Indian Journal of Medical Microbiology Medknow Publications on behalf of Indian Association of Medical Microbiology ISSN: 0255-0857 EISSN: 1998-3646 Vol. 29, Num. 3, 2011, pp. 315-316

Indian Journal of Medical Microbiology, Vol. 29, No. 3, July-September, 2011, pp. 315-316

Correspondence

Newer β-lactam and β-lactamase inhibitor combinations available in India: Consensus and controversies

B Veeraraghavan

Department of Clinical Microbiology, Christian Medical College, Vellore, Tamil Nadu - 632 004, India
Correspondence Address: B Veeraraghavan, Department of Clinical Microbiology, Christian Medical College, Vellore, Tamil Nadu - 632 004, India, vbalaji@cmcvellore.ac.in

Date of Submission: 01-Apr-2009 
Date of Acceptance: 20-Feb-2011

Code Number: mb11078

PMID: 21860121

DOI: 10.4103/0255-0857.83924

Dear Editor,

There are concerns regarding the increased resistance of Gram-negative bacteria to 3 ^rd and 4 ^th generation cephalosporins and emerging resistance to carbapenem. This concern is further strengthened by the lack of new antimicrobial on the horizon for next few years. Accordingly, there is an increased interest in the new β-lactam and β-lactamase inhibitor combinations.

The Clinical Laboratory Standards Institute (CLSI) recommends to report Extended Spectrum β-lactamase (ESBL) producing Escherichia coli and Klebsiella 0spp. as resistant to all penicillins, cephalosporins and monobactam antmicrobials and to report β-lactam and β-lactamase inhibitor result as such. ^[1] This recommendation is based on the understanding that the effectiveness of β-lactamase inhibitor depends upon the nature and number of β-lactamase secreted. For example, clavulanate is effective against β-lactamase encoded by CTX-M, TEM, SHV and VEB but ineffective against OXA and AmpC. ^[2]

Recently, the percentage of resistance to β-lactam and β-lactamase inhibitor has accelerated due to the presence of the plasmid encoded CTX-M-15 often accompanied by OXA-1.^[3] To decrease the resistance, a novel combination of clavulanate with oxyimino-cephalosporin was proposed because: 1) they have higher affinity for the penicillin-binding proteins; 2) they better protect against ESBLs as these are weaker substrates when compared with amoxycillin and ticarcillin; 3) they are stable to inhibitor-resistant penicillinases, including OXA-1 and 4) the pharmacokinetics of clavulanate are also compatible with those of cefotaxime, ceftazidime and cefepime. ^[4]

When combinations of cefotaxime or ceftazidime with clavulanate were tested, over 95% of ESBL-producing E. coli and Klebsiella spp. were susceptible, but Enterobacter spp., was not as clavulanate was a potent inducer of Amp C. ^[4] The Amp C induction, however, was effectively suppressed by combining clavulanate with the Amp C stable cefepime or cefpirome. The resulting combination was found to be effective against virtually all ESBL-producing Enterobacteriacae. Antagonism between cefepime-clavulanate and ESBL-negative AmpC producers was ruled out. It was concluded that cefepime with clavulanate is a recommended choice for empirical therapy. In addition, cefepime-clavulanate is an alternative to carbapenems for severe infections caused by ESBL producers. But these combinations are yet to be evaluated and approved by either FDA or by any antimicrobial standards institute.

Interestingly, the cephalosporin-clavulanate combinations are now available over the counter in the Indian market, but not in any of the Western countries. This includes cefotaxime-sulbactum; ceftriaxone-sulbactum; cefepime-tazobactam; ceftriaxone-tazobactum and cefepime-tazobactum. Very few in vitro susceptibility reports are available ^[5] and there are no published in vivo studies. A number of clinical and diagnostic issues remain to be resolved:

1. None of the newer β-lactam-β-lactamase inhibitor combinations available in the Indian market have been thoroughly evaluated. Furthermore, a guideline does not exist for the interpretation of disk diffusion and minimum inhibitory concentration in any of the reference standard institute such as CLSI, BSAC, EUCAST, SRGA, etc.
2. Use of these new β-lactam-β-lactamase inhibitor combinations requires careful evaluation of pharmacodynamics, as drug concentrations changes in the host. Neither the amount of β-lactamase inhibitor required for potentiating a β-lactam (area under the serum concentration curve) nor the posteffect of the β-lactamase inhibitor is determined.
3. In vitro studies have shown that a β-lactam combined with different β-lactamase inhibitors has differential efficiency against enterobacteriacea. For example, piperacillin-tazobactam exhibit greater activity against E. coli and P. vulgaris than piperacillin-sulbactam. When compared with piperacillin-tazobactam, piperacillin-sulbactam exhibit better antimicrobial activity against Acinetobacter baumannii.^[6] Such information is lacking for newer combinations.
4. The laboratory testing of β-lactam-β-lactamase inhibitor combinations are unstandardized. Certain combinations uses fixed β-lactam-β-lactamase inhibitor combination ratio and other use fixed β-lactamase inhibitor.
5. The β-lactam-β-lactamase inhibitor combination are marketed in different proportions, The reasons for these differences are unclear, and the ideal indications are not well-specified.

Until additional in vitro and in vivo studies are made available, the true effectiveness of these combinations remains difficult to assess. Further, these combinations are unlikely to be developed and evaluated (phase III trial) in the developed countries, because clinical trials in these countries are costly. Moreover, cefepime, cefpirome and clavulanate were developed and patented by different manufacturers. Developed countries are keen to know the clinical efficacy of these combinations against ESBL in India.

References

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