Overview of Antimicrobial TherapyChapter 1

Spectrum. Antibiotic spectrum refers to the range of microorganisms an antibiotic is usually effective against, and is the basis for empiric antibiotic therapy (Chapter 2). Antibiotic susceptibilities are a guide to predicting antibotic effectiveness in blood/well vascularized organs. In vitro testing does not always predict in vivo effectiveness (see p. 6).

Tissue Penetration. Antibiotics that are effective against a microorganism in vitro but unable to reach the site of infection are of little or no benefit to the host. Antibiotic tissue penetration depends on properties of the antibiotic, e.g., lipid solubility, molecular size and tissue, e.g., adequacy of blood supply, presence of inflammation. Antibiotic tissue penetration is rarely problematic in acute infections due to increased microvascular permeability from local release of chemical inflammatory mediators. In contrast, chronic infections, e.g., chronic pyelonephritis, chronic prostatitis, chronic osteomyelitis and infections caused by intracellular pathogens often rely on chemical properties of an antibiotic, e.g., high lipid solubility, small molecular size for adequate tissue penetration. Antibiotics cannot be expected to eradicate organisms from areas that are difficult to penetrate or have impaired blood supply, such as abscesses, which usually require surgical drainage for cure. In addition, implanted foreign materials associated with infection usually need to be removed for cure, since microbes causing infections associated with prosthetic joints, shunts, and intravenous lines produce a slime/biofilm on plastic/metal surfaces that permits organisms to survive despite antimicrobial therapy.

Antibiotic Resistance. Bacterial resistance to antimicrobial therapy may be classified as natural/intrinsic or acquired, and as relative or absolute. Pathogens not covered by the usual spectrum of an antibiotic are termed naturally/intrinsically resistant, e.g., 25% of S. pneumoniae are naturally resistant to macrolides; acquired resistance refers to a previously susceptible pathogen that is no longer susceptible to an antibiotic, e.g., ampicillin-resistant H. influenzae. Organisms with intermediate level (relative) resistance manifests as an increase in minimum inhibitory concentrations (MICs), but are susceptible at achievable serum/tissue concentrations, e.g., penicillin-resistant 3S. pneumoniae. In contrast, organisms with high level (absolute) resistance manifests as a sudden increase in MICs during therapy, and cannot be overcome by higher-than-usual antibiotic doses, e.g., gentamicin-resistant P. aeruginosa. Most acquired antibiotic resistance is agent-specific, not a class specific, and is usually limited to one or two species. Resistance is not related, per se, to volume or duration of use. Some antibiotics have little resistance potential i.e., “low resistance” potential even when used in high volume; other antibiotics can induce resistance, e.g., “high resistance” potential with little use.

Successful antibiotic resistance control strategies include eliminating antibiotics from animal feeds, microbial surveillance to detect resistance problems early, infection control precautions to limit/contain spread of clonal resistant species, restricted hospital formulary i.e., controlled use of high resistance potential antibiotics, and preferential use of “low resistance” potential antibiotics by clinicians. Unsuccessful strategies include rotating formularies, restricted use of certain antibiotic classes, e.g., 3^rd generation cephalosporins, fluoroquinolones, and use of combination therapy. In choosing between similar antibiotics, try to select an antibiotic with “low resistance” potential. Some antibiotics, e.g., ceftazidime are also associated with increased prevalence of methicillin-resistant S. aureus (MRSA); other antibiotics, e.g., vancomycin are associated with increased prevalence of vancomycin-resistant enterococci (VRE).

The antibiotic Resistance Potential of each antibiotic is included in each Drug Summary (see chapter 11).

Safety Profile. Whenever possible, avoid antibiotics with serious/frequent side effects.

Cost. Switching early from IV to PO antibiotics is the single most important cost saving strategy in hospitalized patients, as the institutional cost of IV administration (˜$10/dose) may exceed the cost of the antibiotic itself. Antibiotic costs can also be minimized by using antibiotics with long half-lives, and by choosing monotherapy over combination therapy. Other factors adding to the cost of antimicrobial therapy include the need for an obligatory second antimicrobial agent, antibiotic side effects, e.g., diarrhea, cutaneous reactions, seizures, phlebitis, and outbreaks of resistant organisms, which require cohorting and prolonged hospitalization.

Renal Insufficiency. Since most antibiotics eliminated by the kidneys have a wide “toxic-to-therapeutic ratio,” dosing strategies are frequently based on formula-derived estimates of creatinine clearance (Table 1.1), rather than precise quantitation of glomerular filtration rates. Dosage adjustments are especially important for antibiotics with narrow toxic-to-therapeutic ratios, and for patients who are receiving other nephrotoxic medications or have preexisting renal disease.

Hepatic Insufficiency. Antibiotic dosing for patients with hepatic dysfunction is problematic, since there is no hepatic counterpart to the serum creatinine to accurately assess liver function. In practice, antibiotic dosing is based on clinical assessment of the severity of liver disease. For practical purposes, dosing adjustments are usually not required for mild or moderate hepatic insufficiency. For severe hepatic insufficiency, dosing adjustments are usually made for antibiotics with hepatotoxic potential (Chapter 9). Relatively few antibiotics depend solely on hepatic inactivation/elimination, and dosing adjustment problems in these cases can be circumvented by selecting an appropriate antibiotic eliminated by the renal route.

Combined Renal and Hepatic Insufficiency. There are no good dosing adjustment guidelines for patients with hepatorenal insufficiency. If renal insufficiency is worse than hepatic insufficiency, antibiotics eliminated by the liver are often administered at half the total daily dose. If hepatic insufficiency is more severe than renal insufficiency, renally eliminated antibiotics are usually administered and dosed in proportion to renal function.

Mode of Antibiotic and Excretion/Excretory Organ Toxicity. The mode of elimination/excretion does not predispose to excretory organ toxicity per se, e.g., nafcillin (hepatically eliminated) is not hepatotoxic.

Overview. In vitro susceptibility testing provides information about microbial sensitivities of a pathogen to various antibiotics and is useful in guiding therapy. Proper application of microbiology and susceptibility data requires careful assessment of the in vitro results to determine if they are consistent with the clinical context; if not, the clinical impression usually should take precedence.

Susceptibility Breakpoints for Streptococcus pneumoniae. Because antibiotic susceptibility is, in part, concentration related, the Clinical and Laboratory Standards Institute (CLSI), formerly the National Committee for Clinical Laboratory Standards (NCCLS), has revised its breakpoints for S. pneumoniae susceptibility testing, which differentiate between meningeal and non-meningeal sites of pneumococcal infection (Table 1.5).

Summary. In vitro susceptibility testing is useful in most situations, but should not be followed blindly. Many factors need to be considered when interpreting in vitro microbiologic data, and infectious disease consultation is recommended for all but the most straightforward susceptibility interpretation problems. IV-to-PO switch changes using antibiotics of the same or other antibiotic class is best made when the oral antibiotic can achieve similar blood/tissue levels as the IV antibiotic. For example, IV-to-PO switch from cefazolin 1 gm (IV) to cephalexin 500 mg (PO) may not be effective against all pathogens at all sites, since cephalexin 500 mg (PO) achieves much lower serum concentrations compared to cefazolin 1 gm (IV) (16 mcg/mL vs. 200 mcg/mL).

10Bactericidal vs. Bacteriostatic Therapy. For most infections, bacteriostatic and bactericidal antibiotics inhibit/kill organisms at the same rate, and should not be a factor in antibiotic selection. Bactericidal antibiotics have an advantage in certain infections, such endocarditis, meningitis, and febrile leukopenia, but there are exceptions even in these cases.

Monotherapy vs. Combination Therapy. Monotherapy is preferred to combination therapy for nearly all infections. In addition to cost savings, monotherapy results in less chance of medication error and fewer missed doses/drug interactions. Combination therapy may be useful for drug synergy or for extending spectrum beyond what can be obtained with a single drug. However, since drug synergy is difficult to assess and the possibility of antagonism always exists, antibiotics should be combined for synergy if synergy is based on actual testing. Combination therapy is not effective in preventing antibiotic resistance, except in very few situations (Table 1.6).

Intravenous vs. Oral Switch Therapy. Patients admitted to the hospital are usually started on IV antibiotic therapy, then switched to equivalent oral therapy after clinical improvement/defervescence (usually within 72 hours). Advantages of early IV-to-PO switch programs include reduced cost, early hospital discharge, less need for home IV therapy, and virtual elimination of IV line infections. Drugs well-suited for IV-to-PO switch or for treatment entirely by the oral route include doxycycline, minocycline, clindamycin, metronidazole, chloramphenicol, amoxicillin, trimethoprim-sulfamethoxazole, quinolones, and linezolid.

11Most infectious diseases should be treated orally unless the patient is critically ill, cannot take antibiotics by mouth, or there is no equivalent oral antibiotic. If the patient is able to take/absorb oral antibiotics, there is no difference in clinical outcome using equivalent IV or PO antibiotics. It is more important to think in terms of antibiotic spectrum, bioavailability and tissue penetration, rather than route of administration. Nearly all non-critically ill patients should be treated in part or entirely with oral antibiotics. When switching from IV to PO therapy, the oral antibiotic chosen should have the same spectrum/degree of activity against the presumed/known pathogen and achieve the same blood and tissue levels as the equivalent IV antibiotic (Table 1.7).

Duration of Therapy. Most bacterial infections in normal hosts are treated with antibiotics for 1–2 weeks. The duration of therapy may need to be extended in patients with impaired immunity e.g., diabetes, SLE, alcoholic liver disease, neutropenia, diminished splenic function, etc., chronic bacterial infections e.g., endocarditis, osteomyelitis, chronic viral and fungal infections, or certain bacterial intracellular pathogens (Table 1.8). Infections such as HIV may require life-long therapy. Antibiotic therapy should ordinarily not be continued for more than 2 weeks, even if low-grade fevers persist (Table 1.8). Prolonged therapy offers no benefit, and increases the risk of adverse side effects, drug interactions, and superinfections.