Combination beta-lactamase inhibitors, carbapenems, and monobactams
- Stephen B Calderwood, MD
Stephen B Calderwood, MD
- Editor-in-Chief — Infectious Diseases
- Section Editor — Bacterial Infections
- Professor of Medicine (Microbiology and Immunobiology)
- Harvard Medical School
The spectrum of activity and pharmacology of combination beta-lactamase inhibitors, carbapenems, and monobactams will be reviewed here. The mechanisms of action and resistance and major adverse reactions of the beta-lactam antibiotics, issues related to penicillins and cephalosporins are discussed separately. (See "Beta-lactam antibiotics: Mechanisms of action and resistance and adverse effects" and "Penicillins" and "Cephalosporins".)
BETA-LACTAMASE INHIBITOR COMBINATIONS
Clavulanate, sulbactam, tazobactam, and avibactam are beta-lactamase inhibitors that have little intrinsic antibacterial activity but inhibit the activity of a number of plasmid-mediated beta-lactamases . They generally do not inhibit chromosomally mediated beta-lactamases . Combination of these agents with ampicillin, amoxicillin, ticarcillin, piperacillin, ceftolozane, and ceftazidime results in antibiotics with an enhanced spectrum of activity against many, but not all, organisms containing plasmid-mediated beta-lactamases. In addition, these compounds inhibit the chromosomal beta-lactamase of many Bacteroides species, extending the spectrum of coverage for these organisms as well.
Dosing of combination beta-lactam beta-lactamase inhibitors is listed separately (table 1), and the dosing should be modified in the setting of renal failure (table 2). For piperacillin-tazobactam, an extended infusion (eg, 3.375 g infused over four hours every eight hours) is an alternative to standard dosing; in particular, this strategy has been used for critically ill patients or for pathogens with elevated but susceptible minimum inhibitory concentrations. The benefits of extended infusion over standard dosing have been suggested by some studies but not all [3,4]. Overall, this dosing regimen is at least equivalent and may be superior to standard dosing in appropriate patient populations. (See "Prolonged infusions of beta-lactam antibiotics".)
Amoxicillin-clavulanate — Amoxicillin-clavulanate will inhibit most strains of oxacillin-sensitive Staphylococcus aureus and beta-lactamase producing Haemophilus influenzae in addition to the usual organisms inhibited by amoxicillin alone (see "Penicillins"). At the high drug concentrations achieved in urine, the combination is also active against certain beta-lactamase producing Enterobacteriaceae. Amoxicillin-clavulanate (250 to 500 mg PO Q 8h or 875 mg PO Q12h) can be used as oral therapy for patients with otitis media, sinusitis, lower respiratory infections, bite wounds, and urinary tract infections , although there are no data that this combination is superior to other antibiotics (such as trimethoprim-sulfamethoxazole or the second or third generation oral cephalosporins). (See "Soft tissue infections due to dog and cat bites".)
Ampicilin-sulbactam — Ampicillin-sulbactam is a parenteral formulation that expands the spectrum of ampicillin to include most strains of S. aureus and beta-lactamase producing H. influenzae, some Enterobacteriaceae, and anaerobes (including Bacteroides fragilis). The sulbactam component of ampicillin-sulbactam has activity against many strains of Acinetobacter baumannii. Ampicillin-sulbactam has been used to treat patients with diabetic foot ulcers . This combination has also been used for prophylaxis and therapy of intraabdominal and pelvic infections instead of cefoxitin. Randomized, double-blind trials showed ampicillin-sulbactam to be equivalent to cefoxitin in prophylaxis for abdominal surgery and in the treatment of intraabdominal and pelvic infections [7,8]. However, increasing resistance worldwide to ampicillin-sulbactam of both Enterobacteriaceae and Bacteroides fragilis in intra-abdominal infections renders this drug combination less useful for this purpose [9-11].
- Bush LM, Johnson CC. Ureidopenicillins and beta-lactam/beta-lactamase inhibitor combinations. Infect Dis Clin North Am 2000; 14:409.
- Sensakovic JW, Smith LG. Beta-lactamase inhibitor combinations. Med Clin North Am 1995; 79:695.
- Lodise TP Jr, Lomaestro B, Drusano GL. Piperacillin-tazobactam for Pseudomonas aeruginosa infection: clinical implications of an extended-infusion dosing strategy. Clin Infect Dis 2007; 44:357.
- Falagas ME, Tansarli GS, Ikawa K, Vardakas KZ. Clinical outcomes with extended or continuous versus short-term intravenous infusion of carbapenems and piperacillin/tazobactam: a systematic review and meta-analysis. Clin Infect Dis 2013; 56:272.
- Calver AD, Walsh NS, Quinn PF, et al. Dosing of amoxicillin/clavulanate given every 12 hours is as effective as dosing every 8 hours for treatment of lower respiratory tract infection. Lower Respiratory Tract Infection Collaborative Study Group. Clin Infect Dis 1997; 24:570.
- McKinnon PS, Paladino JA, Grayson ML, et al. Cost-effectiveness of ampicillin/sulbactam versus imipenem/cilastatin in the treatment of limb-threatening foot infections in diabetic patients. Clin Infect Dis 1997; 24:57.
- Messick CR, Mamdani M, McNicholl IR, et al. Pharmacoeconomic analysis of ampicillin-sulbactam versus cefoxitin in the treatment of intraabdominal infections. Pharmacotherapy 1998; 18:175.
- Paladino JA, Rainstein MA, Serrianne DJ, et al. Ampicillin-sulbactam versus cefoxitin for prophylaxis in high-risk patients undergoing abdominal surgery. Pharmacotherapy 1994; 14:734.
- Liu CY, Huang YT, Liao CH, et al. Increasing trends in antimicrobial resistance among clinically important anaerobes and Bacteroides fragilis isolates causing nosocomial infections: emerging resistance to carbapenems. Antimicrob Agents Chemother 2008; 52:3161.
- Hoban DJ, Bouchillon SK, Hawser SP, et al. Susceptibility of gram-negative pathogens isolated from patients with complicated intra-abdominal infections in the United States, 2007-2008: results of the Study for Monitoring Antimicrobial Resistance Trends (SMART). Antimicrob Agents Chemother 2010; 54:3031.
- Hsueh PR, Badal RE, Hawser SP, et al. Epidemiology and antimicrobial susceptibility profiles of aerobic and facultative Gram-negative bacilli isolated from patients with intra-abdominal infections in the Asia-Pacific region: 2008 results from SMART (Study for Monitoring Antimicrobial Resistance Trends). Int J Antimicrob Agents 2010; 36:408.
- Sanders WE Jr, Sanders CC. Piperacillin/tazobactam: a critical review of the evolving clinical literature. Clin Infect Dis 1996; 22:107.
- Zerbaxa (ceftolozane/tazobactam). US FDA approved product information. National Library of Medicine. www.dailymed.nlm.nih.gov (Accessed on January 08, 2015).
- Popejoy M, Cloutier D, Huntington J, et al. Ceftolozane/tazobactam for the treatment of cUTI and cIAI caused by ESBL-producing Enterobacteriaceae. Presented at IDWeek 2014, Philadelphia, PA, October 9, 2014. Abstract #260.
- Wagenlehner FM, Umeh O, Steenbergen J, et al. Ceftolozane-tazobactam compared with levofloxacin in the treatment of complicated urinary-tract infections, including pyelonephritis: a randomised, double-blind, phase 3 trial (ASPECT-cUTI). Lancet 2015; 385:1949.
- Solomkin J, Hershberger E, Miller B, et al. Ceftolozane/Tazobactam Plus Metronidazole for Complicated Intra-abdominal Infections in an Era of Multidrug Resistance: Results From a Randomized, Double-Blind, Phase 3 Trial (ASPECT-cIAI). Clin Infect Dis 2015; 60:1462.
- Zhanel GG, Lawson CD, Adam H, et al. Ceftazidime-avibactam: a novel cephalosporin/β-lactamase inhibitor combination. Drugs 2013; 73:159.
- Mazuski JE, Gasink LB, Armstrong J, et al. Efficacy and Safety of Ceftazidime-Avibactam Plus Metronidazole Versus Meropenem in the Treatment of Complicated Intra-abdominal Infection: Results From a Randomized, Controlled, Double-Blind, Phase 3 Program. Clin Infect Dis 2016; 62:1380.
- Vazquez JA, González Patzán LD, Stricklin D, et al. Efficacy and safety of ceftazidime-avibactam versus imipenem-cilastatin in the treatment of complicated urinary tract infections, including acute pyelonephritis, in hospitalized adults: results of a prospective, investigator-blinded, randomized study. Curr Med Res Opin 2012; 28:1921.
- Carmeli Y, Armstrong J, Laud PJ, et al. Ceftazidime-avibactam or best available therapy in patients with ceftazidime-resistant Enterobacteriaceae and Pseudomonas aeruginosa complicated urinary tract infections or complicated intra-abdominal infections (REPRISE): a randomised, pathogen-directed, phase 3 study. Lancet Infect Dis 2016; 16:661.
- Norrby SR. Carbapenems. Med Clin North Am 1995; 79:745.
- Asbel LE, Levison ME. Cephalosporins, carbapenems, and monobactams. Infect Dis Clin North Am 2000; 14:435.
- Huang H, Hancock RE. Genetic definition of the substrate selectivity of outer membrane porin protein OprD of Pseudomonas aeruginosa. J Bacteriol 1993; 175:7793.
- Calandra G, Lydick E, Carrigan J, et al. Factors predisposing to seizures in seriously ill infected patients receiving antibiotics: experience with imipenem/cilastatin. Am J Med 1988; 84:911.
- Cannon JP, Lee TA, Clark NM, et al. The risk of seizures among the carbapenems: a meta-analysis. J Antimicrob Chemother 2014; 69:2043.
- Cox CE, Holloway WJ, Geckler RW. A multicenter comparative study of meropenem and imipenem/cilastatin in the treatment of complicated urinary tract infections in hospitalized patients. Clin Infect Dis 1995; 21:86.
- Condon RE, Walker AP, Sirinek KR, et al. Meropenem versus tobramycin plus clindamycin for treatment of intraabdominal infections: results of a prospective, randomized, double-blind clinical trial. Clin Infect Dis 1995; 21:544.
- Chang DC, Wilson SE. Meta-analysis of the clinical outcome of carbapenem monotherapy in the adjunctive treatment of intra-abdominal infections. Am J Surg 1997; 174:284.
- Naber KG, Llorens L, Kaniga K, et al. Intravenous doripenem at 500 milligrams versus levofloxacin at 250 milligrams, with an option to switch to oral therapy, for treatment of complicated lower urinary tract infection and pyelonephritis. Antimicrob Agents Chemother 2009; 53:3782.
- Lucasti C, Jasovich A, Umeh O, et al. Efficacy and tolerability of IV doripenem versus meropenem in adults with complicated intra-abdominal infection: a phase III, prospective, multicenter, randomized, double-blind, noninferiority study. Clin Ther 2008; 30:868.
- Zhanel GG, Wiebe R, Dilay L, et al. Comparative review of the carbapenems. Drugs 2007; 67:1027.
- Paterson DL, Depestel DD. Doripenem. Clin Infect Dis 2009; 49:291.
- US Food and Drug Administration. FDA approves label changes for antibacterial Doribax (doripenem) describing increased risk of death for ventilator patients with pneumonia. http://www.fda.gov/Drugs/DrugSafety/ucm387971.htm (Accessed on March 10, 2014).
- Kollef MH, Chastre J, Clavel M, et al. A randomized trial of 7-day doripenem versus 10-day imipenem-cilastatin for ventilator-associated pneumonia. Crit Care 2012; 16:R218.
- Johnson DH, Cunha BA. Aztreonam. Med Clin North Am 1995; 79:733.
- Kishiyama JL, Adelman DC. The cross-reactivity and immunology of beta-lactam antibiotics. Drug Saf 1994; 10:318.