Kent Emmanuel E.

Viquiera II- Medicine

Pharmacology

Antibiotics in the Intensive Care Unit: Focus on Agents for Resistant Pathogens By: David F. Volles, PharmD*, Trisha N. Branan, PharmD Key Points: Antibiotic resistance is increasing faster than the drug industry can develop and market new antibiotics. Gram-negative bacteria, like Pseudomonas, Acinetobacter, and ESBL producing strains of Klebsiella and E. coli. These pathogens are not just encountered in the ICU, but are spilling out into the rest of the hospital and even the community.

Clinicians should be familiar with treatment strategies for these resistant pathogens, due to the lack of novel agents to treat resistant infections. Clinicians must use antibiotics judiciously and appropriately to limit further development of resistance. when treating serious life-threatening infections. It is appropriate to cover very broadly (ie, gram-positive, gram-negative, anaerobes), initially using aggressive doses taking advantage of pharmacodynamic principles. Early, appropriate cultures of the blood, urine, sputum and suspected source, ideally obtained before antibiotic initiation, allow for future de-escalation of antibiotics, or the decision to discontinue antibiotics.

Antibiotics in the Intensive Care Unit: Focus on Agents for Resistant Pathogens David F. Volles, PharmD*, Trisha N. Branan, PharmD
General principles of antibiotic use in the ICU For most serious infections in the ICU, it is appropriate to start with very broad spectrum, aggressive therapy to ensure coverage for possible resistant pathogens, with a narrowing of antibiotic coverage when culture and susceptibility data are known. An accurate diagnosis is important when deciding on appropriate antimicrobial therapy, and the noninfectious possibilities should be eliminated to avoid unnecessary treatment with antibiotics. Knowledge of the site of infection helps predict the most likely pathogens that would need to be targeted with empiric treatment. An understanding of antibiotic penetration into various sites of infection is also crucial when considering difficult to treat infections such as meningitis, osteomyelitis, and endocarditis. On a national level, bacterial antimicrobial resistance continues to increase as MRSA rates are approximately 60% and Pseudomonas aeruginosa resistant to imipenem, third generation cephalosporins, and fluoroquinolones are 21%, 32%, and 30% respectively. There are wide regional variations in the incidence of each resistant pathogen and these epidemiologic factors must be considered when making decisions about empiric antibiotics. Clinicians should rely on updated institution specific information highlighting local antibiotic susceptibility and resistance patterns. Local outbreaks of resistant organisms alter the specific pathogens that may require coverage with empiric therapy. Specifically, ESBL producing strains of Escherichia coli and Klebsiella species, multidrug-resistant Pseudomonas aeruginosa and Acinetobacter baumannii, and the resistant gram positive organisms, MRSA and VRE, are the organisms causing great concern and may require empiric coverage depending on hospital specific or ICU specific antibiograms. Despite the need for broad spectrum coverage initially for empiric coverage, it is appropriate to de-escalate the antibiotic regimen based on culture and susceptibility reports, or even reasonable to discontinue antibiotics if an infectious process is no longer suspected. Timing issues are also important when treating infections in the critically ill. Decreasing the time it takes for patients to receive appropriate antibiotic therapy is important. Timely and appropriate antibiotic administration, within the first hour of hypotension, in septic shock patients improved survival by an estimated 79.9%. Every hour delay of antibiotic delivery after hypotension recognition during the first 6 hours resulted in a 7.9% increased mortality. Durations of antibiotic therapy should also be defined in an effort to limit antibiotic regimens to the shortest possible course to avoid unnecessary use, but for many infections, unfortunately, this is not adequately defined. Use of combination therapy, involving two agents from different classes to provide synergy or additive effects is often done for empiric treatment for serious infections and for select pathogens such as Pseudomonas aeruginosa, but combination therapy is a controversial topic. Most studies evaluating the benefit of combination therapy have not found any mortality or other benefits over monotherapy for gram-negative infections. One meta-analysis did identify a mortality benefit in a subgroup of patients with Pseudomonas, but not in patients with other gram-negative organisms. Combination therapy may be appropriate for empiric treatment of severe infections such as sepsis and ventilator-associated pneumonia if drug resistant strains are suspected. Despite not being associated with a mortality benefit, double

coverage may be employed initially to increase the chance of at least having one drug on board with activity against the offending pathogen. In many circumstances, it may be appropriate to initiate combination therapy, but to discontinue one of the agents after a 57 day course or even less time if drugresistant pathogens are not identified. Pharmacokinetic and pharmacodynamic principles must be taken into account when designing antimicrobial regimens as it has become increasingly clear that suboptimal antibiotic concentrations at the site of infection may contribute to increased microbial resistance and treatment failures. In general, antibiotics can be divided into drugs that possess concentration dependent killing of pathogens, which refers to faster eradication of bacteria pathogens with higher concentrations, and concentration- independent killing, referring to maximal efficacy associated with maintaining concentrations above the pathogens minimum inhibitory concentration. For drugs with concentrationdependent killing, such as aminoglycosides, colistin, and fluoroquinolones, maximal efficacy is associated with giving larger doses less frequently, but for many drugs the dose given is limited by toxicity and clinical experience. The efficacy for drugs that possess concentration-independent killing, such as penicillins, carbapenems, and cephalosporins, can be maximized by more frequent administration in an effort to keep the concentration above the MIC for at least 40%70% of the dosing interval. Due to rising MICs for common pathogens, many standard doses used for non-acute patients may be inadequate for these more resistant bacterial species encountered in the critically ill. It is often prudent to use the most aggressive tolerated dose until cultures and susceptibilities are known. Even in patients with renal insufficiency or failure, aggressive initial doses can be used for the first 24 hours and then adjusted accordingly based on organ function and patients clinical response. References [1] Eggimann P, Pittet D. Infection control in the ICU. Chest 2001;120(6):205993. [2] Weber DJ, Raasch R, Rutala WA. Nosocomial infections in the ICU. Chest 1999;15(3): 35s41s. [3] Jones ME, Draghi DC, Thornsberry C, et al. Emerging resistance among bacterial pathogens in the intensive care unit: a European and North American surveillance study (20002002). Ann Clin Microbiol Antimicrob 2004;3(14):111. [4] CDC NNIS System. National nosocomial infections surveillance (NNIS) system report data summary from January 1992 through June 2004, issued October 2004. Am J Infect Control 2004; 32:470 85. [5] Karam GH, Hener JE. Emerging issues in antibiotic resistance in blood-borne infections. Am J Respir Crit Care Med 2000;162:16106. [6] Esposito S, Leone S. Antimicrobial treatment for intensive care unit (ICU) infections including the role of the infectious disease specialist. Int J Antimicrob Agents 2007;29:494500. [7] Nicasio AM, Kuti JL, Nicolau DP. The current state of multidrug-resistant gram-negative bacilli in North America. Pharmacotherapy 2008;28(2):23549. [8] Alvarez-Lerma F. Modication of empiric antibiotic treatment in patients with pneumonia acquired in the intensive care unit. Intensive Care Med 1996;22:38794. [9] Kollef MH, Sherman G, Ward S, et al. Inadequate antimicrobial treatment of infections: a risk factor for hospital mortality among critically ill patients. Chest 1999;115:46274. [10] Ibrahim EH, Sherman G, Ward S, et al. The inuence of inadequate antimicrobial treatment of bloodstream infections on patient outcomes in the ICU setting. Chest 2000;118:14655.