Bishwaranjan Jana

[Downloaded free from http://www.ijmm.org on Thursday, October 15, 2020, IP:-] Brief Communication Relative Potency of Different Generic Brands of Meropenem, Colistin and Fosfomycin: Implications for Antimicrobial Therapy and Antimicrobial Formulary Parijat Das, Bishwaranjan Jana, Kingshuk Dhar, Gaurav Goel, Sanjay Bhattacharya, Mammen Chandy1 Departments of Microbiology and 1Clinical Hematology, Tata Medical Center, Kolkata, West Bengal, India Abstract There is a need of a relatively simple and inexpensive method for the determination of relative potency of various generic brands of antibiotics in comparison to original products. The current study describes an agar diffusion method which can be performed in any microbiology laboratory, is cheap (costs $2 per test) and its results can be available after overnight incubation. The results show that neither all generics are reliable nor are all generic antibiotics of poor quality. Keywords: Agar diffusion, colistin, fosfomycin, generic brands, meropenem, relative potency Introduction A general perception exists among practitioners in infectious diseases that generic antimicrobial agents are inferior to innovator products. This perception has arisen from empirical evidence and anecdotal reports. Generic medicines when tested under controlled laboratory conditions or used in clinical practice were sometimes reported to have inadequate pharmacological quality or clinical response. Generic drugs are considered to be equivalent to the innovator formulation if they have the same active pharmaceutical ingredient (API), pharmaceutical form and bioequivalence compared to reference medicinal product. The main concerns regarding the effect of poor‑quality generic drugs have been the possible increased duration of disease because of suboptimal quality of products used during treatment and possible therapeutic failure. Supraoptimal concentration of generic drug can also be detrimental by exposing patients to an increased risk of dose‑dependent side effects.[1] However, the technical challenges in testing quality of generic antimicrobial agents against innovator products are significant, and this has resulted in a situation where very few clinical users are having adequate understanding about the actual quality of generic antibiotics. High‑performance liquid chromatography (LC) along with mass spectrometry (MS) are the standard methods for quality Access this article online Quick Response Code: Website: www.ijmm.org DOI: 10.4103/ijmm.IJMM_18_248 checks, and these techniques are generally not used in routine laboratory practice because of high equipment cost, expertise needed in standardisation and quality control and cost of tests. Therefore, there is a need of a low‑cost and relatively simple technique which can enable resource‑constrained laboratories in testing generic antibiotics locally. Procedure The current study was done in the microbiology department of Tata Medical Center, Kolkata, India. Test methodology for relative potency testing was based on the agar diffusion technique. Antibiotic samples from generic or innovator brands were reconstituted (with the diluents provided or analytical grade sterile Milli‑Q water), and the initial stock solution started with concentration based on the median Cmax of meropenem, colistin or fosfomycin reported in previous pharmacokinetic studies. Standard strains used to test relative Address for correspondence: Dr. Parijat Das, Tata Medical Center, 14 Major Arterial Road (E‑W), New Town, Rajarhat, Kolkata ‑ 700 160, West Bengal, India. E-mail:- This is an open access journal, and articles are distributed under the terms of the Creative Commons Attribution‑NonCommercial‑ShareAlike 4.0 License, which allows others to remix, tweak, and build upon the work non‑commercially, as long as appropriate credit is given and the new creations are licensed under the identical terms. For reprints contact:- How to cite this article: Das P, Jana B, Dhar K, Goel G, Bhattacharya S, Chandy M. Relative potency of different generic brands of meropenem, colistin and fosfomycin: Implications for antimicrobial therapy and antimicrobial formulary. Indian J Med Microbiol 2019;37:95-8. © 2019 Indian Journal of Medical Microbiology | Published by Wolters Kluwer - Medknow 95 [Downloaded free from http://www.ijmm.org on Thursday, October 15, 2020, IP:-] Das, et al.: Antibiotic relative potency testing by agar diffusion potency were selected as per the Clinical Laboratory Standard Institute recommendations. Each test was carried out in triplicate, and median zone diameter was used for calculation of product lot relative potency.[2] The zone diameters were read after overnight incubation, and the turnaround time of the test was 1 day. Cost of consumables (except the cost of the antibiotics) for doing the agar diffusion test was ~$2 per 5 antibiotic brands tested.[3] Our results showed a difference of +1.7% to −48% in relative potency of meropenem brands, 0% to 0.98% for colistin brands and −10% to −57% for fosfomycin brands when compared against the original research brand [Tables 1a‑c]. During the relative potency testing of all the three drugs (meropenem, colistin and fosfomycin brands), it was observed that the price was not necessarily an indicator of quality. The second observation was that the potency varied with regard to quality control (QC) strains used, and the third major observation was that the brand name was not necessarily a good way to judge the potency of a specific drug. Sometimes, inexpensive brands performed as well as the original brand. For example, Merolan and Meronem with respect to pseudomonas had similar relative potency, although its cost was much lower than Meropen or Menem. Second, the performance of the brand or a company also seemed to vary with its molecule, for example, colistin from United Biotech was equally good as other colistin products used in this study whereas it was significantly inferior when it comes to its meropenem product. It was reassuring to note that most colistin brand available in the market had little variation in potency; however, the same was not true about fosfomycin brands where larger variations were noted in the indigenous brand compared to the international brand. Testing for pharmaceutical equivalence, bioequivalence, therapeutic equivalence by in vitro and in vivo models are technically demanding, time‑consuming and resource intensive. These techniques are beyond the scope of most prescribers and generally can only be done by focussed research centres or regulatory organisations. For example, in one study, generic brands were compared using microbiological susceptibility testing, LC/MS and in vivo (neutropenic guinea pig soleus infection model and neutropenic mouse thigh–brain–lung infection models).[4] Apparently insignificant chemical deviations among bioequivalent generic antibiotics can lead to therapeutic Table 1a: Zone diameters of different generic brands of meropenem against the innovator brand as determined by the agar diffusion method Median zone diameters (mm) of different brands of meropenem by agar diffusion method against various bacterial isolates Manufacturer Product name Vial Lot number Price Klebsiella Variation Escherichia Variation Pseudomonas Variation strength in US pneumoniae (%) coli ATCC (%) aeruginosa (%) (g) dollar ATCC- (MIC (MIC (MIC ≤1 mg/L) ≤1 mg/L) ≤2 mg/L) Mylan Pharmaceutical Merolan 1 MI-A 6.22 39 +1.7 39 −19 39 Same United Biotech (P) Ltd Menem 1 MNDJ5B- Same 37 −45 34 −26 Zuventus Healthcare Ltd Merotec 1 Z1D- −34 37 −45 35 −11 Fusion Healthcare MeroReach- −48 37 −45 34 −26 Lupin Ltd Merotrol 1 ZLM- −20 37 −45 37 −10 AstraZeneca Pharma Meronem 1 MJ- NA 40 NA 39 NA India Ltd The comparator brand is at the end row of each table in bold. NA: Not available, MIC: Minimum inhibitory concentration, ATCC: American type culture collection Table 1b: Zone diameters of different generic brands of colistin against the original brand as determined by the agar diffusion method Median zone diameters (mm) of different brands of colistin by agar diffusion method against various bacterial isolates Manufacturer Product name Vial strength (g) Lot number Price Klebsiella Variation Escherichia Variation Pseudomonas Variation in US pneumoniae (%) coli ATCC (%) aeruginosa (%) dollar ATCC- (MIC (MIC (MIC ≤1 mg/L) ≤1 mg/L) ≤2 mg/L) Cipla Xylistin forte 2 MIU A- +0.98 29 None 31 None Gufic Bioscience Ltd Sudostar 2 MIU AP- None 29 None 31 None Glenmark Promistin‑DS 2 MIU- None 28 −0.97 31 None Pharmaceutical Ltd United Biotech Colicraft Forte 2 MIU CQDF6B- None 28 −0.97 31 None Glenmark Coly Monas 2 MIU- NA 29 NA 31 NA Pharmaceutical Ltd The comparator brand is at the end row of each table in bold. NA: Not available, MIC: Minimum inhibitory concentration, ATCC: American type culture collection 96 Indian Journal of Medical Microbiology ¦ Volume 37 ¦ Issue 1 ¦ January-March 2019 [Downloaded free from http://www.ijmm.org on Thursday, October 15, 2020, IP:-] Das, et al.: Antibiotic relative potency testing by agar diffusion Table 1c: Zone diameters of different generic brands of fosfomycin against the innovator brand as determined by the agar diffusion method Manufacturer Product name Vial strength (g) Lot number Price in US dollar Klebsiella pneumoniae Variation Escherichia coli Variation ATCC 700603 (MIC (%) ATCC 25922 (%) ≤64 mg/L) (MIC ≤64 mg/L) Cipla Crifos 4 CFSAQO- −57 14 Glenmark Fonyl 4 DFSAQO- −28 17 Intas Fosfotas 4 AFSAQO- −24 18 Northeast Pharmaceutical Fosfomycin 2 NA- NA 22 Group Co., Ltd. sodium Zone diameters marked in bold represent the highest diameter in each experiment. NA: Not available, MIC: Minimum inhibitory concentration, ATCC: American type culture collection non‑equivalence. In a Columbian study, it was found that trisodium adducts in a bioequivalent generic of meropenem made a meropenem brand more susceptible to dehydropeptidase hydrolysis and less stable at room temperature, resulting in therapeutic non‑equivalence. These failing generics are compliant with the United States Pharmacopeia requirements and would remain undetectable under many current regulations.[5] Another Columbian study showed that for therapeutic equivalence of drugs like metronidazole, pharmaceutical, pharmacokinetic and pharmacodynamic identities are required. The generic and the innovator products can be identical in terms of the concentration and potency of the API, chromatographic and spectrographic profiles, minimum inhibitory concentration and minimal bactericidal concentrations and mouse pharmacokinetic model and yet differ in therapeutic equivalence.[4] A post‑marketing clinical study on healthy volunteers in Italy reported lack of pharmacokinetic bioequivalence between generic and branded amoxicillin formulations. The mean pharmacokinetic profiles showed that the area under the curve value of branded amoxicillin was 8.5% and 5.4% greater than that estimated for generic A and B, respectively.[6] The results of relative potency testing using similar methods in our previous study showed a difference of −11%–−36% of the potency of the generic brands of piperacillin–tazobactam when compared against the original research brands.[3] Despite all the negative publicity, there are good financial and clinical reasons why generic drug market sustains and flourishes. Generic medicines are widely used in developing countries because of low costs and easy accessibility. The side effect profile and patient acceptances were sometimes comparable to innovator products. An observational study among patients with chronic diseases attending a public hospital in Kolkata, India, reported that 93% of generic and 87% branded drug users believed that their drugs were effective in controlling their ailments. No significant difference (9% generic and 10% branded drug users) was observed in reported adverse effects between generic and branded drug users. Moreover, 82% and 77% of patients were adherent to generic and branded drugs, respectively.[7] This −30 −17 −10 NA study is important because, since 2012, the local government in India had initiated exclusive generic drug outlets called ‘fair price medicine shop’ inside the government hospital premises in a ‘public–private partnership’ model.[7] Clinical studies on generic antibiotics in Thailand had previously demonstrated non‑inferiority (overall clinical outcome, mortality and adverse effects) of some generic products of piperacillin–tazobactam.[8] Another study from Thailand reported therapeutic equivalence of generic imipenem– cilastatin with innovator brands in terms of mortality and adverse effect.[9] Conclusion Agar diffusion method represents a relatively inexpensive, simple test which could be performed in basic microbiology laboratories for determination of relative potency of antibiotic formulations. The information available from such studies may be useful to provide feedback to pharmaceutical companies, drug manufacturers and drug controllers and help in deciding hospital antibiotic formularies. It is important that more accurate techniques on multiple batches using LC‑MS be used to verify API concentration. Our results also show that in terms of API, not all generics are inferior. Acknowledgements We would like to thank the medical administration of Tata Medical Center, Kolkata, India, for supporting this study. Financial support and sponsorship Nil. Conflicts of interest There are no conflicts of interest. References 1. 2. 3. 4. Gallelli L, Palleria C, De Vuono A, Mumoli L, Vasapollo P, Piro B, et al. Safety and efficacy of generic drugs with respect to brand formulation. J Pharmacol Pharmacother 2013;4:S110‑4. Bonev B, Hooper J, Parisot J. Principles of assessing bacterial susceptibility to antibiotics using the agar diffusion method. J Antimicrob Chemother 2008;61:1295‑301. Das P, Mahto R, Goel G, Chandy M, Bhattacharya S. Relative potency of different generic brands of piperacillin‑tazobactam: Implications for public health. J Infect Public Health 2017;10:901‑2. Agudelo M, Vesga O. Therapeutic equivalence requires pharmaceutical, Indian Journal of Medical Microbiology ¦ Volume 37 ¦ Issue 1 ¦ January-March 2019 97 [Downloaded free from http://www.ijmm.org on Thursday, October 15, 2020, IP:-] Das, et al.: Antibiotic relative potency testing by agar diffusion 5. 6. 98 pharmacokinetic, and pharmacodynamic identities: True bioequivalence of a generic product of intravenous metronidazole. Antimicrob Agents Chemother 2012;56:2659‑65. Agudelo M, Rodriguez CA, Pelaez CA, Vesga O. Even apparently insignificant chemical deviations among bioequivalent generic antibiotics can lead to therapeutic nonequivalence: The case of meropenem. Antimicrob Agents Chemother 2014;58:1005‑18. Del Tacca M, Pasqualetti G, Di Paolo A, Virdis A, Massimetti G, Gori G, et al. Lack of pharmacokinetic bioequivalence between generic and branded amoxicillin formulations. A post‑marketing clinical study on healthy volunteers. Br J Clin Pharmacol 2009;68:34‑42. 7. 8. 9. Das M, Choudhury S, Maity S, Hazra A, Pradhan T, Pal A, et al. Generic versus branded medicines: An observational study among patients with chronic diseases attending a public hospital outpatient department. J Nat Sci Biol Med 2017;8:26‑31. Charoenpong L, Tongsai S, Thamlikitkul V. Effectiveness and safety of generic formulation of piperacillin/tazobactam (Astaz‑P) for treatment of infected patients at Siriraj hospital. J Med Assoc Thai 2013;96 Suppl 2:S104‑10. Piyasirisilp S, Premprawat W, Thamlikitkul V. Therapeutic equivalence of generic imipenem/cilastatin for therapy of infections at Siriraj hospital. J Med Assoc Thai 2010;93 Suppl 1:S117‑25. Indian Journal of Medical Microbiology ¦ Volume 37 ¦ Issue 1 ¦ January-March 2019