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Year : 2014  |  Volume : 8  |  Issue : 1  |  Page : 1-3

Treating infections caused by carbapenemase producing Gram-negative bacteria

Department of Medical Microbiology, Ahmadu Bello University Teaching Hospital, Shika, Zaria, Kaduna State, Nigeria

Date of Web Publication18-Sep-2014

Correspondence Address:
Shamsudin Aliyu
Department of Medical Microbiology, Ahmadu Bello University Teaching Hospital, Shika, Zaria, Kaduna State
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Source of Support: None, Conflict of Interest: None

DOI: 10.4103/0331-3131.141020

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How to cite this article:
Aliyu S. Treating infections caused by carbapenemase producing Gram-negative bacteria. Ann Nigerian Med 2014;8:1-3

How to cite this URL:
Aliyu S. Treating infections caused by carbapenemase producing Gram-negative bacteria. Ann Nigerian Med [serial online] 2014 [cited 2021 Apr 18];8:1-3. Available from: https://www.anmjournal.com/text.asp?2014/8/1/1/141020

The global medical community is today facing a serious challenge in the treatment of infections caused by the global spread of carbapenemase producing Gram-negatives (CPGNs). Infections caused by multidrug-resistant bacteria increase mortality, treatment costs, disease spread, and duration of illness. [1] This challenge is even greater in Africa, due to poor implementation of antibiotic steward programs, nonavailability of newer antimicrobial agents, and the scourge of fake and substandard drugs. Hence, there is a need to ensure that clinicians have the necessary basic understanding of treatment modalities, and the challenges associated with managing infections caused by CPGNs bacteria.

   Antimicrobial Treatment Top

Antimicrobial agents are crucial in the management of CPGN infections. One of the challenges faced when managing these infections, is associated with the fact that CPGNs show widespread resistance to carbapenems, penicillins, and cephalosporins, as well as resistance to most of the commonly used antibiotics, such as aminoglycosides and quinolones. [2] Clinical infections associated with these multidrug-resistant bacteria are usually healthcare associated, and include bacteremia, ventilator-associated pneumonia, urinary tract, and surgical site infections.

Another challenge associated with managing these infections is the fact that even at present, optimal treatment guidelines are not well-established because experience on antibacterial treatment of CPGN infections and clinical outcomes are based on a limited number of patients, and evidence from low to medium grade studies. [3]

Detection of CPGN is another challenge faced in the management of these infections. This is because there are varying types of carbapenemases, which are found on many different organisms. [4],[5] The consequence of this is that different laboratory methods are required to detect all the different types of enzymes.

Despite these limitations, it is crucial that the results of antimicrobial susceptibility tests and site of infections be considered in the selection of the right antimicrobial agent.

   Antibiotic Options Top

Limited antibiotic options are available for the treatments of infection caused by CPGNs. Below are some of the commonly used antimicrobial agents used as monotherapy or in combination therapy.


It is a glycylcycline, bacteriostatic, and has good susceptibility profile in vitro. [6] There is, however, limited experience in the use of tigecycline in the management of CPGN infections. Primary bloodstream infections and urinary tract infections, however, present a challenge for the use of tigecycline in CPGN infections. [7] Currently, available only as a parenteral agent.


This polymyxin antibiotic is a cationic polypeptide that acts by disrupting bacterial membrane function. It is very active against carbapenemase producing Acinetobacter baumannii and Pseudomonas aeruginosa. Currently available as oral and parenteral formulations.


Fosfomycin which is a naturally occurring phosphonic acid derivative acts by inhibiting cell wall biosynthesis at an earlier stage than β-lactam antibiotics. It is administered both orally and parenterally. Fosfomycin displays good in vitro activity against CPGN. [8] The potential for emergence of resistance during therapy has resulted in it being considered as the last resort in the treatment of CPGN infections. [9]

   Monotherapy Versus Combination Therapy Top

Combination therapy using several classes of antibiotics for the treatment of CPGN infections has been shown to be associated with greater success, as well as delayed development of resistance. [10] Synergistic action between rifampicin and either colistin or a carbarpenem (imipenem, meropenem, doripenem) has been documented. [11] In a multicenter study conducted among 125 patients with bloodstream infections caused by Klebsiella pneumoniae carbapenemases-producing Klebsiella pneumoniae, the mortality rate was significantly higher in the monotherapy group (54% vs. 34%) than in combination therapy group. Combination of tigecycline, coilistin, and meropenem was found to be associated with decreased risk of death on multivariate analysis. [12]

Tzouvelekis et al. also concluded after a review of 20 clinical studies that treatment with a single in vitro active agent resulted in mortality rates not significantly different from that observed in patients treated with no active therapy, whereas combination therapy with two or more in vitro active agents was superior to monotherapy (mortality rate, 27.4% vs. 38.7%; P < 0.001). Interestingly, they also observed that the lowest mortality rate (18.8%) were in patients treated with carbapenem-containing combinations. [13] In 2013, an International Working group came up with recommendations for the antimicrobial treatment of infections caused by Carbapenamase Producing Enterobacteriaceae. Summary of the recommendations of this International Working Group are listed in [Table 1]. [3]
Table 1: Antimicrobial treatment of infections causes by CPE:
Summary of recommendations by the International Working

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   Newer Antimicrobial Agents Top

There are other promising agents for use in treating CPGN infections under development such as newer carbapenem compounds like topopenem, [14] antibiotics in other classes such as plazomicin, eravacycline; as well as carbapenemase inhibitors. [15]

   Conclusion Top

Carbapenemase producing Gram-negative bacteria have spread worldwide, causing serious infections with increasing frequency. These bacteria are usually multidrug resistant, and this complicates therapy and limits treatment options. Prompt and adequate treatment is crucial; the management of these serious and life-threatening infections; and treatment decisions should be guided by reliable antimicrobial susceptibility test results. The development of newer antimicrobial agents will be required to turn the tide in favor of the clinician and his patients, in this battle between man and CPGN bacteria.

   References Top

1.Laxminarayan R, editor. Battling Resistance to Antibiotics and Pesticides: An Economic Approach. Washington D.C.: RFF Press; 2003.  Back to cited text no. 1
2.Carmeli Y, Akova M, Cornaglia G, Daikos GL, Garau J, Harbarth S, et al. Controlling the spread of carbapenemase-producing Gram-negatives: Therapeutic approach and infection control. Clin Microbiol Infect 2010;16:102-11.  Back to cited text no. 2
3.Levy Hara G, Gould I, Endimiani A, Pardo PR, Daikos G, Hsueh PR, et al. Detection, treatment, and prevention of carbapenemase-producing Enterobacteriaceae: Recommendations from an International Working Group. J Chemother 2013;25:129-40.  Back to cited text no. 3
4.Nordmann P, Naas T, Poirel L. Global spread of carbapenemase-producing Enterobacteriaceae. Emerg Infect Dis 2011;17:1791-8.  Back to cited text no. 4
5.Hirsch EB, Tam VH. Detection and treatment options for Klebsiella pneumoniae carbapenemases (KPCs): An emerging cause of multidrug-resistant infection. J Antimicrob Chemother 2010;65:1119-25.  Back to cited text no. 5
6.Castanheira M, Sader HS, Deshpande LM, Fritsche TR, Jones RN. Antimicrobial activities of tigecycline and other broad-spectrum antimicrobials tested against serine carbapenemase- and metallo-beta-lactamase-producing Enterobacteriaceae: Report from the SENTRY Antimicrobial Surveillance Program. Antimicrob Agents Chemother 2008;52:570-3.  Back to cited text no. 6
7.Falagas ME, Karageorgopoulos DE, Dimopoulos G. Clinical significance of the pharmacokinetic and pharmacodynamic characteristics of tigecycline. Curr Drug Metab 2009;10:13-21.  Back to cited text no. 7
8.Popovic M, Steinort D, Pillai S, Joukhadar C. Antimicrobial susceptibility of gram negative non urinary bacteria to fosfomycin and other antimicrobials. Future Microbiol 2010;5:961-70.  Back to cited text no. 8
9.Karageorgopoulos DE, Miriagou V, Tzouvelekis LS, Spyridopoulou K, Daikos GL. Emergence of resistance to fosfomycin used as adjunct therapy in KPC Klebsiella pneumoniae bacteraemia: Report of three cases. J Antimicrob Chemother 2012;67:2777-9.  Back to cited text no. 9
10.Rahal JJ, Urban C, Segal-Maurer S. Nosocomial antibiotic resistance in multiple gram-negative species: Experience at one hospital with squeezing the resistance balloon at multiple sites. Clin Infect Dis 2002;34:499-503.  Back to cited text no. 10
11.Tripodi MF, Durante-Mangoni E, Fortunato R, Utili R, Zarrilli R. Comparative activities of colistin, rifampicin, imipenem and sulbactam/ampicillin alone or in combination against epidemic multidrug-resistant Acinetobacter baumannii isolates producing OXA-58 carbapenemases. Int J Antimicrob Agents 2007;30:537-40.  Back to cited text no. 11
12.Tumbarello M, Viale P, Viscoli C, Trecarichi EM, Tumietto F, Marchese A, et al. Predictors of mortality in bloodstream infections caused by Klebsiella pneumoniae carbapenemase-producing K. pneumoniae: Importance of combination therapy. Clin Infect Dis 2012;55:943-50.  Back to cited text no. 12
13.Tzouvelekis LS, Markogiannakis A, Piperaki E, Souli M, Daikos GL. Treating infections caused by carbapenemase-producing Enterobacteriaceae. Clin Microbiol Infect 2014.  Back to cited text no. 13
14.Koga T, Sugihara C, Kakuta M, Masuda N, Namba E, Fukuoka T. Affinity of Tomopenem (CS-023) for penicillin-binding proteins in Staphylococcus aureus, Escherichia coli, and Pseudomonas aeruginosa. Antimicrob Agents Chemother 2009;53:1238-41.  Back to cited text no. 14
15.Karaiskos I, Giamarellou H. Multidrug-resistant and extensively drug-resistant gram-negative pathogens: Current and emerging therapeutic approaches. Expert Opin Pharmacother 2014;15:1351-70.  Back to cited text no. 15


  [Table 1]


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