Gram-negative combination therapy at The Nebraska Medical Center Background:
Therapy for infections where resistant Gram-negative pathogens such as Pseudomonas aeruginosa are a possibility usually includes a broad-spectrum beta-lactam such as piperacillin/tazobactam, cefepime, or meropenem. The addition of a second antimicrobial agent can expand the empiric coverage for resistant Gram-negative pathogens. This combination therapy has been advocated by international consensus guidelines in critically ill patients in severe sepsis or septic shock given delays to active therapy in this population has been associated with an increased mortality.1,2 Despite the clear mortality benefit of initially active therapy in critically ill patients, combination therapy remains controversial.3-5 Therefore, the addition of a second agent should be based on patient severity of illness, the likelihood of isolating resistant Gram-negative pathogens, and the potential adverse effects of additional therapy. The choice of agent (fluoroquinolone or aminoglycoside) to expand Gram-negative coverage can be based on a combination antibiogram (figure 1). This combination antibiogram was developed to determine what antimicrobial combinations would provide the greatest empiric activity against Gram-negative pathogens that are resistant to a beta-lactam.
Fig. 1: Susceptibility of Gram-negative Pathogens Resistant to Broad-spectrum Beta-lactams in TNMC ICUs
(800C, 850C, AICU) July 2008 July 2011
Refer to current annual unit-specific antibiogram to determine susceptibility rates for single agents.
Gram-negative combination therapy at The Nebraska Medical Center Summary of findings:
1. Empirically, the addition of ciprofloxacin or other fluoroquinolone to a beta-lactam such as piperacillin/tazobactam does not contribute significantly to the spectrum of Gram-negative activity of the regimen.
a. At TNMC, if a Pseudomonas aeruginosa is resistant to piperacillin/tazobactam, ciprofloxacin will be active only 28% of the time. The lack of additional activity of ciprofloxacin is also demonstrated in resistant enteric pathogens such as E. coli and Klebsiella oxytoca.
2. For empiric P. aeruginosa coverage in critically ill patients, the addition of tobramycin to a beta-lactam provides the most additional activity.
a. Tobramycin has an 88% chance of covering a piperacillin/tazobactam-resistant P. aeruginosa
3. For empiric coverage of enteric pathogens such as E. coli, the addition of an aminoglycoside (specifically gentamicin or amikacin) to a beta-lactam provides the most additional activity in critically ill patients.
a. Amikacin has a 92% chance of covering piperacillin/tazobactam-resistant E. coli. Gentamicin has a 71% chance of covering piperacillin/tazobactam-resistant E. coli. However, amikacin is frequently on drug shortage and may be unavailable; thus gentamicin is generally recommended.
4. Most patients do not require empiric combination Gram-negative therapy. The decision to use combination therapy to expand the empiric coverage for resistant Gram-negative pathogens should be based on patient severity of illness, the likelihood of isolating resistant Gram-negative pathogens, and potential for additional drug toxicity.
a. Aminoglycosides are associated with reversible nephrotoxicity that is rare in courses of therapy lasting
Gram-negative combination therapy at The Nebraska Medical Center References: 1. Dellinger RP, Levy MM, Carlet JM, et al. Surviving Sepsis Campaign: international guidelines for management of severe sepsis and septic shock: 2008. Crit Care Med. 2008 Jan;36(1):296-327. 2. Kumar A, Ellis P, Arabi Y, et al: Initiation of inappropriate antimicrobial therapy results in a five-fold reduction of survival in human septic shock. Chest 2009; 136:12371248 3. Boyd N, Nailor MD. Combination antibiotic therapy for empiric and definitive treatment of gram-negative infections: insights from the Society of Infectious Diseases Pharmacists. Pharmacotherapy. 2011 Nov;31(11):1073-84. 4. Johnson SJ, Ernst EJ, Moores KG. Is double coverage of gram-negative organisms necessary? Am J Health Syst Pharm. 2011 Jan 15;68(2):119-24. 5. Kumar A, and the Cooperative Antimicrobial Therapy of Septic Shock (CATSS) Database Research Group. Early combination antibiotic therapy yields improved survival compared with monotherapy in septic shock: a propensity-matched analysis. Crit Care Med. 2010 Sep;38(9):1773-85.