The discovery of penicillin and its therapeutic potential in the management of bacterial infections is one of the greatest advances in therapeutic medicine.1,2 Penicillin ushered in the age of antibiotics1 with its extensive use beginning in the 1940s, and it is still valuable today.1,2 Penicillins are bactericidal and effective over a spectrum of gram-positive, gram-negative, and anaerobic microorganisms.2 The appearance of resistant bacterial strains has limited their use in recent years;3,4 however, penicillins are still very useful in the management of some respiratory tract infections (e.g., tonsillitis, pneumonia), skin and soft tissue infections (e.g., cellulitis, erysipelas), and gastrointestinal tract infections (Helicobacter pylori, diarrhea of bacterial etiology), among others.5,6 Penicillins are currently the most widely used antibiotics in Colombia7 and worldwide.3,8

Antimicrobial resistance is among the top 10 threats to global health and has significant socioeconomic and public health impacts.9 These impacts are usually more serious in low- and middle-income countries.3,4 Various factors are involved in their effects on public health, but the excessive or improper use of antibiotics is the main factor leading to the emergence of antimicrobial resistance.9 The inappropriate use of antibiotics is commonly due to incorrect drug selection or determination of a dose and duration of treatment that do not correspond to the recommendations of clinical practice guidelines.4,10 Sociodemographic conditions and factors of the prescriber and/or patients contribute to the inappropriate use of antibiotics.11 For this reason, the World Health Organization (WHO) constantly promotes the rational use of antibiotics in populations.10 Multidrug-resistant microorganisms are responsible for 700,000 deaths worldwide each year and are projected to cause 10 million deaths by 2050.12 These infections are associated with increased costs of care, prolonged hospital stays, and increased mortality.12,13

The Colombian health system has a health benefits plan that provides universal coverage to all people through two paths (contributory and subsidized). The contributory regimen is paid for by people with a work contract and their employers, as well as independent workers with the ability to pay and people who are retired. The subsidized regimen is paid for by the state. The health benefit plan is the same for both regimens and includes several penicillins at different dosages.14 The access route to the Colombian health system is through the general practitioner. They can refer patients to being evaluated by specialist doctors. Studies have been conducted in the country on patients with skin and soft tissue infections, as well as on patients with Helicobacter pylori infections, and evidence of inappropriate use of antibiotics has been found.15,16 However, the specific use of penicillins in the outpatient setting, the degree of adherence to the recommendations of drug regulatory agencies, and their use in approved and unapproved indications in Colombia are unknown. The objective of this study was to determine the prescription patterns and approved and unapproved indications for the use of penicillins in a group of patients from Colombia.

This study revealed the prescription patterns of penicillins and their use for approved and unapproved indications in outpatients from different geographic regions of Colombia. A predominance of amoxicillin prescriptions was observed, and some therapeutic behaviors were not consistent with the recommendations of the clinical practice guidelines. Studies with real-world evidence provide insight into how drugs are used in populations, allowing the use of interventions to improve the quality of prescriptions if their use is not appropriate. The WHO has estimated that more than half of the world's medicines are improperly prescribed, dispensed or sold.10 However, the implementation of antimicrobial optimization programs in Colombia aims to improve the rational use of antibiotics and reduce antimicrobial resistance.21,22

The consumption of penicillins in this study was greater than that reported in the WHO and European registries.3,8 According to the WHO Global Antimicrobial Resistance and Use Surveillance System (GLASS), which includes data from 27 countries on different continents, the consumption of penicillins is 7.1 DDD per 1000 inhabitants per day.3 According to the European Surveillance of Antimicrobial Consumption Network (ESACNet), in outpatients from 28 European countries, the consumption of penicillins is 8.0 DDD per 1000 inhabitants/day.8 Amoxicillin was the most commonly used penicillin in this study, which is consistent with findings in Colombia7 and worldwide.3,8 The high prescription of amoxicillin may be due to its low cost since all pharmaceutical forms of amoxicillin are covered by the Colombian Health System.14 Additionally, amoxicillin is an essential antibiotic and belongs to the WHO “Access” group of antibiotics, which are recommended as first- or second-line empirical treatment options for many common infections.23 In contrast, the high prescription rate could also indicate an overuse of antibiotics or their use for unapproved indications.10,24 Furthermore, it is important to highlight that resistance to this penicillin is common, which could lead to therapeutic failure in some patients.25

The prescription of penicillins for unapproved indications was found in 31.1 % of patients, which is greater than the rate reported in other international studies with real-world evidence.26-28 In China, 6.6 % of penicillin prescriptions were documented as inappropriate,26 whereas in Canada and the U.S., this figure is 18.3 % and 19.5 %, respectively.27,28 However, in a meta-analysis on the prescription of antibiotics in primary care in low- and middle-income countries, most patients received antibiotics inappropriately (79.7 %; range: 7.9 %‒100 %).4 In Colombia, the use of macrolides (31.3 %) for unapproved indications has also been reported.29 According to the WHO, the inappropriate use and overuse of antimicrobials are the main risk factors for the development of drug resistance.9 Thus, the WHO recommends various interventions to promote the rational use of antimicrobials, including the use of clinical practice guidelines, continuing medical education, the establishment of drug and therapeutic committees, supervision and auditing, among others.10

The main unapproved use of penicillins in this study was for the management of acute rhinopharyngitis, a condition that is generally secondary to viral infections.30,31 This finding is consistent with previous findings reported in Colombia, where antibiotics were used in 24.8 % of patients with viral infections of the upper respiratory tract, and the prescription of penicillins was widely predominant (73.3 %).24 The use of penicillins in purulent skin and soft tissue infections was also common. A study in Colombia revealed that 82.0 % of purulent infections are improperly managed.15 The Colombian clinical practice guidelines recommend the empirical use of penicillins for purulent methicillin-resistant Staphylococcus Aureus (MRSA) infections due to its high prevalence.32 However, no penicillin has a favorable effect on MRSA.5,6,32 Penicillins are also used for the management of urinary tract infections; however, their empirical use is not recommended because of increasing resistance to these medications in gram-negative bacilli such as Escherichia coli, which are the most common etiological agents of urinary tract infections.33,34 The literature describes multiple barriers that can lead to low adherence to the recommendations of clinical practice guidelines.35,36 For example, lack of knowledge of guidelines, lack of training, lack of time, lack of specialized personnel, and patients' sociocultural beliefs, among others.35,36

Helicobacter pylori infection was the most common approved indication in this study. This finding is consistent with that reported in a Colombian study on Helicobacter pylori eradication schemes, where amoxicillin was predominantly used (91.1 %).16 Clinical practice guidelines recommend treatment regimens that involve two or three antibiotics combined with a proton pump inhibitor and, in many cases, bismuth salts.37,38 The extensive use of amoxicillin in eradication schemes is because Helicobacter pylori continues to have good sensitivity to amoxicillin in Colombia (resistance 1.9 %‒9.5 %), in contrast to other antibiotics, such as nitroimidazoles or fluoroquinolones, where resistance is common (72.0 %‒88.0 % and 11.8 %‒27.3 %, respectively).39 However, eradication regimens containing metronidazole or levofloxacin were common. The problem previously identified in Colombia persists,16 which would go against the recommendations of the country's clinical practice guidelines.38 Finally, it is important to confirm the eradication of the microorganism once the treatment regimen is completed.37

Some variables that increased the probability of receiving penicillins for unapproved indications were identified. Younger patients from dispersed regions and prescriptions given by general medicine practitioners increased the risk of receiving penicillins for unapproved indications, which has already been observed in other real-world studies in Colombia.29 Variations in prescriptions between regions may be due to differences in the academic training of physicians, their prescription habits, the local epidemiology of infections, and the availability of medications.29 In Colombia, general practitioners reportedly have low levels of knowledge, attitudes and practices related to antibiotics, contributing to the inappropriate use of these drugs.40 Similarly, patients with a diagnosis of skin and soft tissue infections and infections of the lower respiratory tract were at greater risk of being improperly managed. This increased risk is due to inadequate antibiotic efficacy against MRSA in purulent skin and soft tissue infections5,6,32 and the use of antibiotics in infections that are usually of viral etiology, such as acute bronchitis and bronchiolitis.5,6,31 Patients who had recently used antibiotics were more likely to receive penicillins for unapproved indications. This result may reflect an uncertain diagnosis, antimicrobial resistance, poor adherence to clinical practice guidelines and even the demand for antibiotics by the patient.11

Some limitations should be considered in the interpretation of the results. Antibiotics purchased by patients with their own money are not included in the drug dispensing database of the pharmaceutical manager. The diagnosis for which penicillin was prescribed could not be identified for all patients because the database includes information only on the main diagnosis. The patients’ clinical history was not entered, and the patients were not contacted to document the diagnostic tests they received or to verify the diagnoses and their severity. It was also not possible to determine whether the antibiotic was used for the treatment of infections or for prophylaxis. Among the strengths of the study are the large sample size, the extensive distribution of patients throughout the national territory and the inclusion of patients from the two affiliation regimes of the country's health system.

In this study, penicillins were prescribed mainly by general practitioners, and amoxicillin was the most common penicillin used in outpatients, followed by dicloxacillin, with oral presentations in tablets or capsules. In addition, approximately one-tenth of the patients received another antibiotic, particularly macrolides, and analgesics and anti-inflammatory agents were frequently used. The most common infections for which penicillins were prescribed were those of the upper respiratory tract and gastrointestinal tract, but one-third-of patients received prescriptions for indications that are not approved by regulatory agencies or clinical practice guidelines, especially patients with skin infections, purulent soft tissue infections or lower respiratory tract infections and those who recently used antibiotics.

Finally, these results highlight the need to improve pharmacovigilance and rational antibiotic prescribing systems. It is essential to review and disseminate updated evidence-based clinical guidelines adapted to the local context and the sensitivity and resistance results identified by healthcare institutions. It is important to implement continuing medical education programs and incorporate training in antimicrobial resistance and rational antibiotic use from the undergraduate level. Other strategies include prescription audits and feedback to physicians, as well as the implementation of digital tools in electronic medical records that alert physicians to unindicated prescriptions or recommended alternatives.

LFVR participated in the drafting, data collection, data analysis, description of results, and discussion. BSAC participated in the drafting, description of results. LMLT participated in the drafting, description of results. MVJL participated in the drafting, description of results. MOR participated in the drafting, description of results. JEMA participated in the drafting, data collection, data analysis, description of results, discussion, critical revision of the article, and evaluation of the final version of the manuscript.

This study did not receive funding.