JAC- Antimicrobial Resistance JAC Antimicrob Resist doi:10.1093/jacamr/dlz063 Continuous rise in cephalosporin and fluoroquinolone consumption in Pakistan: a 5 year analysis (2014–18) 1 1,2 Farrukh Malik * and Albert Figueras 1 Eu2P European Programme in Pharmacovigilance & Pharmacoepidemiology, Université de Bordeaux, Bordeaux, France; 2Fundació Institut Català de Farmacologia; Department of Pharmacology, Therapeutics, & Toxicology, Universitat Autònoma de Barcelona, Barcelona, Spain *Corresponding author. E-mail: malikfj@gmail.com Received 18 July 2019; returned 2 October 2019; revised 4 October 2019; accepted 15 October 2019 Background: Pakistan was third on the list of the highest antibiotic-consuming countries among low- and middle-income countries in 2015. Studies have suggested that areas with higher consumption of antibiotics are likely to have higher antibiotic resistance rates. Objectives: With limited surveillance data on consumption and resistance in Pakistan, this study investigated the 5 year trends (April 2014 to March 2019) in consumption of the two highest-sold antibiotic classes, cephalosporins [Anatomical Therapeutic Chemical (ATC) group J01D] and fluoroquinolones (ATC group J01MA). Methods: IQVIA Pakistan data (retail) on antibiotic sales presented in units were used. These data were standar- dized and a DDD was assigned to all formulations, based on WHO’s ATC/DDD index, and the data expressed as DIDs (DDDs per 1000 inhabitants per day). WHO’s AWaRe classification of antimicrobials was used for the analyses, especially of those categorized as ‘Watch’. Results: The findings showed a significant increase in consumption trends for ‘Watch’ cephalosporins (61.5%) while the use of ‘Reserve’ cephalosporins doubled during the studied period. In 2018, combined consumption of second- and third-generation cephalosporins (both in the ‘Watch’ group) was nearly five times higher than that of the first-generation cephalosporins. For fluoroquinolones, the total consumption only showed a major increase for ciprofloxacin, with 127820 more persons per day. The consumption of cephalosporins and fluoroqui- nolones in Pakistan increased by 1.86 DIDs in just 5 years. Conclusions: It is urgent to establish a National Antimicrobial Commission in Pakistan, to critically analyse the pharmaceutical market offerings and implement surveillance systems and antimicrobial stewardship. Introduction While surveillance data have helped multiple countries realize and intervene in their high consumption of antibiotics,5 the Evidence has shown an association at an individual patient level absence of national surveillance data on consumption and between the prescribing of antibiotics in primary healthcare and resistance, along with limited laboratory facilities, is a significant antimicrobial resistance (AMR) in bacteria at different sites, with hindrance to knowing the correct numbers and designing the best the strongest effects in the month after antibiotic consumption, interventions.6 but detectable for up to 12 months.1 Since 2007, the rates of The emergence of Escherichia coli strains resistant to third- antibiotic-resistant bacteria-related infections in Europe have generation cephalosporins and fluoroquinolones is worrying.7 continuously increased in comparison with other infections2 Similarly, resistance has been developing to extended-spectrum and countries with higher consumption of antibiotics have cephalosporins, including third- and fourth-generation cephalo- higher AMR rates.3 Pakistan is the third highest antibiotic-con- sporins in the Asia–Pacific Rim region, since 20098 and increasing suming country among low- and middle-income countries and worrying exposure to these high-end cephalosporins has been (LMICs) and in 16 years the number of DDDs increased by 65%. observed in the paediatric population in Pakistan.9 Multiple studies The consumption rates were 19.6 DDDs per 1000 inhabitants from Pakistan have shown E. coli and Klebsiella pneumoniae to per day (i.e. 19.6 DIDs) in 2015.4 be significantly associated with ESBL production, with one C The Author(s) 2019. Published by Oxford University Press on behalf of the British Society for Antimicrobial Chemotherapy. V This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http:// creativecommons.org/licenses/by-nc/4.0/), which permits non-commercial re-use, distribution, and reproduction in any medium, provided the original work is properly cited. For commercial re-use, please contact journals.permissions@oup.com 1 of 4 Malik et al. multicentre study showing 46% of E. coli and 31.9% of K. pneumo- cephalosporins (‘Watch’ group) was nearly five times higher in niae to be MDR strains.10,11 2018 in comparison with the sales of first-generation (‘Access’ Any suboptimal administration of antibiotics provides an group) cephalosporins (2.4463 and 0.5254 DIDs, respectively). opportunity for the susceptible microorganism to develop survival Thus, the population exposed to ‘Watch’ group cephalosporins mechanisms and hence contribute to antibiotic resistance. increased from 315000 inhabitants/day in 2014 to 508000 inhabi- The present study was planned to investigate the trends in tants/day in 2018, while for the ‘Reserve’ group (fourth generation) consumption of cephalosporin and fluoroquinolone antibiotics an estimated increased consumption from 311 to 623 inhabitants/ in Pakistan over 5 years. day meant that the population treated daily with these highly important cephalosporins doubled in 5 years (Figure 1). Methods The ‘Access’ cephalosporins deserve special comment. While there was a small increase in consumption of the ‘Access’ We estimated the national antibiotic consumption of cephalosporins cephalosporins included in the EML, there was a decrease in the [Anatomic Therapeutic Chemical (ATC) classification J01D group] and fluo- consumption of ‘Access’ cephalosporins not included in the EML. roquinolones (ATC J01MA group) using the IQVIA Pakistan data for 5 years Notwithstanding this, it should be noted that the sales of cephalo- (April 2014 to March 2019). sporins not included in the EML were 4.5 times higher. In the case of IQVIA data are from retail audits capturing sales directly from distributors ‘Watch’ cephalosporins, consumption of those included in the EML to pharmacies, wholesalers and retail pharmacies in small private hospitals. In the case of Pakistan, this database comprises 85% actual sales and 15% pro- was 10 times higher than of those not included in the EML (Table 1). jected data for companies not sharing their distributor’s data. In each sector, data is collected monthly to record direct sales from the manufacturer’s desig- Fluoroquinolone consumption nated distributors. This data is granulated into national, regional, city, brick (a Regarding fluoroquinolone antimicrobials, all were considered group of pharmacies) and pharmacy/medical-store levels for different distri- under the ‘Watch’ group of the AWaRe classification. The net in- bution channels. IQVIA data on antibiotic sales are presented as brands and crease for the whole class during the study period was 0.9990 DIDs presentations, which are further shown as units that represent a unit carton of (approximately 208000 more people were treated each day). The a certain number or volume of tablets, capsules or liquids. All medicines in the country are available as ‘Innovator’ or ‘Generic’ brands, while each brand can increase in total consumption of ciprofloxacin was 0.6152 DIDs, have multiple dosage strengths (e.g. 5, 10 or 20 mg in the case of rosuvastatin) while for all other quinolones it was 0.3838 DIDs. It should be high- called presentations. All units were converted into DDDs using the ATC lighted that the consumption of ‘other quinolones’ in 2018 (2.5991 Classification System and DDD methodology (ATC/DDD, 2019) developed by DIDs) was higher than that of ciprofloxacin (2.1709 DIDs) (Table 1). the WHO Collaborating Centre for Drug Statistics Methodology.12 The number of DIDs was calculated using population estimates from Discussion the 2017 national census (207770000 inhabitants), as all other population numbers between 2013 and 2018 were estimates calculated with The present sales analysis of cephalosporin and fluoroquinolone growth rate factored in. We used the biggest denominator in order to avoid antibiotics in Pakistan over 5 years showed a combined increase of overestimations in the first years. 1.8598 DIDs, i.e. in 2018, an additional 386000 patients were In order to classify the different antimicrobials, the WHO AWaRe classifi- receiving one of these antimicrobials each day. These figures are cation was used, including ‘Access’, ‘Watch’ and ‘Reserve’ antimicrobials.13 relevant because most of the consumed cephalosporins and all of As a reference, the 2019 WHO Essential Medicines List (EML) was used.14 the fluoroquinolones belonged to the ‘Watch’ group; thus, special attention should be paid to their indications of use as well as actual Ethics treatment patterns. This study was conducted in accordance with the rules and guidelines There could be multiple factors driving the high consumption applicable to such studies as no formal ethical approval was needed. of cephalosporins and fluoroquinolones observed in Pakistan. Excessive prophylactic usage is probably an important driver of high and potentially inappropriate consumption.15 The data used for this Results study showed an enormously high number of presentations of Cephalosporins and fluoroquinolones were the highest selling these antimicrobials from multiple manufacturers, generating anti-infective medicines in the country. The number of brands and significant annual revenues. Additionally, it should be taken into presentations were 667 and 1934, respectively, for cephalosporins account that about 10%–15% of antibiotics are believed to be spuri- and 582 and 1139, respectively, for fluoroquinolones. ous or falsified in the Pakistan market, with quinolones and cephalo- sporins as the most common classes, both of which are perceived to be the best-choice antibiotics by physicians and patients.6 Cephalosporin consumption The underlying question is: ‘How many are too many when we Over the 5 years studied, the net increase in consumption for the are talking about antimicrobials?’ The appropriate selection of anti- whole class was 0.8608 DIDs (approximately 179000 more people microbials by prescribers, according to clinical, microbiological and treated each day in 2018 compared with 2014). The highest in- pharmacological aspects, has an extraordinary role in improving the crease was observed for third-generation cephalosporins (‘Watch’ use of antimicrobials16 but public policies are also undoubtedly ef- group) as their net increase was 0.8855 DIDs (approximately fective in promoting more rational use of medicines.17 The absence 184000 more people treated each day at the end of the study). of robust surveillance data limits the ability of the regulatory author- The consumption of cephalosporins not included in the EML ities to monitor the registrations, renewals, sales and resistance pat- (0.6558 DIDs) was around 22% of the total consumed in 2018. terns for high-risk antibiotics. In the case of Pakistan, the weaker Combined consumption of second- and third-generation healthcare regulations exacerbate the industry’s influence on the 2 of 4 Cephalosporin and fluoroquinolone consumption in Pakistan JAR 3 2.5 2 DID 1.5 1 0.5 0 2014 2015 2016 2017 2018 Year Access Watch Reserve Figure 1. Five-year DID sales trend for ‘Access’, ‘Watch’ and ‘Reserve’ cephalosporins in Pakistan (IQVIA Pakistan data). Table 1. Evolution of the sales of cephalosporins and fluoroquinolones in Pakistan Antimicrobialsa 2014 2015 2016 2017 2018 Net increase Cephalosporins ‘Access’ group in EML 0.0913 0.1008 0.0993 0.0988 0.0942 !0.0029 not in EML 0.5064 0.5827 0.4014 0.4134 0.4312 #0.0752 total 0.5977 0.6835 0.5007 0.5122 0.5254 #0.0723 ‘Watch’ group in EML 1.3678 1.6432 1.8610 2.0746 2.2247 !0.8569 not in EML 0.1469 0.1868 0.2063 0.1963 0.2216 !0.0747 total 1.5147 1.830 2.0673 2.2709 2.4463 !0.9316 ‘Reserve’ group 0.0015 0.0018 0.0020 0.0025 0.0030 !0.0015 total cephalosporins 2.1139 2.5153 2.5700 2.7856 2.9747 !0.8608 Fluoroquinolones ciprofloxacin 1.5557 1.8000 1.9221 2.0543 2.1709 !0.6152 other quinolones in EML 1.9183 2.2220 2.3375 2.4148 2.3794 !0.4611 not in EML 0.2970 0.2909 0.2738 0.2567 0.2197 #0.0773 total 2.2153 2.5129 2.6113 2.6715 2.5991 !0.3838 total fluoroquinolones 3.7710 4.3128 4.5334 4.7258 4.7700 !0.9990 Values are DIDs during the study period. Data source: IQVIA Pakistan. a ‘Access’, ‘Watch’ and ‘Reserve’ categories according to the AWaRe classification. prescribers,6,18 which could be an important factor in what we see The threat of antibiotic resistance in a developing country like as an antibiotic-flooded pharmaceutical market by a higher number Pakistan, where the population has limited access to education and of presentations than are reasonably needed, as well as the coexist- healthcare services, is considerable. AMR will remain a major problem ence of so many brand names containing the same antimicrobial. in managing various ever-evolving infections unless urgent steps are While physicians widely acknowledge the weak regulations in taken to control the influx of more brands and presentations into an the country,18 antibiotic stewardship programmes (including edu- already saturated market for cephalosporins and fluoroquinolones. cation, formulary restriction, prior approval programmes, stream- lining, antibiotic cycling and automated or computer-assisted Limitations prescribing)19 or increased awareness and control of selling The present study has some limitations, the most important being antimicrobials without prescription20 are necessary for slowing the that the data used are sales data and do not necessarily reflect development of antibiotic resistance. actual consumption by patients. Despite this, IQVIA sales data are 3 of 4 Malik et al. considered a proxy for consumption and are exceptionally consistent 2 Cassini A, Hogberg LD, Plachouras D et al. Attributable deaths for time comparisons within the same country, as is the case here. and disability-adjusted life-years caused by infections with antibiotic- Additionally, IQVIA sales data in Pakistan are not representative of resistant bacteria in the EU and the European Economic Area in 2015: a population-level modelling analysis. Lancet Infect Dis 2019; 19: 56–66. hospital usage for inpatients and also do not include individuals buy- ing over-the-counter antimicrobials for self-medication. Despite 3 Goossens H, Ferech M, Vander Stichele R et al. Outpatient antibiotic use in Europe and association with resistance: a cross-national database study. this, owing to the lack of any officially validated drug utilization data Lancet 2005; 365: 579–87. maintained at the provincial or federal government level, these 4 Klein EY, Van Boeckel TP, Martinez EM et al. Global increase and geographic results can be considered a first approach to the problem. convergence in antibiotic consumption between 2000 and 2015. Proc Natl In conclusion, the increasing use of ‘Watch’ cephalosporins and Acad Sci USA 2018; 115: E3463–70. fluoroquinolones observed in Pakistan during the last 5 years raises 5 Goossens H, Guillemot D, Ferech M et al. National campaigns to improve huge concerns regarding its potential role in the growing AMR antibiotic use. Eur J Clin Pharmacol 2006; 62: 373–9. crisis. Critical analyses of the pharmaceutical market in Pakistan, 6 Center for Disease Dynamics Economics & Policy. Situation Analysis Report as well as the promotion of surveillance systems based on drug on Antimicrobial Resistance in Pakistan. 2018. https://cddep.org/wp-content/ utilization data at the individual level, are urgent needs in order to uploads/2018/03/Situational-Analysis-Report-on-Antimicrobial-Resistance- try to increase the awareness of society in general and health in-Pakistan.pdf. professionals in particular and, at the same time, try to reduce 7 Collignon P. Resistant Escherichia coli—we are what we eat. Clin Infect Dis exposure to these antibiotics that should be reserved for the 2009; 49: 202–4. patients in need of them. 8 Bertrand X, Dowzicky MJ. Antimicrobial susceptibility among Gram- negative isolates collected from intensive care units in North America, Europe, the Asia-Pacific Rim, Latin America, the Middle East, and Africa be- Acknowledgements tween 2004 and 2009 as part of the Tigecycline Evaluation and Surveillance We thank PharmEvo (Pvt.) Ltd for supporting this study with IQVIA data. Trial. Clin Ther 2012; 34: 124–37. The datasets used for analyses during the current study are from 9 Ali SR, Ahmed S, Lohana H. Trends of empiric antibiotic usage in a IQVIA (formerly IMS) Pakistan. secondary care hospital, Karachi, Pakistan. Int J Pediatr 2013; 2013: The authors declare that this manuscript is an honest, accurate and 832857. transparent account of the study being reported; that no important 10 Abrar S, Vajeeha A, Ul-Ain N et al. Distribution of CTX-M group I and group aspects of the study have been omitted; that any discrepancies from the III b-lactamases produced by Escherichia coli and Klebsiella pneumoniae in study as planned (and, if relevant, registered) have been explained; and Lahore, Pakistan. Microb Pathog 2017; 103: 8–12. there are no competing interests. 11 Fatima S, Muhammad IN, Khan MN et al. Phenotypic expression and prevalence of multi drug resistant extended spectrum b-lactamase pro- ducing Escherichia coli and Klebsiella pneumoniae in Karachi, Pakistan. Pak J Pharm Sci 2018; 31: 1379–84. Funding 12 WHO. WHO Collaborating Centre for Drug Statistics Methodology. 2018. This study was conducted as part of our routine work. https://www.whocc.no/atc_ddd_index/. 13 Hsia Y, Lee BR, Versporten A et al. Use of the WHO Access, Watch, and Reserve classification to define patterns of hospital antibiotic use (AWaRe): Transparency declarations an analysis of paediatric survey data from 56 countries. Lancet Glob Health 2019; 7: e861–71. None to declare. 14 WHO. WHO Model List of Essential Medicines 21st list. 2019. https://apps. who.int/iris/bitstream/handle/10665/325771/WHO-MVP-EMP-IAU-2019.06- Author contributions eng.pdf?ua"1. All the authors collaboratively designed the study. F.M. planned the first 15 Saleem Z, Hassali MA, Versporten A et al. 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