INTRODUCTION

Antimicrobials are among the most common with most important drugs prescribed for the critical care patient (CCP).¹ Timely, effective antimicrobial therapy is a crucial determinant of outcome in the CCP²; however, the advent of antimicrobial resistance has profoundly altered its use. The goal of antimicrobial therapy includes the safe eradication of infection while minimizing the advent of resistance.

The CCP is particularly at risk for infections with antimicrobial resistant bacteria. The risk of infection increases because of bacterial translocation from the gastrointestinal (GI) tract, the use of invasive procedures, and foreign surfaces conducive to bacterial colonization (e.g., catheters). Patients are often immunocompromised. Cardiovascular, renal, and hepatic dysfunction or responses alter all aspects of drug disposition, increasing the risk of either adverse drug events or therapeutic failure. Polypharmacy, or the use of multiple medications in an individual patient, increases the risk of adverse drug events and drug interactions. Finally, the sense of urgency accompanying therapeutic decision making generally leads to empiric antimicrobial use.

The principles guiding antimicrobial therapy are regularly reviewed.³ This chapter summarizes those principles, with a focus on their relevance to the CCP. Included is a description of antimicrobial resistance, including factors predisposing to its emergence, methods by which resistance might be avoided, and then a step-wise decision path that might be implemented as antimicrobial therapy is considered in the CCP. The Infectious Diseases Society of America (http://www.idsociety.org) offers guidelines for the use of antimicrobial agents, many of which are specific to conditions characterized as critical. These guidelines are reassessed and modified on a cyclical basis.

ANTIMICROBIAL RESISTANCE

Reducing Environmental Microbial Resistance

ICUs have implemented a number of techniques intended to reduce antimicrobial resistance. Each proposed or implemented strategy has theoretic benefits and limitations, but good data on their efficacy in controlling antimicrobial resistance are limited.^18,19 Hospital strategies involve a multitiered approach.

Primary Prevention

Primary prevention is accomplished by decreasing length of hospital stays, using fewer invasive devices, and placement of catheters or invasive devices by individuals educated and trained in proper (aseptic) placement (chlorhexidine is the preferred antiseptic).

Improving Infection Control

Improving infection control includes using selective decontamination procedures, preventing horizontal transmission via handwashing, glove, and gown use, using effective alternatives to soap, and improving the workload of and facilities for health care workers. New approaches include innovative catheter designs, including silver or antimicrobial impregnation. Overcrowding in the ward should be prevented. The importance of hand cleansing between patient contacts as a means to prevent transmission of infections cannot be overemphasized. Soap and water should be used first in the presence of soiling, and alcohol hand rubs can be used if soiling is not present.⁶ Selective GI decontamination to prevent antimicrobial infection is controversial.⁶ Strategies that decrease patient exposure to antimicrobial agents are preferred to decontamination.

Education

Education of hospital personnel, including staff and clinicians concerning the existence, causes, and need for reduction of antimicrobial resistance is imperative.⁶

Changing Antimicrobial Prescribing Behaviors

Antimicrobial drug prescribing behaviors are the most significant mechanism by which bacterial resistance is likely to be reduced in the critical care environment.²⁰ Protocols should be designed and subsequently implemented with the intent to deescalate antimicrobial use. Deescalation is among the more rational paradigms for empiric antimicrobial use in hospitalized patients with serious bacterial infections.²⁰ The goal of deescalation is to prescribe an initial antibacterial regimen that will cover the most likely bacterial pathogens associated with infection, thus balancing the need for appropriate therapy, while minimizing the risk of emerging antibacterial resistance.²⁰ The three-pronged approach includes narrowing the antibacterial regimen through culture, assessing the susceptibility for dosage determination, and choosing the shortest course of therapy clinically acceptable.

Although preapproval of selected drug use (e.g., by a committee) and antibiotic restriction practices may be useful, recommended and more reasonable deescalation procedures include rotating the use of antimicrobial drugs on a regular schedule, and designing the dosing regimen such that therapeutic success is maximized, resistance is minimized, and duration of therapy can be reduced.¹⁸ Deescalation procedures in humans have been associated with a return to susceptibility for ceftazidime, piperacillin, imipenem, and fluoroquinolones.

The risk of antimicrobial resistance is associated with both dose and duration of therapy. Basing drug selection on culture and susceptibility information, with accompanying minimum inhibitory concentration (MIC) data, is critical both to identify current bacterial resistance in patients at risk and to best design an individual patient dosing regimen. Approaches to dosage adjustment are discussed next. However, increasingly in human medicine, dosages are being based on the mutant prevention concentration (MPC) rather than the MIC.⁵

The MPC is defined as the highest MIC identified in a patient population of susceptible isolates (≥10⁷) of an organism, thus including those CFUs or isolates that have undergone the first-step mutation. The MIC obtained from culture and susceptibility testing most likely reflects the majority of CFUs causing infection in the patient. However, the MIC is less likely to reflect those CFUs that already have undergone the first-step mutation (i.e., are characterized by higher MIC). Should drug therapy target the MIC, competing isolates will be inhibited or killed, allowing the mutants to emerge. In healthy patients, this population can probably be controlled by host defenses. However, in less capable patients, the new emergent population will be characterized by a higher MIC that is potentially unattainable with a safe dosing regimen.

Unfortunately, determining the MPC of an isolate cultured from a patient requires culture based on 10⁷ or more organisms; current techniques cannot achieve this large an inoculum. Experimentally, the ratio of MPC to MIC for various fluoroquinolones given for infection by human pathogens ranges from a low of 6 to 10 for E. coli but 23 to 50 (and as high as 125) for selected drugs given for infection by Staphylococcus aureus.

Rational combination antimicrobial therapy can be a powerful tool for enhancing efficacy while reducing resistance in the CCP. Combination therapy should be considered routinely for organisms often associated with MDR (e.g., P. aeruginosa, Enterococcus spp, and MRSA). Resistance to a combination of antimicrobial drugs should be anticipated when the population reaches 10¹⁴ or more CFUs. Drugs chosen for combination therapy should be selected rationally, based on target organisms. Mechanisms of action should complement, rather than antagonize, one another.²¹

In general, “bacteriostatic” drugs that inhibit ribosomes and thus microbial growth (e.g., chloramphenicol, tetracyclines, and erythromycin) should not be combined with drugs whose mechanism of action depends on protein synthesis, such as growth of the organism (e.g., β-lactams) or formation of a target protein. The bactericidal activity of β-lactams and fluoroquinolones depend on continued synthesis of bacterial proteins. Antagonistic effects have been well documented between β-lactam antimicrobials and inhibitors of ribosomal activity.²¹

Chemical antagonism is also possible among two or more antimicrobials; the prototypical example is chemical inactivation of aminoglycosides and quinolones by β-lactams. However, chemical antagonism is unlikely to occur at concentrations achieved systemically in the clinical patient. In contrast to antagonism, drugs that have the same mechanism of action may act in an additive or synergistic fashion. The prototypical example of synergism is the combination of β-lactams and aminoglycosides; aminoglycoside penetration is facilitated by penicillin-induced cell wall failure.²¹ Indeed, aminoglycoside activity against Enterococcus spp is adequate only when the agent is used synergistically with a cell wall–active antibiotic, such as a β-lactam or vancomycin. Synergism has also been demonstrated against some strains of Enterobacteriaceae, P. aeruginosa, staphylococci (including MRSA), and other microorganisms. Enhanced movement into the bacteria may occur with other drugs (e.g., potentiated sulfonamides, fluoroquinolones) when combined with a β-lactam.

Combination antimicrobial therapy may be selected for a polymicrobial infection. Aminoglycosides or fluoroquinolones are often combined with β-lactams, metronidazole, or clindamycin to target both aerobic gram-positive and gram-negative infections, or aerobic infections caused by both aerobes and anaerobes. The combined use of selected antibiotics may result in effective therapy against a given microbe, even when either drug alone would be ineffective.

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