The causes and consequences of non-prescription antimicrobial use are varied. Poor regulation of antimicrobials results from absent policies or, more commonly, from absent enforcement of policies, as happens in southern European countries.51–55
Community antimicrobial resistance was common in several studies that examined communities with frequent use of nonprescription antimicrobials.6–11
Antimicrobial use, whether it is prescription or non-prescription, exerts antimicrobial selection pressure.3–5
No studies have shown that non-prescription antimicrobial use is worse than equally frequent prescription antimicrobial use. However, non-prescription antimicrobials are associated with very short courses41,48,82,85,88,93,101
and inappropriate drug and dose choice.10,41,74,83,85,88
These factors make non-prescription use a greater concern than prescription use. Of note, most community surveys relied on patient reporting of antimicrobial use (with a variable degree of confirmation). Since some surveys reported that patients often do not know they were prescribed an antimicrobial, the true proportion of patients using antimicrobials is probably higher than reported.93
In support of this assumption, more widespread antimicrobial use was identified with urine sampling than with patient selfreport. 97,115–118
Expansion of internet commerce provides virtual worldwide access to non-prescription antimicrobials; those available on the internet are diverse and generally seem to originate in countries in which non-prescription antimicrobials are available.86
Non-prescription use of antimicrobials is inherently associated with little guidance regarding appropriate antimicrobial selection for individual syndromes and safe practices to minimise adverse drug effects (even when provided by a pharmacist).76,81,82,87
Appropriate antimicrobial use is complex and must be based on local susceptibility patterns. In areas where antimicrobial susceptibility data is unavailable, antimicrobial selection is difficult, even for skilled providers.14–16
Uninformed patients or undertrained pharmacy staffrarely have access to basic information regarding appropriate antimicrobial use and do not appreciate the complexity involved in decisions surrounding drug selection.64,67,76,83
As a result, financial concerns often guide antimicrobial selection resulting in short duration of treatment.15,35,119
The conflict of interest inherent in the same individual prescribing and dispensing antimicrobials is a potential target for regulatory intervention.
Despite concerns about inappropriate use, nonprescription status of antimicrobials might be an important mechanism of access to antimicrobials in resource-limited settings. Interventions to reduce inappropriate antimicrobial use, be they focused on prescription or non-prescription, must be monitored so as to not limit access to antimicrobials for those patients with true bacterial disease.120
Receipt of appropriate antimicrobials in a timely fashion is a determinant of good outcome in pneumonia and other serious bacterial illnesses.121
Clear evidence that antimicrobials obtained without prescription are used less appropriately than prescription antimicrobials does not exist. Providers, pharmacists, and patients might be equally as likely to overuse antimicrobials in any given setting.39,64,67
Studies with patients simulated by actors showed that inappropriate antimicrobial dispensing by pharmacists without a prescription occurred frequently.74–83,85
In low-income to medium-income countries, training of health-care workers as part of WHO’s Integrated Management of Childhood Illness strategy has been shown to increase appropriate use of antimicrobials and decrease inappropriate use.122–125
Non-physician health-care workers trained in integrated management of childhood illness might use antimicrobials more judiciously than physician providers. In resource-limited settings, training of nonphysician providers could increase both access to and appropriate use of antimicrobials; this is especially important in regions where inadequate numbers of physician providers could drive non-prescription antimicrobial use.126
Inappropriate antimicrobial use by patients with true bacterial infections is associated with treatment failure and masking of the underlying clinical syndrome.97
In patients treated inappropriately, either because they do not have an underlying bacterial infection or receive an inappropriate drug or suboptimum duration of treatment, patients are exposed to the risks of an antimicrobial without benefit. Although widely perceived as low-risk drugs, antimicrobials are the second most common cause of adverse drug events in the USA,103
and nonprescription antimicrobial use has been associated with severe adverse events including death.98,99
Non-prescription use of antituberculosis drugs for non-tuberculosis indications was common. Since up to a third of the world’s population is estimated to be infected with tuberculosis,13
substantial use of antituberculosis drugs in countries with a high prevalence of tuberculosis is concerning. Essential firstline antituberculosis drugs include rifampicin, isoniazid, pyrizinamide, ethambutol, and streptomycin.13
Although these drugs are generally poor antibiotics, they are available and used for tuberculosis and nontuberculosis indications in many countries with a high prevalence of tuberculosis. Previous use of antituberculosis drugs is a risk factor for development of multidrug-resistant tuberculosis. Second-line drugs including fluoroquinolones and aminoglycosides are also available without a prescription in most countries, which could be a factor in the emergence of extremely drug-resistant tuberculosis.
We have not reviewed interventions to improve nonprescription use, because solutions are often specific to a culture, country, or region.14,15,35
Many groups have described comprehensive guidelines that emphasise development of health-care systems, including a WHO report on containment of antimicrobial resistance.14,33–35,127
Chile and South Korea are notable examples of countries that improved regulation of non-prescription antimicrobial use and seem to have improved resistance profiles.128–130
However, whether or how quickly resistance can be reversed in response to a reduction in selective pressure is unknown.131,132
The contribution of non-prescription antimicrobial use to the worldwide development and spread of antimicrobial resistance genes and bacteria is not known. Hospital and community prescription use and antimicrobial use in livestock production all exert selection pressure for antimicrobial resistance.26
Countries with high levels of community antimicrobial resistance often have non-prescription antimicrobial use. Non-prescription use has been speculated to play an important role in selecting and maintaining these high levels of community antimicrobial resistance.18,20,133,134
Our Review has limitations including the combination of studies with heterogeneous populations and the analysis of studies over a broad time period. Data might not mirror current practice in countries included in our Review. Data about dispensing practices in regions were extrapolated, and although many neighbouring countries probably had similar practices, exceptions exist such as Chile in South America. As in any review, a positive publication bias could affect some findings. Our Review is not meant to be a reference for policy or enforcement of such policy in specific countries, but is meant to be a broad overview of general issues associated with non-prescription antimicrobial use. Future studies are needed that include standardised definitions and methods and sample many countries, such as those done in Europe by Grigoryan and colleagues.52
Studies that focus on individual patients or providers are important to accurately identify practice and not just policy in those regions where substantial differences might exist.83
Studies of antimicrobial use should assess the appropriateness of prescription and non-prescription use so that local interventions could be best targeted for the greatest effect.
Despite many publications describing the frequency of non-prescription use and the adverse effects of such a practice, high-quality research is scarce. In the absence of rigorous studies, interventions to improve nonprescription antimicrobial use by effective restriction of national formularies to safe antimicrobials should be used; this should include restriction of aminoglycosides and other injectable antimicrobials. Essential first-line antituberculosis drugs should be restricted to prescription-only use in all countries, and secondary antituberculosis should be restricted in countries with a high prevalence of multidrug-resistant tuberculosis. Appropriate labelling of anti microbials including common indications, treatment duration, and side-effects could improve safety. Restriction of dispensing to a set number of pills, ideally in blister packs, could aid in appropriate use when healthcare practitioners are not available. In middle-income to high-income countries with reliable access to health-care practitioners, antimicrobials should be restricted to prescription-only status.
Community antimicrobial stewardship must include a focus on non-prescription antimicrobials. Most methods of monitoring antimicrobial use including pharmacy prescription monitoring or health-care insurance billing do not reliably detect non-prescription use. Pharmacy exit interviews or community surveys more accurately identify total antimicrobial use. In countries with high levels of non-prescription use, interventions to decrease community antimicrobial use should focus on the general public. Countries that have effectively decreased non-prescription use have done so by combining regulation with expanded access to health care.