Biomarker-guided antibiotic use in primary care in resource-constrained environments
Authors: Rune Aabenhus, Jens-Ulrik Stæhr Jensen
Journal: The Lancet Global Health (2016)

Because of antimicrobial resistance, the global overuse of antibiotics is now a threat to one of the most effective and mortality-lowering interventions in modern medicine.1WHOAntimicrobial resistance: global report on surveillance.http://www.who.int/drugresistance/documents/surveillancereport/en/Date: 2014Google Scholar One of the most important challenges is to substantially lower the use of antibiotics when these drugs are not needed. The fear of missing a severe case of pneumonia can incite health-care providers to ignore the fact that, in many non-severe cases of respiratory tract infections, antibiotic treatment will probably not markedly alter the outcome for the individual patient.2Arroll B Antibiotics for upper respiratory tract infections: an overview of Cochrane reviews.Resp Med. 2005; 99: 255-261Summary Full Text Full Text PDF PubMed Scopus (109) Google Scholar Reduction of antibiotic use will require reliable and broadly applicable segregation of non-bacterial infection and trivial bacterial infections from serious bacterial infections. In the Lancet Global Health, Nga Do and colleagues3Do NTT Ta NTD Tran NTH et al.Point-of-care C-reactive protein testing to reduce inappropriate use of antibiotics for non-severe acute respiratory infections in Vietnamese primary health care: a randomised controlled trial.Lancet Glob Health. 2016; (published online Aug 2.)http://dx.doi.org/10.1016/S2214-109X(16)30142-5PubMed Google Scholar report the results of a large (more than 2000 participants) randomised controlled trial of a point-of-care antibiotic strategy guided by C-reactive protein concentrations compared with usual best practice in primary care patients with non-severe acute respiratory tract infection in Vietnam. The results demonstrate that a point-of-care C-reactive protein intervention can reduce antibiotic prescribing in this setting, albeit with only a moderate reduction in absolute risk (adjusted 12·5%; intervention 64·4% vs control 77·9%). Importantly, there were no apparent differences in serious adverse effects or delayed patient recovery. Do and colleagues should be congratulated on completing this ambitious, large-scale trial to assess a point-of-care biomarker-guided antibiotic strategy in a resource-constrained environment. The results expand the current evidence base by showing that such a stewardship approach is applicable in low-income and middle-income countries. Furthermore, Do and colleagues performed a very sensitive sample size calculation to prove the trial robust for subgroup analysis in children. The effect size was similar to adults. The results support the findings from randomised trials in Europe, summarised in a 2014 Cochrane review,4Aabenhus R Jensen JU Jorgensen KJ Hrobjartsson A Bjerrum L Biomarkers as point-of-care tests to guide prescription of antibiotics in patients with acute respiratory infections in primary care.Cochrane Database Syst Rev. 2014; 11 (Cd010130.)Google Scholar which found C-reactive protein effective in reducing antibiotic use with no apparent risk to patient safety. So, why was the effect of the current approach only moderate? Some limitations to the study should be mentioned. First, the cut-off applied in the current study (10 mg/L in children younger than 6 years, 20 mg/L in all other patients) is low, allowing for antibiotic use in many low-risk patients and patients without bacterial infection. Second, overruling of the algorithm was very common; in fact, 88% of all C-reactive protein measurements were below 20 mg/L and thus the potential to reduce antibiotic use seems much higher than the actual numbers in the current study. In order to improve the effect size we should start looking at ways to optimise use of this tool. Undoubtedly, part of this optimisation comes down to issues of public health and cultural habits among both patients and physicians. Physicians should be trained to adhere to the algorithm to a much larger extent. Improved education and associated increased adherence to the algorithm could lead to further reductions in antibiotic use, as can be read from the large degree of heterogeneity detected (I2=84%) corresponding to differences in effect size among sites, which is a specific concern and limitation of the current study. Previous studies have shown that education in communicative skills works well together with point-of-care C-reactive protein testing.5Little P Stuart B Francis N et al.Effects of internet-based training on antibiotic prescribing rates for acute respiratory-tract infections: a multinational, cluster, randomised, factorial, controlled trial.Lancet. 2013; 382: 1175-1182Summary Full Text Full Text PDF PubMed Scopus (280) Google Scholar, 6Cals JW Butler CC Hopstaken RM Hood K Dinant GJ Effect of point of care testing for C reactive protein and training in communication skills on antibiotic use in lower respiratory tract infections: cluster randomised trial.BMJ. 2009; 338: b1374Crossref PubMed Scopus (342) Google Scholar It has also been shown that doctors that do not understand a specific strategy well use it poorly.7Bickell NA McEvoy MD Physicians' reasons for failing to deliver effective breast cancer care: a framework for underuse.Med Care. 2003; 41: 442-446PubMed Google Scholar Arguably, many of these patients should not have a C-reactive protein test done in the first place. Only non-severe infections were included, thus increasing the risk of spectrum bias. Biomarker tests should ideally be used to rule out a high risk of severe infection when the provider is uncertain if antibiotic prescribing is likely to be beneficial, and to negotiate a perceived strong patient demand for an antibiotic prescription. Future trials in settings like the current should consider increasing the cut-off for no antibiotic therapy. If the patient is in no acute distress, with a C-reactive protein level below 50 mg/L, a serious bacterial infection is rarely present. Alternatively, all cases of acute respiratory tract infections that do not need urgent admission to hospital could be included.4Aabenhus R Jensen JU Jorgensen KJ Hrobjartsson A Bjerrum L Biomarkers as point-of-care tests to guide prescription of antibiotics in patients with acute respiratory infections in primary care.Cochrane Database Syst Rev. 2014; 11 (Cd010130.)Google Scholar, 5Little P Stuart B Francis N et al.Effects of internet-based training on antibiotic prescribing rates for acute respiratory-tract infections: a multinational, cluster, randomised, factorial, controlled trial.Lancet. 2013; 382: 1175-1182Summary Full Text Full Text PDF PubMed Scopus (280) Google Scholar, 8Cals JW Schot MJ de Jong SA Dinant GJ Hopstaken RM Point-of-care C-reactive protein testing and antibiotic prescribing for respiratory tract infections: a randomized controlled trial.Ann Fam Med. 2010; 8: 124-133Crossref PubMed Scopus (157) Google Scholar However, reduction of antimicrobial resistance cannot be achieved merely by the introduction of a single test. Access to education, the promotion of a change of behavioural norms, vaccination coverage, and other preventive measures must work in concert to preserve antibiotic efficacy. Regulatory authorities need to consider the vast self-purchase of antibiotics (eg, in Vietnam around 90% of prescriptions are self-purchased)9Nga do TT Chuc NT Hoa NP et al.Antibiotic sales in rural and urban pharmacies in northern Vietnam: an observational study.BMC Pharmacol Toxicol. 2014; 15: 6Crossref PubMed Scopus (137) Google Scholar and legislate to prevent this bypass of proper medical control of over-the-counter sales. Implementation of antibiotic stewardship strategies often awaits proof of cost effectiveness.10Oppong R Jit M Smith RD et al.Cost-effectiveness of point-of-care C-reactive protein testing to inform antibiotic prescribing decisions.Br J Gen Pract. 2013; 63: e465-e471Crossref PubMed Scopus (58) Google Scholar This convention must be challenged: we are facing a problem of a magnitude that urges us to implement effective strategies even if they are marginally more expensive. The rise in antimicrobial resistance suggests that short-term savings of the current strategy could be vastly outweighed by future costs for hospital treatment of otherwise trivial infections with highly resistant infectious pathogens.11Smith R Coast J The true cost of antimicrobial resistance.BMJ. 2013; 346: f1493Crossref PubMed Scopus (312) Google Scholar We declare no competing interests. Point-of-care C-reactive protein testing to reduce inappropriate use of antibiotics for non-severe acute respiratory infections in Vietnamese primary health care: a randomised controlled trialC-reactive protein point-of-care testing reduced antibiotic use for non-severe acute respiratory tract infection without compromising patients' recovery in primary health care in Vietnam. Health-care providers might have become familiar with the clinical picture of low C-reactive protein, leading to reduction in antibiotic prescribing in both groups, but this would have led to a reduction in observed effect, rather than overestimation. Qualitative analysis is needed to address differences in context in order to implement this strategy to improve rational antibiotic use for patients with acute respiratory infection in low-income and middle-income countries. Full-Text PDF Open Access