|Year : 2016 | Volume
| Issue : 2 | Page : 208-209
Fixed-dose combinations of antimicrobials: A need for special attention
N Shafiq1, G Kumar1, V Gautam2, P Ray2, S Malhotra1
1 Department of Pharmacology, Post Graduate Institute of Medical Education and Research, Chandigarh - 160 012, India
2 Department of Microbiology, Post Graduate Institute of Medical Education and Research, Chandigarh - 160 012, India
|Date of Submission||04-Jul-2015|
|Date of Acceptance||13-Dec-2015|
|Date of Web Publication||14-Apr-2016|
Department of Pharmacology, Post Graduate Institute of Medical Education and Research, Chandigarh - 160 012
Source of Support: None, Conflict of Interest: None
Objective: To highlight the issue of freely available fixed-dose combinations (FDCs) of antimicrobials. Methods: A critique of two such antimicrobial FDCs was undertaken wherein the following aspects were assessed - rational and regulatory issues and justification for clinical use. Available in vitro, in vivo (animals and humans) evidence from published literature was analysed. Conclusions: There are several inadequately addressed aspects of the considered FDCs which are available in Indian market. In view of the growing problem of antimicrobial resistance, this issue must get the required attention.
Keywords: Antimicrobials, fixed-dose combinations, rationale, use
|How to cite this article:|
Shafiq N, Kumar G, Gautam V, Ray P, Malhotra S. Fixed-dose combinations of antimicrobials: A need for special attention. Indian J Med Microbiol 2016;34:208-9
|How to cite this URL:|
Shafiq N, Kumar G, Gautam V, Ray P, Malhotra S. Fixed-dose combinations of antimicrobials: A need for special attention. Indian J Med Microbiol [serial online] 2016 [cited 2019 Nov 15];34:208-9. Available from: http://www.ijmm.org/text.asp?2016/34/2/208/180305
Those involved in undertaking antimicrobial stewardship face various problems in developing countries. An often-overlooked issue is that of availability of fixed-dose combinations (FDCs). We relate here cases of two FDCs of antimicrobials - that of meropenem-sulbactam and the other one of ceftriaxone-sulbactam-ethylenediaminetetraacetic acid (EDTA). The exact indications for which these combinations are approved are not clear. On searching electronic data, the following becomes evident. For meropenem-sulbactam combination (albeit not fixed dose), PubMed shows only in vitro evidence ,,, and case reports.  Incidentally, in the case reports, 3 of 4 patients had received imipenem and in in-vitro synergy studies, synergy was seen in only a fraction of isolates.  The best available evidence in the support of meropenem and sulbactam comes in the form of an in-vitro and in-vivo study. 
FDCs have been categorised by Central Drugs Standards Controls Organization (CDSCO), India, and the data required for obtaining marketing approval of these compounds have been detailed out.  While meropenem is used for Gram negative infections, it is not clear for what indication sulbactam is included. If it is being considered as an old drug, chemically it is a penicillanic acid sulfone and shows particular activity against Class A beta-lactamases only.  It has no activity against Class B, C or D beta-lactamases. The beta-lactamases known to produce resistance to carbapenems include chromosomal AmpC cephalosporinase (along with decreased outer membrane permeability), IMI-1, IMP-1, Nmc-A, Sme-1 and CfiA.  It is worth noting that some of these are not Class A enzymes (AmpC, IMP-1 and CfiA) and these will not be inhibited by sulbactam. Hence, clubbing all beta-lactamases under one category and allowing a beta-lactamase inhibitor-based combination on the pretext of an already known use of the agent will not be appropriate. In view of the paucity of epidemiological data regarding the prevalence of these enzymes in various clinical isolates, there is a great potential for misuse.
One may argue that sulbactam has an intrinsic activity against Acinetobacter species. However, the best evidence for the same can be regarded as preclinical.  Since it is not an approved indication for sulbactam, combining it with meropenem in a FDC would put it in the category I of FDC. This would warrant it to be treated as a new drug and require submission of all the pertinent documents for its approval.  The current communication is not to treat a particular fixed-dose antimicrobial combination in isolation as the same prudence and caution is needed for other FDCs of antimicrobials.
Another example is the combination of ceftriaxone-sulbactam-EDTA. The best evidence indeed comes in the form of clinical trials. A critical appraisal of these trials shows that they were multi-centric, although only two authors are included in the final report. , The demographic and baseline characteristics, concomitant medications and several other aspects of a clinical trial report are conspicuously missing. On the other hand, the genotype data are much emphasised. A justification for this combination exists in the form of microbiological data.  As discussed earlier, in-vitro synergy should not be a sufficient case for developing a FDC. It is important to note that EDTA, a component of the FDC, itself has side effects and drug interaction potentials. 
When we are sitting on a precipice of increasing incidence of multi-drug resistant organisms across our hospitals, it is important that regulatory authorities should take due measures to see that drug combinations of antimicrobials are allowed to enter into the market after consideration of all aspects. A recent study does show that several of the FDCs may not even have gone through the required process of approval from CDSCO.  It is very important to keep a check on this, since once these FDCs make a foray into the market; they are backed by pharmaceutical company's promotional materials which are again not scrutinised for correctness. This practice would have an amplified effect on the problem of irrational use of antimicrobials. At the same time, it must be noted that there exist examples where there is a rationale and sufficient evidence to suggest advantage of certain FDCs. Such FDCs need not be put in the same bracket of FDCs devoid of sufficient rationale and clinical evidence.
Financial support and sponsorship
Conflicts of interest
There are no conflicts of interest.
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