Although meropenem is a broad spectrum antibiotic that covers many gram-negative and gram-positive organisms as well as anaerobes, its activity against enterococci is generally poor and leaves much to be desired.
In a study of ampicillin-sensitive E. faecalis isolates from hospitalized patients, only 36% of isolates were considered susceptible (MIC≤4 mg/L); activity against E. faecium isolates was similarly poor.1 Several other studies have reported the suboptimal activity of meropenem against both E. faecalis and E. faecium, 2-4 with susceptibility rates as low as 8.6% depending on the MIC break point used.3
A popular textbook and a handbook on infectious diseases also do not recommend the use of meropenem for treatment of enterococcal infections. 5,6
Of interest, the package insert states that meropenem is indicated for complicated skin and soft tissue infections due to a variety of organisms, including E. faecalis (vancomycin-susceptible isolates only), but not for complicated intra-abdominal infections or meningitis due this organism.7
In our patient with intraabdominal infection, we may consider piperacillin-tazobactam instead. Piperacillin-tazobactam is a broad spectrum antibiotic with excellent coverage against anaerobes and ampicillin-susceptible E. faecalis.1,8
- Endtz HP, van Dijk WC, Verbrugh HA, et al. Comparative in-vitro activity of meropenem against selected pathogens from hospitalized patients in the Netherlands. J Antimicrob Chemother 1997;39:149-56. https://www.ncbi.nlm.nih.gov/pubmed/9069534
- Pfaller MA, Jones RN. A review of the in vitro activity of meropenem and comparative antimicrobial agents tested against 30,254 aerobic and anaerobic pathogens isolated world wide. Diag Microbiol Infect Dis 1997;28:157-63. https://www.ncbi.nlm.nih.gov/pubmed/9327242
- Hallgren A, Abednazari H, Ekdahl C, et al. Antimicrobial susceptibility patterns of enterococci in intensive care units in Sweden evaluated by different MIC breakpoint systems. J Antimicrob Chemother 2001;48:53-62. https://www.ncbi.nlm.nih.gov/pubmed/11418512
- Hoban DJ, Jones RN, Yamane N, et al. In vitro activity of three carbapenem antibiotics comparative studies with biapenem (L-627), imipenem, and meropenem against aerobic pathogens isolated worldwide. Diag Microbiol Infect Dis 993;17:299-305.https://www.ncbi.nlm.nih.gov/pubmed/8112045
- Chambers HF. Carbapenem and monobactams. In Mandell GL et al. eds. Principles and practice of infectious diseases. 2010, pp 341-45.
- Cunha CB, Cunha BA. Antibiotic essentials. 2017, pp 689-91.
- Perry CM, Markham A. Piperacillin/tazobactam. Drugs 1999;57:805-43. https://link.springer.com/article/10.2165%2F00003495-199957050-00017
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The incidence of cefepime-induced neurotoxicity (CIN) has varied from 1% to 15%.1 Potential clinical manifestations of CIN include delirium, impaired level of consciousness, disorientation/agitation, myoclonus, non-convulsive status epilepticus, seizures, and aphasia.1 Many of these signs and symptoms (eg, delirium) are common among hospitalized patients.
Although renal dysfunction and inadequately adjusted dosages are often cited as risk factors, one-half of patients develop suspected CIN despite apparently proper adjustment for renal function.1 In addition, several case reports of CIN have involved patients with normal renal function. 2 A study of 1120 patients receiving cefepime found epileptiform discharges in 14 cases, most having normal renal function.3 Of interest, in the same study, the prevalence of epileptiform discharges was 6-fold higher than that of meropenem!
Proposed mechanisms for CIN include its avidity for central nervous system GABA-A receptors (higher than that of many beta-lactam antibiotics) combined with its high concentration in brain tissue.1 Renal impairment, decreased protein binding, and increased organic acid accumulation can increase transfer of cefepime across the blood brain barrier from an expected 10% to up to 45% of its serum concentration, further contributing to its neurotoxicity.4
- Appa AA, Jain R, Rakita RM, et al. Characterizing cefepime neurotoxicity: a systematic review. Open Forum Infectious Diseases 2017 Oct 10;4(4):ofx170. doi: 10.1093/ofid/ofx170. eCollection 2017 Fall. https://www.ncbi.nlm.nih.gov/pubmed/29071284
- Meillier A, Rahimian D. Cefepime-induced encephalopathy with normal renal function. Oxford Medical Case Reports, 2016;6, 118-120. https://academic.oup.com/omcr/article/2016/6/118/2362353
- Naeije G, Lorent S, Vincent JL, et al. Continuous epileptiform discharges in patients treated with cefpime or meropenem Arch Neurol 2011;68:1303-7. https://www.ncbi.nlm.nih.gov/pubmed/21987544
- Payne LE, Gaganon DJ, Riker RR, et al. Cefepime-induced neurotoxicity: a systematic review. Critical Care 017;21:276. https://www.ncbi.nlm.nih.gov/pubmed/29137682
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“SPICE” often stands for the following bacterial species: Serratia spp, Providencia spp, indole-positive Proteae (e.g. Proteus spp. [not mirabilis], Morganella spp., Providencia spp.), Citrobacter spp., and Enterobacter spp. Some have also included Pseudomonas spp (“P”).
These organisms (as well as Acinetobacter spp., at times “A” in SP”A”CE organisms) often have inducible chromosomal AmpC ß-lactamase genes that may be derepressed during therapy, conferring in vivo ß-lactam resistance despite apparent sensitivity in vitro (1,2). Because AmpC genes in clinical isolates are not routinely screened for in the laboratory, the following treatment approach to these organisms is often adopted (1).
Third generation cephalosporins (e.g. ceftriaxone and ceftazidime) are usually avoided irrespective of in vitro susceptibility. For less serious infections (e.g. urinary tract infections) or severe infections in carefully monitored clinically stable patients, piperacillin-tazobactam and cefepime in particular may be used due to their lower risk of induced resistance. For severe infections (e.g. pneumonia and bacteremia) in seriously ill patients, carbapenems (e.g. meropenem, imipenem-cilastatin) are often the drugs of choice.
A small retrospective study of patients with infection due to SPICE organisms (about 50% with bacteremia) found cefepime to be as effective as meropenem, but cautioned its use when adequate source control has not been achieved (3). Fluroroquinolones and aminoglycosides may also be considered.
- MacDougall C. Beyond susceptible and resistant, part I: treatment of infections due to Gram-negative organisms with inducible ß-lactamases. J Pediatr Pharmacol Ther 2011;16:23-30. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3136230/
- Jacoby GA. AmpC ß-lactamases. Clin Microbiol Rev 2009;22:161-182. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2620637/
- Tamma PD, Girdwood SCT, Gopaul R, et al. The use of cefepime for treating AmpC ß-lactamase-producing Enterobacteriaceae. Clin Infect Dis 2013;57:781-8. https://academic.oup.com/cid/article/57/6/781/330020
Contributed in part by Avi Geller, Medical Student, Harvard Medical School, Boston, MA
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