxicillin or ampicillin; risk of anaphylaxis may be increased in patients taking beta-blockers |
| Cephalosporins | C difficile colitis; less often associated with allergy than penicillins; cefepime associated with mental status change in elderly patients with renal insufficiency | Minimal |
| Carbapenems | Seizures, especially when doses not properly adjusted for renal function; seizure risk is highest with imipenem, and lowest with meropenem; C difficile colitis | Decreased levels of valproic acid |
| Aminoglycosides | Nephrotoxicity, ototoxicity, neuromuscular blockade in critically ill patients | Increased risk of nephrotoxicity with use of other nephrotoxic agents, such as cyclosporine, cisplatin, NSAIDs, and vancomycin; increased ototoxicity when administered with diuretics |
| Sulfa drugs | Rash, fever, hyperkalemia, cytopenias, crystalluria (at high doses or with impaired renal function) | Increased anticoagulation with warfarin |
| Macrolides | Gastrointestinal upset, hepatitis, cholestatic jaundice, pancreatitis, QT interval prolongation | Increases the levels of many drugs by inhibiting hepatic cytochrome P450 metabolism, including cyclosporine, tacrolimus, theophylline, ergot alkaloids, carbamazepine, antihistamines, cisapride, warfarin, statins, class I antiarrthymics, and some benzodiazepines and neuroleptics |
| Lincosamides (eg, clindamycin) | Diarrhea, including C difficile colitis; rash | May potentiate the effect of warfarin |
| Fluoroquinolones | C difficile colitis; tendinopathy; mental status changes; rash | Oral absorption inhibited by antacids, ferrous sulfate, cimetidine |
| Tetracyclines | Diarrhea, photosensitivity, hepatitis, pill esophagitis | Oral absorption inhibited by antacids, ferrous sulfate, calcium supplements, tube feedings |
| Glycopeptides (eg, vancomycin) | Infusion-related flushing (red person syndrome), nephrotoxicity, ototoxicity | Use with caution when patient taking other potentially nephrotoxic agents, such as aminoglycosides, cisplatin, or colistin |
| Oxazolidinones (eg, linezolid) | Nausea, diarrhea, cytopenias, neuropathy | Serotonin syndrome in patients also taking selective serotonin reuptake inhibitors (SSRIs) |
| Lipopeptides (eg, daptomycin) | Gastrointestinal upset, creatine kinase elevations | Rhabdomyolysis in patients also taking statin therapy |
| Polymixins (eg, colistin) | Nephrotoxicity (20%), neuropathy (7%) | May potentiate neuromuscular blockade associated with aminoglycosides and curariform muscle relaxants |
| Polyene antifungals (amphotericin B) | Febrile infusion reaction (nearly universal side effect); renal tubular injury with severe potassium and magnesium wasting, metabolic acidosis, and nephrogenic diabetes insipidus; electrolyte imbalances and possibly direct cardiotoxicity may lead to life-threatening arrhythmias; cytopenias |
