® Drug-specific considerations in antimicrobial selection include spectrum of activity, effects on nontargeted microbial flora, appropriate dose, pharmacokinetic and pharmacodynamic properties, adverse-effect and drug-interaction profile, and cost (Table 69-2).
Spectrum of Activity and Effects on Nontargeted Flora
Most initial antimicrobial therapy is empirical because cultures usually have not had sufficient time to identify a pathogen. Empirical therapy should be based on patient-and antimicrobial-specific factors such as the anatomic location of the infection, the likely pathogens associated with the presentation, the potential for adverse effects in a given patient, and the antimicrobial spectrum of activity. Prompt initiation of appropriate therapy is paramount in hospitalized patients who are critically ill. Patients who receive initial antimicrobial therapy that provides coverage against the causative pathogen survive at twice the rate of patients who do not receive adequate therapy initially. Empirical selection of antimicrobial spectrum of activity should be related to the severity of the illness. Generally, acutely ill patients may require broader-spectrum antimicrobial coverage, whereas less ill patients may be managed initially with narrow-spectrum therapy. While a detailed description of antimicrobial pathogen-specific spectrum of activity is beyond the scope of this chapter, this information can be obtained readily from a number of sources. ,10
Table 69-2 Considerations for Selecting Antimicrobial Regimens
Spcctrum of activity and effects on riorrtargeted flora Dosing
Pharmacokinetic properties Pharmacodynamic properties Ad verse-effect potential Drug-interaction potential Cost
A nato m i c locat i on of infect \on A1 "li"-: ■ = I :i-jI I iisl:.":r v Drug allergy history Renal and hcpatic function Concomitant medications Pregnancy or lactation ■: :Hi:in
Collateral damage is defined as the development of resistance occurring in a patient's nontargeted antimicrobial flora that can cause secondary infections. For example, clindamycin is an excellent antimicrobial for treating streptococcal infections. However, many antimicrobials can treat this relatively susceptible pathogen. Clinda-mycin also readily selects for resistance in a nontargeted organism that may be present in the intestinal tract, namely, Clostridium difficile. Collateral damage is manifested because clindamycin is considered to be a major risk factor for C. difficile-associated diarrhea.11 If several different antimicrobials possess activity against a targeted pathogen, the antimicrobial that is least likely to be associated with collateral damage may be preferred.
A common subject of debate involves the need to provide similar bacterial coverage with two antimicrobials for serious infections. Proponents state that double coverage may be synergistic, prevent the emergence of resistance, and improve outcome. However, there are few clinical examples in the literature to support these assertions.
Examples where double coverage is considered superior are limited to infections associated with large bacterial inocula and in species that are known to readily develop
resistance such as active tuberculosis or enterococcal endocarditis. ' A study of patients with Pseudomonas aeruginosa infections, an intrinsically resistant organism, demonstrated that empirical double coverage with two antipseudomonal antimicrobials improved survival.14 The analysis found that combination therapy increased the likelihood of appropriate empirical coverage; however, once organism susceptibilities were known, there was no difference in outcome between double coverage and mono-therapy. Double antimicrobial coverage with similar spectra of activity may be beneficial for selected infections associated with high bacterial loads or for initial empirical coverage of critically ill patients in whom antimicrobial-resistant organisms are suspected. Monotherapy usually is satisfactory once antimicrobial susceptibilities are established.
Clinicians should be aware that dosage regimens with the same drug maybe different depending on the infectious process. For example, ciprofloxacin, a fluoroquinolone, has various dosage regimens based on site of infection. The dosing for uncomplicated UTIs is 250 mg twice daily for 3 days. For complicated UTIs, the dose is 500 mg twice daily for 7 to 14 days. Severe complicated pneumonia requires a dosage regimen of 750 mg twice daily for 7 to 14 days. Clinicians are encouraged to use dosing regimens designed for treatment of the specific diagnosed infection because they have demonstrated proven efficacy and are most likely to minimize harm.
Pharmacokinetic properties of an antimicrobial may be important in antimicrobial regimens. Pharmacokinetics refers to a mathematical method of describing a patient's drug exposure in vivo in terms of absorption, distribution, metabolism, and elimination. Bioavailability refers to the amount of antimicrobial that is absorbed orally relative to an equivalent dose administered intravenously. Drug-related factors that may affect oral bioavailability include the salt formulation of the antimicrobial, the dosage form, and the stability of the drug in the gastrointestinal tract. Frequently, absorption may be affected by gastrointestinal tract blood flow. All patients that manifest systemic signs of infection such as hypotension or hypoperfusion should receive intravenous antimicrobials to ensure drug delivery. In almost all cases where patients have a functioning gastrointestinal tract and are not hypotensive, antimicrobials with almost complete bioavailability (greater than 80%) such as the fluoroquinolones, fluconazole, and linezolid may be given orally. With antimicrobials with modest bioavailability (e.g., many ^-lactams), the decision to choose an oral product will depend more on the severity of the illness and the anatomic location of the infection. In sequestered infections, where higher systemic concentrations of antimicrobial may be necessary to reach the infected source (e.g., meningitis) or for antimicrobials with poor bioavailability, intravenous formulations should be used.
Several points regarding how the antimicrobial distributes into tissue are worth mentioning. First, only antimicrobials not bound to albumin are biologically active. Protein binding is likely clinically irrelevant in antimicrobials with low or intermediate protein binding. However, highly protein bound antimicrobials (greater than 50%) also may not be able to penetrate sequestered compartments, such as cerebral spinal fluid, resulting in insufficient concentration to inhibit bacteria. Second, some drugs may not achieve sufficient concentrations in specific compartments based on distribution characteristics. For example, Legionella pneumophilia is a nonenteric gramnegative organism that causes severe pneumonia. The organism is known to survive and reside inside pulmonary macrophages. Treatment with an antibiotic that works by inhibiting bacterial cell wall synthesis, such as a cephalosporin, will be ineffective because it only distributes into extracellular host tissues. However, macrolide or fluoroquinolone antimicrobials, which concentrate in human pulmonary macrophages, are highly effective against pneumonia caused by this organism.
Many antimicrobials undergo some degree of metabolism once ingested. Metabolism may occur via hepatic, renal, or nonorgan-specific enzymatic processes. The route of elimination of the metabolic pathway may be exploited for infections associated with tissues related to the metabolic pathways. For example, many fluoroquinolone antimicrobials are metabolized only in part and undergo renal elimination. Urinary concentrations of active drug are many times those achieved in the systemic circulation, making several of these agents good choices for UTIs.
Pharmacodynamics describes the relationship between drug exposure and pharmacologic effect of antibacterial activity or human toxicology. Antimicrobials generally are categorized based on their concentration-related effects on bacteria. Concentration-dependent pharmacodynamic activity occurs where higher drug concentrations are associated with greater rates and extents of bacterial killing. Concentration-dependent antimicrobial activity is maximized when peak antimicrobial concentrations are high. In contrast, concentration-independent (or time-dependent) activity refers to a minim al increase in the rate or extent of bacterial killing with an increase in antimicrobial dose. Concentration-independent antimicrobial activity is maximized when these antimicrobials are dosed to maintain blood and/or tissue concentrations above the MIC in a time-dependent manner. Fluoroquinolones, aminoglycosides, and metronidazole are examples of antimicrobials that exhibit concentration-dependent activity, whereas P-lactam and glycopeptide antimicrobials exhibit concentration-independent activity. Pharmacodynamic properties have been optimized to develop new dosing strategies for older antimicrobials. Examples include single-daily-dose aminoglycoside or P-lactam therapy administered by continuous infusion. The product labeling for many new antimicrobials takes pharmacodynamic properties into account.
Antimicrobials also can be classified as possessing bactericidal or bacteriostatic activity in vitro. Bactericidal antibiotics generally kill at least 99.9% (3 log reduction) of a bacterial population, whereas bacteriostatic antibiotics possess antimicrobial activity but reduce bacterial load by less than 3 logs. Clinically, bactericidal antibiotics may be necessary to achieve success in infections such as endocarditis or meningitis. A full discussion of the application of antimicrobial pharmacodynamics is beyond the scope of this chapter, but excellent sources of information are available.15
A major concern when selecting antimicrobial regimens should be the propensity for the regimen to cause adverse effects and the potential for interaction with other drugs. Patients may possess characteristics or risk factors that increase their likelihood of developing an adverse event, emphasizing the need to obtain a good patient medical history. In general, if several different antimicrobial options are available, antimicrobials with a low propensity to cause specific adverse events should be selected, particularly for patients with risk factors for a particular complication. Risk factors for adverse events may include the coadministration of other drugs that are associated with a similar type of adverse event. For example, coadministration of the known nephrotoxin gentamicin with vancomycin increases the risk for nephrotoxicity compared with administration of either drug alone.16 Other drug interactions may predispose the patient to dose-related toxicity through inhibition of drug metabolism. For example, erythromycin has the potential to prolong cardiac QT intervals in a dose-dependent manner, potentially increasing the risk for sudden cardiac death. A cohort study of patients taking oral erythromycin found that patients with concomitantly prescribed medications that inhibited the metabolism of erythromycin exhibited a fivefold increase in cardiac death versus controls.17
A final consideration in selecting antimicrobial therapy relates to cost. It is important to remember that the most inexpensive antimicrobial is not necessarily the most cost-effective antimicrobial. Antimicrobial costs constitute a relatively small portion of the overall cost of care. Frequently, regulatory studies are not designed to identify differences in hospital length of stay, less common adverse events, monitoring costs, collateral damage, or antimicrobial-specific resistance issues, all of which may contribute to medical costs. Careful consideration of antimicrobial microbiologic, pharmacolo-gic, and patient-related factors such as compliance and a variety of clinical outcomes is necessary to establish the cost versus benefit of an antimicrobial in a given patient. If there is no difference or a small difference in these factors, the least costly antimicrobial may be the best choice.
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