Tuberculosis (TB) the second most lethal infectious disease killer after COVID-19 around the world in 2021, with approximately 1.6 million people died from TB in 2021 (1). Among the 22 countries in the Eastern Mediterranean region, Pakistan ranks 6th in terms of TB disease burden and 1.5 million among 210 million suffers from TB (2). Antibiotic resistance (AR) is increasing drastically around the globe and Pakistan is no exception with the increase of 65% in antibiotic consumption between the years 2000 and 2015, with the number of DDDs rising from 0.8 to 1.3 billion (3, 4). In TB patients its emergence is elevating due to various factors, including delays in diagnosis, inappropriate drug regimens, treatment costs, treatment discontinuation and incomplete courses, poor follow-up, and lack of social support (5). A time series analysis conducted from 2000 to 2017 in the Eastern European region and Central Asian region revealed the emergence of multidrug-resistant tuberculosis (MDR-TB), particularly AR, in treatment regimens (6). In lower-income countries, antibiotics used in the treatment of TB are readily accessed through community pharmacies, and community pharmacies are serving as the primary point of contact for initial TB care (7). TB patients often seek medical care from private health sectors, private practitioners, clinics, NGOs, and community pharmacies. At the initial stage, TB symptoms such as cough, chest pain, and fever may lead many TB patients to approach community pharmacies for temporary relief, which can ultimately contribute to the emergence of AR (8).

The involvement of pharmacists at community pharmacies in TB management is crucial in combating AR in TB. The dispensing of antibiotics at community pharmacies raises concerns in TB management, as antibiotics are often dispensed without a prescription and in the absence of a qualified pharmacist (9). Study from South Africa, India, Uganda, Vietnam, Zambia, and Pakistan revealed that approximately 60% of TB patients seek assistance from community pharmacies before receiving a proper diagnosis of TB (10–12). The dispensing of broad-spectrum antibiotics to TB patients is a major contributing factor to the development of MDR-TB (13). While the drug regulatory authority of Pakistan has mandated the presence of a qualified pharmacist at community pharmacies for antibiotic dispensing in TB cases, the common practice of dispensing antibiotics without prescription still persists in Pakistan (14, 15).

The dispensing practices of antibiotics can be monitored through the use of the standardized client method. Also known as the simulated or mystery client method, this approach is considered the gold standard tool for monitoring the dispensing practices of antibiotics worldwide (16). A simulated study conducted in South Africa, India, China, and Vietnam yielded promising results in identifying the dispensing practices of antibiotics in TB (17–20). The mystery client method is highly effective approach for observing the dispensing practices of antibiotics in TB, as many patients initially seek care at community pharmacies (21). The use of standardized patient (SP) surveys is an ideal method to assess the clinical and dispensing skills in real-life settings at community pharmacies. Mystery shoppers, acting as trained actors following predefined standardized protocols, evaluate the actual dispensing practices and counseling skills of qualified personnel in various disease management scenarios (10). In Pakistan, community pharmacies are extensively distributed and offer healthcare services, with 96% of them dispensing antibiotics as over-the-counter (OTC) drugs without a prescription. As a result, community pharmacies play a crucial role in TB management but also contribute to the development of MDR-TB due to inappropriate dispensing of antibiotics (22). As part of the “WHO End TB Strategy” program, the World Health Organization (WHO) has implemented the National TB control program in Pakistan, giving top priority to community pharmacies and private sector stakeholders to promote TB control. However, despite the concurrent efforts of the government and the availability of national TB guidelines, there is still a misuse of antibiotics in TB management in Pakistan (23). The most common dispensing practice in TB at community pharmacies is the provision of fluoroquinolones and corticosteroids for temporary relief of symptoms (24). Previous cross-sectional and qualitative studies have reported the irrational dispensing of antibiotics in TB in lower-income countries (25, 26). A study conducted in China reported the non-prescription dispensing of antibiotics for upper respiratory tract infections and diarrhea by SP (21). Simulated patient surveys have been conducted in both lower-income and high-income countries to monitor the dispensing practices of antibiotics at community pharmacies. These surveys are widely accepted, cost-effective, and can be completed within a limited time frame (11, 27). To the best of our knowledge, there is a lack of studies utilizing the SP approach to evaluate the dispensing practices of antibiotics in TB management at the community level in Pakistan. The aim of our study is to assess the non-prescription dispensing of antibiotics through simulated patients at community pharmacies.

One hundred seventy-one (56.0%) of pharmacists referred Case 1 to HCPs, but because in 58 (33.9%) of 171 cases the SP was also given any medication, so ideal case management occurred in 115 (37.7%) of 305 Case 1 interactions. Antibiotics were dispensed in 71 of 305 instances (23.3%), steroids in 46 (15.1%), and fluoroquinolones in 18 (5.9%). OTC drugs (e.g., ibuprofen or cetirizine) use was amazingly very low 42 (13.8%) of total case 1 occasions. The dispensing of Schedule G drugs was nil (0 [0%] of 305) but there was only one case for TB drugs (1 [0.3%]).

In contrast to Case 1, 215 (79.6%) of 270 pharmacies referred Case 2 to HCPs. As before, some SPs received medications even with a referral, so ideal case management was observed in 130 (48.1%) of 270 interactions. Antibiotics was used in 27 (10.0%) of 270 occasions, steroids in 19 (7.0%), and fluoroquinolones in 29 (10.7%), OTC drugs were still dispensed in 28 (10.4%) of 270 interactions. But amazingly anti-TB drugs were given in 19 (7.0%) of total instances. Table 1 provides the percentage of the key outcome variables in three cities combined for Case 1 and Case 2.

In terms of referral, significant differences existed between Case 1 and Case 2, with a larger proportion of Case 2 being referred to HCPs. Figure 1 shows the proportions of interactions that received antibiotics, steroids, fluoroquinolones, or no drugs, separated by case and referral decision. We observed variable response patterns across the three cities, with high rates of referrals and ideal case management observed in Lahore. There were two notable differences: the use of antibiotics and steroids was high in Islamabad, while the use of fluoroquinolones and anti-TB drugs was much higher in Sialkot (Figure 2).

In terms of the number of drugs given, for Case 1, pharmacies dispensed an average of 1.62 medicines. The most commonly dispensed drugs were antibiotics [71/305 (23.3%)], followed by steroids (15.1%) and OTC medications (13.8%). Among antibiotics, the most commonly dispensed were amoxicillin (36/305, 11.8%) and Cefixime (24/305, 7.9%). Eighteen pharmacies (5.9%) dispensed fluoroquinolones (such as levofloxacin, ciprofloxacin, ofloxacin), while 46 (15.1%) of 305 gave steroids such as prednisolone and betamethasone.

For Case 2, pharmacies dispensed an average of 1.42 drugs. The drugs dispensed for this case were similar to Case 1 but with lower frequencies, except for fluoroquinolones and Anti-TB drugs, which increased to 10.4% from 5.9 and 7.0% from 0.3%, respectively.

To the best of our knowledge, this study is the first of its kind to employ the SP method to evaluate the treatment patterns of TB patients by pharmacies in Punjab, Pakistan. The use of SPs allowed for consistent presentation of the underlying condition across different HCPs (20, 21). The study results are valid, reliable, and comparable across pharmacies. Our key findings indicate that one patient presenting Case 1 and 19 SPs with confirmed diagnoses were given first-line anti-TB drugs. This raises concerns about the dispensing of anti-TB medications by pharmacies in major cities (Lahore and Sialkot), as pharmacies may be a potential source of irrational dispensing practices contributing to MDR-TB. In a study in Pakistan 96.9% pharmacies and medical stores dispensed antibiotics without asking for prescription and only 3.1% of pharmacies not agreeing to dispense antibiotics. The most frequently dispensed antibiotic was ciprofloxacin (22.1%) (30) Further research is needed to understand the reasons behind the dispensing of TB drugs by pharmacies, considering that their dispensing is strictly supposed to be on a prescription basis. These findings contrast with a study conducted in India where no cases were dispensed anti-TB drugs (18). Despite India and Pakistan having similar demographic distributions, there is a notable difference in regulations. In India, since 2013, regulations have been strengthened, specifically for anti-TB drugs and certain fluoroquinolones (such as moxifloxacin and levofloxacin), which are listed on Schedule H1. These drugs require a prescription from a qualified HCPs, and there is a mandatory register to record patient information, prescriber details, and the quantity of drugs supplied (18).

Although 23.3% of patients presenting with TB symptoms but without test results were dispensed medications, the use of fluoroquinolones (5.9%) and steroids in 15.1% of interactions is particularly concerning. These drugs can potentially delay the diagnosis of TB, which is alarming (31). Fluoroquinolones are essential for MDR-TB treatment, making their misuse a grave concern (31). The wide use of antibiotics and steroids for respiratory ailments has led to an increase in community-acquired infections. Unnecessary use of fluoroquinolones contributes to diarrheal illness and the development of resistant Gram-negative enteric bacteria, particularly in Pakistan and India (32). Our study also observed high utilization of amoxicillin (aminopenicillins) and azithromycin (macrolides) for respiratory ailments, which can contribute to the development of resistant strains among common respiratory pathogens like Haemophilus influenzae and Streptococcus pneumoniae (33). The use of steroids can increase the risk of cellulitis, herpes zoster, candidiasis, and other respiratory tract infections, as well as potentially delaying the diagnosis of TB. Furthermore, we observed a significantly higher utilization of anti-TB drugs and steroids in Sialkot compared to Lahore, indicating differences across cities. Despite our efforts to capture a diverse sample across these three cities, the variation remains unexplained. Similar findings were observed in a previous study conducted in Patna, India, where there was an increased use of antibiotics and steroids (18).

The information provided by patients to pharmacists plays a crucial role in the management of TB and AR. In the case of Case 2, which involved confirmed diagnoses, there was a noticeable increase in ideal case management, indicating that pharmacists may face challenges in diagnosing the condition. However, the change in management in confirmed cases suggested that pharmacists tend to decrease the use of medicines once a diagnosis is confirmed. The reasons behind why some pharmacies dispensed antibiotics while others did not, and why pharmacy personnel are reluctant to follow drug use regulations in these three cities, remain unknown. Better training on TB symptoms and promoting early referrals for patients with TB symptoms could also be helpful in addressing this issue. Additionally, a qualitative evaluation of pharmacists is necessary, as past studies have suggested that various factors may play a role, including local providers’ business models, pharmaceutical industry marketing practices, and patient demand for medicines (34). WHO in its end of TB work recommended TB preventive treatment for people living with HIV, household contacts of those confirmed TB, and risk groups. Globally in 2021, TB preventive treatment was provided to 3.5 million people, slightly higher from 3.2 million in 2020 (1). In order to tackle the emergence of AR and irrationality of antibiotic use AMS is one way forward. AMS refers to acceptance and implementation of interventions to reduce antimicrobial use and bacterial resistance. This program promote surveillance to follow prescribing guidelines and to promote CME among HCPs. The implementation of AMS is associated with reduced antibiotic use, fewer new prescriptions and higher physician satisfaction. Moreover, a US study showed a significant reduction in the number of unnecessary antimicrobial prescriptions after adopting AMS programs in their emergency department (35).

Our study has strengths such as firstly, demonstrated the effectiveness of the SP method in identifying inappropriate antibiotic use for TB patients. Secondly, SP method is gold standard procedure for the evaluation of practices related to any behavior in healthcare system. By using SP method, we concluded that the dispensing behavior varies as we move from unconfirmed to confirmed disease. By developing 2 different SP case presentations, we studied how providers dealt with various stages of TB disease and varying levels of diagnostic certainty our large-scale, 3-city quality of TB care at pharmacies provides accurate estimates of provider behavior that may inform not only quality-improvement efforts in health but also interventions to improve TB care and reduce transmission in the community. It also has some limitations such as it does not provide insights into the actions taken by pharmacists when they encounter regular clients or clients who return after ineffective treatment. Second, our cases are designed as one-time interactions, and the SP data do not reflect follow-up visit pathways, which have been shown by other studies. This study was conducted during the COVID-19 pandemic and findings should be considered within this unique context.

High antibiotic use was observed in both cases, and in the case of Case 1, this could be potentially delaying the diagnosis. Pharmacies also dispensed anti-TB drugs, stronger fluoroquinolone antibiotics, and steroids, although in low frequencies. However, no drugs from restricted classes were given. Interestingly, there was a sharp decrease in antibiotic use in the case of confirmed diagnosis. These findings highlight the need for interventions to actively involve pharmacies in TB control and promote antimicrobial stewardship practices.

The original contributions presented in the study are included in the article/Supplementary material, further inquiries can be directed to the corresponding authors.

We obtained ethical approvals from the medical research ethics committee of Xi’an Jiaotong University China (XJTMD11-2020), and research ethical review board committee of the Superior University, Lahore (ERB-PH2020). The studies were conducted in accordance with the local legislation and institutional requirements. The ethics committee/institutional review board waived the requirement of written informed consent for participation from the participants or the participants’ legal guardians/next of kin because it was observational study of standardized patients so getting approval would tip of the Pharmacist and increase detection rate of SP.

AG, HA, and YF conceptualized the study. AG, HA, HM, MU, SX, WJ, KB, JC, and CY, conducted simulated client training and collected the data. AG and HA analyzed the data. AG and HA wrote the initial draft. YF supervised the whole study. All authors contributed to the article and approved the submitted version.