Abstract
Background
Obesity is on course to overtake being underweight as a global disease burden. Obesity alters antibacterial pharmacokinetics (PK) and pharmacodynamics (PD). Historically, drug PK/PD parameters have not been studied in obese populations. This means dose recommendations risk being sub-therapeutic in a population at increased risk of infection. Suboptimal antibacterial prescribing is widely associated with treatment failure, worse clinical outcomes, unnecessary escalation to broad-spectrum therapy and the emergence of antimicrobial resistance (AMR).
Objectives
To analyse current information provided by pharmaceutical companies, for the most commonly prescribed antibacterial agents in the UK, for evidence of dosing guidance for obese adults.
Methods
We analysed the manufacturers' Summary of Product Characteristics (SPC) for 42 of the most clinically important and frequently prescribed antibacterial agents dispensed across both primary and secondary care. The manufacturer's SPC was reviewed, and cross-referenced with the online British National Formulary, to assess dosing guidance for obese adults.
Results
No advice was provided to guide dosing for obese adults in 35 (83%) of 42 of the most clinically important and frequently prescribed antibacterial agents in the UK. Seven (17%) antibacterial agents (tigecycline, vancomycin, daptomycin, amikacin, gentamicin, tobramycin and teicoplanin) provided variable levels of advice.
Conclusions
There is a paucity of advice and evidence in the UK to guide dosing common antibacterial agents in the obese. The literature on antibacterial PK/PD studies in obese populations remains scarce. In the face of the increasing risks of AMR combined with the global rise of obesity there is an urgent need to address this significant research gap.
Introduction
Obesity carries a disease burden that is affecting all regions of the world. If current trends continue, by 2025, global prevalence will reach 18% in men and surpass 21% in women.1 In the UK alone, it is estimated that 7 in 10 of the adult population will be obese by 2030.2 Within England, there were five times as many hospital admissions with a primary diagnosis of obesity in 2013–14, when compared with 2003–04,3 with 1 in 5 hospitalized inpatients currently being obese.4 Obesity increases the risk of infection after neurosurgery,5 cardiothoracic surgery,6 orthopaedic surgery,7 colorectal surgery8 and obstetric surgery;9 in addition to increasing the risk of periodontitis and a range of nosocomial-associated infections.10,11 Achieving therapeutic antibacterial dosing for the prophylaxis and treatment of infections in obese patients is an increasingly common challenge faced by healthcare professionals today.12 Optimizing antibacterial therapy in this population is of utmost importance given these patients' vulnerability to infection and the risks associated with suboptimal antibacterial prescribing. These risks include worse clinical outcomes and the emergence of antimicrobial resistance (AMR). Obesity has been identified as an independent risk factor for MRSA nasal colonization13 and bacteraemia,14 in addition to the development of a range of MDR organism infections post-operatively.15,16 The rising prevalence of both obesity and AMR represent a huge challenge and their complex interaction is an unprecedented threat to global health and economic security.17,18
Obesity alters antibacterial pharmacokinetics (PK) and pharmacodynamics (PD)
Antibacterial agents may be classified as lipophilic or hydrophilic, depending on their propensity to partition into fat or water. The fluoroquinolones, macrolides and tigecycline are lipophilic; with a larger volume of distribution they more likely to penetrate deep tissues and be metabolized hepatically. In contrast, the β-lactams (penicillins, cephalosporins, carbapenems), aminoglycosides and glycopeptides are hydrophilic agents, giving them a smaller volume of distribution and making them more likely to be renally excreted.19
The volume of distribution, alterations in protein binding, hepatic metabolism and renal excretion are affected by both obesity and the pathophysiology of infection.20 An increased volume of distribution in obesity is partly attributed to the water content of adipose tissue (through which hydrophilic agents will partition), increased serum fatty acids (which may displace drugs from protein-binding sites) or reduced plasma albumin concentration (as a result of critical illness). Changes in hepatic metabolism, although not fully understood, in combination with enhanced renal clearance are also a concern in obesity.21 To compound this, clinical tools commonly used to guide antibacterial dosing, such as the estimation of creatinine clearance (CLCR) using the Cockcroft–Gault formula,22 have not been validated for obese populations. The Cockcroft–Gault formula often overestimates CLCR when used with total body weight and generally underestimates CLCR when calculated with ideal body weight. Unclear recommendations on whether to use total body weight, ideal body weight or an adjusted body weight when prescribing for obese adults increases the risk of incorrect dosing and may contribute to increased rates of toxicity for a range of antimicrobial agents. Of particular concern, nephrotoxicity associated with the aminoglycosides has been seen more commonly in obese adults despite serum concentrations being within range,23 highlighting the importance of appropriate advice on safe and efficacious dosing.
The ultimate outcome of obesity on drug processing is complicated and multipartite, reflecting patient, condition, pathogen and drug parameters. It is clear, however, that any of the PK/PD factors mentioned increase the risk that currently recommended dosing strategies, which adopt a ‘one size fits all’ approach, are providing inadequate drug exposure, promoting AMR and risking clinical failure on a large scale.
We report here our findings on the current guidance, provided by pharmaceutical companies, for the most commonly prescribed antibacterial agents in the UK, for evidence of dosing strategies in obese adults.
Methods
Data collection
National antibiotic prescribing and consumption data were retrieved from the report published in 2015 by the English Surveillance Programme on Antimicrobial Use and Resistance (ESPAUR).24 We reviewed all antibacterial agents that had been identified nationally with an ascribed DDD per 1000 inhabitants per day in England in 2014. Of these antibacterials, we identified the most commonly prescribed by including those with a DDD >0.014 per 1000 inhabitants per day. We subsequently broadened our inclusion to antibacterials that despite not being associated with a DDD per 1000 inhabitants per day were identified in the ESPAUR report to be of additional prime clinical importance across both primary and secondary care.24 Antifungal, antiviral, antileprotic and combined antituberculous therapies were excluded.
For each antibacterial agent that met the inclusion criteria (Table 1) the manufacturer's Summary of Product Characteristics (SPC) was reviewed from the electronic medicines compendium (EMC) web site (www.medicines.org.uk). Approximately 200 pharmaceutical companies inform the EMC, with the UK Medicines and Healthcare Regulatory products Agency (MHRA) approving the information supplied. The SPCs were cross-referenced with the online British National Formulary (www.medicinescomplete.com). Guidance provided by either source was classified according to whether there was: (i) advice to alter the dose for obese adults; (ii) a caution provided that the dose may need to be altered; (iii) advice suggesting that no dosing adjustment is necessary for obese adults; or (iv) no advice provided for dosing in obesity. Analysis occurred between 5 April 2016 and 13 April 2016.
Table 1.
The most commonly prescribed antibacterial agents in England in 201424
| Antibacterial class/agent | DDD per 1000 inhabitants per day |
|---|---|
| Penicillins | |
| benzylpenicillina | |
| amoxicillin | 5.60 |
| flucloxacillin | 1.91 |
| co-amoxiclav | 1.73 |
| phenoxymethylpenicillin | 0.84 |
| piperacillin/tazobactam | 0.10 |
| temocillina | |
| Tetracyclines | |
| doxycycline | 2.23 |
| lymecycline | 1.80 |
| oxytetracycline | 0.84 |
| minocycline | 0.08 |
| tetracycline | 0.05 |
| Macrolides | |
| clarithromycin | 1.87 |
| erythromycin | 1.01 |
| azithromycin | 0.44 |
| Cephalosporins | |
| cefalexin | 0.28 |
| cefuroxime | 0.03 |
| ceftriaxone | 0.03 |
| cefradine | 0.02 |
| cefotaxime | 0.02 |
| cefaclor | 0.014 |
| Carbapenems | |
| meropenem | 0.07 |
| ertapenem | 0.01 |
| imipenem/cilastatin | 0.00055 |
| Quinolones | |
| ciprofloxacin | 0.46 |
| ofloxacin | 0.04 |
| levofloxacin | 0.04 |
| moxifloxacin | 0.02 |
| Sulphonamides and trimethoprim | 1.61 |
| co-trimoxazolea | |
| trimethoprima | |
| sulfadiazinea | |
| Aminoglycosides | 0.13 |
| amikacina | |
| gentamicina | |
| tobramycina | |
| Glycopeptides | |
| teicoplanin | 0.06 |
| vancomycin | 0.02 |
| Others | |
| nitrofurantoin | 0.88 |
| daptomycin | 0.0057 |
| clindamycina | |
| metronidazolea | |
| linezolida | |
| tigecycline | 0.00298 |
aDDD for the individual antibacterial agents were not published in the ESPAUR report.
Results
We analysed the SPCs for the most commonly used and clinically important antibacterials registered in the UK (n = 42). Fifteen agents accounted for 85% of total antibacterial use in secondary care and 27 agents were considered to be of clinical importance across both primary and secondary care.24 Figure 1 shows a breakdown of advice provided in the SPC data by antibacterial class.
Figure 1.
Advice provided on dosing in obese adults for the most commonly dispensed and frequently prescribed antibacterial agents in the UK.18
No advice was provided to optimize antibacterial dosing for obese patients in 35 (83%) of 42 of the most frequently prescribed and clinically important antibacterials in the UK. Limited advice was provided for 7 (17%) antibacterial agents. This was concordant with results obtained after cross-referencing with the online British National Formulary.
The SPC for tigecycline suggests no dosing adjustment is necessary for increased weight as area the under the curve (AUC) is not appreciably different among patients with different body weights, including those weighing ≥125 kg. However, no data were available for patients weighing >140 kg.25 For vancomycin and daptomycin the SPC cautions that the dose may need to be adjusted for patients with increased weight. For amikacin, gentamicin, tobramycin and teicoplanin the SPCs recommended adjusting the dose for patients with increased weight by taking into consideration laboratory parameters such as CLCR, careful clinical observations for side effects and efficacy, in addition to therapeutic drug monitoring where possible. The SPC for tobramycin gave detailed dosing advice for obesity by recommending the appropriate dose be calculated by using the patient's estimated lean body weight (LBW), plus 40% of the excess weight.
For the three classes of antibacterial agents most commonly prescribed in the UK in 2014 (penicillins, 45%; tetracyclines, 22%; macrolides, 15%),24 no advice was provided on whether dose adjustment is required in obese patients.
Discussion
Despite evidence of a global obesity epidemic, information to optimize the dosing of antibacterial therapy in obese adults, for both the prophylaxis and treatment of infection, is limited and variable. Suboptimal antibacterial prescribing is associated with a range of unintended adverse consequences,26 with obesity and body composition adding a layer of complexity to the management of infection through their influence on the PK of antibacterial agents.20,21
The SPCs (n = 7) that included a strategy for dosing based on body weight were all intravenous agents. The majority of antibiotics in England are prescribed in general practice (74%), followed by hospital inpatients (11%), hospital outpatients (7%) and patients in other community settings (8%).24 The lack of dosing data on oral agents in obese adults is of particular concern.
Improving clinical trial design and reporting
The lack of information on dosing in obese adults in the SPC guidance contrasts with a relatively larger amount of published literature.21 The existing data on optimal dosing in obesity are conflicting, with wide variation in research quality and design, and an apparent disparity between agents that are more frequently investigated and those that are more commonly used,21 and thus it remains difficult to draw definitive conclusions. There also exist variations in the optimal dosing strategies between surgical prophylaxis and treatment. Whether optimal dosing involves adjusting the dose, or the dosing interval, will differ for different agents in different clinical scenarios and is largely unknown. In addition, the most appropriate measure of body size will be different for different agents, with recommendations for dosing adjustment requiring the correct dosing weight to be determined. The lack of consensus and gaps in the scientific literature emphasize the urgent need for prospective well-designed interventional studies and clinical trial data, augmented with detailed PK analysis to improve our understanding of antibacterial dosing in obesity.
Role of regulators, international collaboration and research funding
Regulatory requirements to identify appropriate dosing regimens for obese adults should promote opportunities for funding, enabling investigator-led, real-world PK/PD studies of antibacterial safety and efficacy. Population PK/PD modelling will improve our ability to describe and understand the PK of antibacterial agents in obese adults. Building capacity to conduct these studies and complete the complex modelling required will assist the re-evaluation of older agents in a variety of patient populations, for which concern also exists regarding optimal drug handling and exposure. The SPCs should be regarded as ‘living documents’, with regulatory frameworks that require their rapid revision when licensing bodies are supplied with high-quality evidence that improves our understanding of their use. Methods have been proposed to pool the evidence for antibacterial dosing in children,27 and efforts have been made to conduct meta-analysis of PK data for other medicines in morbidly obese adults.28 However, systematic review and meta-analysis of PK studies is widely regarded as challenging due to heterogeneity.29 Expert consensus will be necessary to determine high-quality PK studies of antibacterial agents in obese adults, which merit inclusion in the SPC. This consensus will also ensure investigators' efforts are directed prudently and will increase the likelihood of future meta-analyses as real-world studies become more uniformly conducted. Regulatory requirements for industry-led studies during the drug registration process will further ensure our understanding of new antibacterial agents for obese populations.
It is clear that significant funding will be required to improve our understanding of dosing in obese adults across the full range of antibacterial agents. International collaboration will allow the mobilization of resources to investigate a range of agents in parallel, ensuring also the generalizability of results. However, setting this issue as a priority on the global research agenda will require stakeholders and funding bodies to realize the necessity of the work. It is hoped that the final UK Report on Antimicrobial Resistance, which cites the importance of improving the use of our existing antibacterial agents, will provide the political and economic incentive needed.30
Optimizing and re-evaluating the most commonly used antibacterial agents
Historically, antibacterial PK/PD parameters have not been studied in obese populations. This may have been due to pressures on the pharmaceutical industry to limit PK variability within drug registration trials. A lack of specific PK/PD data may also have contributed to the exclusion of obese adults. Many of our ‘workhorse’ antibacterial agents were developed at a time when there was little requirement to evidence efficacy through rigorous clinical trials and the principles of PK/PD were under investigation.31 To compound this, the prevalence of obesity was considerably lower. Given that a growing proportion of our adult population is classed as overweight or obese, the issue of defining pharmacometrics for obese adults requires judicious reassessment. Published PK/PD data on antibacterial agents in obese populations needs to be at the forefront of the global research agenda. There remain additional gaps in our understanding of these medicines in a variety of other patient groups, including paediatric and pregnant populations, for which obesity may also play a role.31 The association between obesity and AMR deserves specific attention and applied research, given the magnitude of the potential public health crises.
Individualized antibacterial therapy in obese patients will optimize dosing, improve clinical outcomes, help to prevent the ecological effects of the emergence of AMR and ensure our existing arsenal of antibacterial agents remain effective to meet the needs of our society for generations to come. Significant funding is being deployed for international antimicrobial drug development, with regulatory frameworks demanding demonstration of average population effectiveness. Yet an urgent need remains to bridge the research gap in order to improve our understanding of effective dosing of existing antibacterial agents in obese adults, across a variety of healthcare settings with particular emphasis on community-based prescribing, before the horse has truly bolted.
Funding
The research was partially funded by the National Institute for Health Research Health Protection Research Unit (NIHR HPRU) in Healthcare Associated Infections and Antimicrobial Resistance at Imperial College London in partnership with Public Health England (PHE) and Imperial College Healthcare NHS Trust.
Transparency declarations
A. H. H. consulted for bioMérieux in 2013 and 2014. All other authors: none to declare.
Disclaimer
The views expressed in this publication are those of the authors and not necessarily those of the NHS, the National Institute for Health Research, the UK Department of Health, or Public Health England.
Acknowledgements
We would like to acknowledge the National Institute for Health Research (NIHR) Imperial Biomedical Research Centre and the NIHR Health Protection Research Unit in Healthcare Associated Infections and Antimicrobial Resistance at Imperial College London, in partnership with Public Health England and the NIHR Imperial Patient Safety Translational Research Centre. G. F. is an NIHR Senior Investigator and S. E. B. is an NIHR Academic Clinical Fellow.
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