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  Table of Contents  
BRIEF COMMUNICATION
Year : 2016  |  Volume : 34  |  Issue : 2  |  Page : 208-209
 

Fixed-dose combinations of antimicrobials: A need for special attention


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 Submission04-Jul-2015
Date of Acceptance13-Dec-2015
Date of Web Publication14-Apr-2016

Correspondence Address:
N Shafiq
Department of Pharmacology, Post Graduate Institute of Medical Education and Research, Chandigarh - 160 012
India
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/0255-0857.180305

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 ~ Abstract 

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 [1],[2],[3],[4] and case reports. [5] 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. [5] The best available evidence in the support of meropenem and sulbactam comes in the form of an in-vitro and in-vivo study. [6]

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. [7] 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. [8] 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. [9] 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. [10] 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. [8] 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. [11],[12] 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. [13] 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. [14]

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. [15] 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

Nil.

Conflicts of interest

There are no conflicts of interest.

 
 ~ References Top

1.
Turk Dagi H, Kus H, Arslan U, Tuncer I. In vitro synergistic activity of sulbactam in combination with imipenem, meropenem and cefoperazone against carbapenem-resistant Acinetobacter baumannii isolates. Mikrobiyol Bul 2014;48:311-5.  Back to cited text no. 1
    
2.
Ji J, Du X, Chen Y, Fu Y, Wang H, Yu Y. In vitro activity of sulbactam in combination with imipenem, meropenem, panipenem or cefoperazone against clinical isolates of Acinetobacter baumannii. Int J Antimicrob Agents 2013;41:400-1.  Back to cited text no. 2
[PUBMED]    
3.
Deveci A, Coban AY, Acicbe O, Tanyel E, Yaman G, Durupinar B. In vitro effects of sulbactam combinations with different antibiotic groups against clinical Acinetobacter baumannii isolates. J Chemother 2012;24:247-52.  Back to cited text no. 3
    
4.
Lee NY, Wang CL, Chuang YC, Yu WL, Lee HC, Chang CM, et al. Combination carbapenem-sulbactam therapy for critically ill patients with multidrug-resistant Acinetobacter baumannii bacteremia: Four case reports and an in vitro combination synergy study. Pharmacotherapy 2007;27:1506-11.  Back to cited text no. 4
    
5.
Kiffer CR, Sampaio JL, Sinto S, Oplustil CP, Koga PC, Arruda AC, et al. In vitro synergy test of meropenem and sulbactam against clinical isolates of Acinetobacter baumannii. Diagn Microbiol Infect Dis 2005;52:317-22.  Back to cited text no. 5
    
6.
Ko WC, Lee HC, Chiang SR, Yan JJ, Wu JJ, Lu CL, et al. In vitro and in vivo activity of meropenem and sulbactam against a multidrug-resistant Acinetobacter baumannii strain. J Antimicrob Chemother 2004;53:393-5.  Back to cited text no. 6
    
7.
Available from: http://www.cdsco.nic.in/writereaddata/D and %20C%20AMMENDMENT%20BILL.pdf. [Last accessed on 2015 May 13].  Back to cited text no. 7
    
8.
Drawz SM, Bonomo RA. Three decades of beta-lactamase inhibitors. Clin Microbiol Rev 2010;23:160-201.  Back to cited text no. 8
    
9.
Yigit H, Queenan AM, Anderson GJ, Domenech-Sanchez A, Biddle JW, Steward CD, et al. Novel carbapenem-hydrolyzing beta-lactamase, KPC-1, from a carbapenem-resistant strain of Klebsiella pneumoniae. Antimicrob Agents Chemother 2001;45:1151-61.  Back to cited text no. 9
    
10.
Higgins PG, Wisplinghoff H, Stefanik D, Seifert H. In vitro activities of the beta-lactamase inhibitors clavulanic acid, sulbactam, and tazobactam alone or in combination with beta-lactams against epidemiologically characterized multidrug-resistant Acinetobacter baumannii strains. Antimicrob Agents Chemother 2004;48:1586-92.  Back to cited text no. 10
    
11.
Choudhary M, Payasi A. A randomized, open label, prospective, multicentric phase-III clinical trial of Elores in lower respiratory tract and urinary tract infection. J Pharm Res 2013;6:409-14.  Back to cited text no. 11
    
12.
Choudhary M, Payasi A. Clinical, microbial efficacy and tolerability of Elores, a novel antibiotic adjuvant entity in ESBL producing pathogens: Prospective randomized controlled clinical trial. J Pharm Res 2013;7:275-80.  Back to cited text no. 12
    
13.
Sahu M, Sanjith S, Bhalekar P, Keny D. Waging war against extended spectrum beta lactamase and metallobetalactamase producing pathogens- novel adjuvant antimicrobial agent cse1034- an extended hope. J Clin Diagn Res 2014;8:DC20-3.  Back to cited text no. 13
    
14.
Byrns MC, Penning TM. Environmental toxicology: Carcinogens and heavy metals. In: Brunton LL, Chabner BA, Knowllmann BC, editors. Goodman & Gilman′s the Pharmacological Basis of Therapeutics. 12 th ed. United States: McGraw Hill; 2011. p. 1873-4.  Back to cited text no. 14
    
15.
McGettigan P, Roderick P, Mahajan R, Kadam A, Pollock AM. Use of fixed dose combination (FDC) drugs in India: Central regulatory approval and sales of FDCs containing non-steroidal anti-inflammatory drugs (NSAIDs), metformin, or psychotropic drugs. PLoS Med 2015;12:e1001826.  Back to cited text no. 15
    




 

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