1 Introduction

The landscape of pharmaceutical compounding has evolved significantly, introducing both advancements and challenges in contemporary healthcare. Compounding, defined as the customization of medications to meet specific patient needs, plays a pivotal role in tailoring therapies [1]. The practice of pharmaceutical compounding, aimed at tailoring medications to individual patient needs, stands at the intersection of innovation and potential risk. While compounding offers personalized solutions, concerns have arisen regarding its implications for patient safety, specifically in contributing to adverse drug events (ADEs) and antimicrobial resistance (AMR) [2, 3].

ADEs and AMR represent significant challenges in healthcare, with pharmaceutical compounding increasingly recognized as a contributing factor to their occurrence [4]. Studies have documented instances where compounded medications have been associated with adverse outcomes, emphasizing the need to understand the extent of this phenomenon [5]. For instance, research has highlighted incidents such as the 2012 fungal meningitis outbreak [6, 7] and cases of Streptococcus endophthalmitis in 2011 [8], linking inappropriate pharmaceutical compounding to severe medical complications. These incidents underscore the potential contribution of compounded medications to ADEs, prompting concerns about patient safety and regulatory oversight in the compounding industry. Furthermore, the emergence and spread of AMR have become global health concerns, with inappropriate use of antibiotics identified as a key driver [9].

Compounded drugs, by their nature, deviate from standardized manufacturing processes, potentially leading to variations in quality, potency, and stability [10]. Such variations may contribute to ADEs, underscoring the importance of investigating healthcare professionals' awareness of these risks.

Globally, the landscape of pharmaceutical compounding faces challenges related to quality control, standardization, and potential variations in compounded formulations [4, 5]. Moreover, the global concern surrounding AMR has prompted scrutiny of all facets of drug use, including compounding practices. Compounded antimicrobials, in particular, pose challenges due to their potential role in fostering resistant strains [11]. The extent to which healthcare professionals recognize and address the link between compounding practices and AMR remains unclear. Understanding how healthcare professionals perceive the link between compounding and AMR is vital for developing strategies to mitigate these risks.

Healthcare providers, including physicians, nurses, and pharmacists, play integral roles in pharmaceutical compounding, ensuring the safety and efficacy of customized medications for individual patient needs [12, 13].Physicians are primarily responsible for prescribing compounded medications based on their patients' specific medical conditions, therapeutic requirements, and medication tolerances [12]. Nurses, on the other hand, collaborate closely with physicians to gather patient-specific information, monitor treatment responses, and provide valuable input regarding medication efficacy and potential adverse effects during the compounding process [13]. Pharmacists, as medication experts, oversee the compounding process with meticulous attention to detail, ensuring compliance with established quality standards, accurate dosage formulations, and proper documentation [12]. They also play a crucial role in verifying the compatibility of ingredients, assessing stability considerations, and providing patients with comprehensive counselling on medication administration, potential side effects, and necessary precautions [13].

There is no study that systematically examined healthcare professionals' knowledge and perceptions regarding the contribution of pharmaceutical compounding to ADEs and AMR in the Ethiopian context. Therefore, this study aimed to assess the practice and perceptions of healthcare professionals regarding the contribution of inappropriate pharmaceutical compounding to ADEs and AMR at Pawi General Hospital in the Metekel Zone, Benishangul-Gumuz Region.

This study is significant to contribute to the existing literature by assessing healthcare professionals' practice and perceptions of pharmaceutical compounding contribution to ADEs and AMR. By exploring this multifaceted issue, we aim to identify areas of improvement in education and practice, ultimately enhancing patient safety and the quality of compounded medications.

2 Methods

2.1 Study setting and design

A crossectional study design was utilized to assess the practice and perceptions of healthcare professionals regarding the contribution of inappropriate pharmaceutical compounding to ADEs and AMR. The research was conducted at Pawi General Hospital, situated in the Metekel Zone of the Benishangul-Gumuz Region in Ethiopia. Pawi General Hospital, found in Pawi town, a pivotal healthcare institution in the region, offers a wide array of medical services, including pharmaceutical compounding. It serves close to 500,000 people from nearby districts. Since its establishment in 1985, Pawi General Hospital has been catering to the healthcare needs of the community. Pawi town is situated in the northwest region of Ethiopia, approximately 526 km away from the capital, Addis Ababa, and 421 km from Assosa city in the Benishangul Gumuz regional state. The town is bordered by Jawi to the north, Dangur to the northwest, and Gilgel Beles to the northeast. Pawi town consists of 20 kebeles, the smallest administrative units in Ethiopia, each with a population ranging from 500 families to 3500 to 4000 individuals. The total population of Pawi town stands at 89,807, with 44,960 males and 44,847 females. The town is serviced by one governmental hospital and two health centers. The hospital comprises various specialized departments catering to outpatient, inpatient, and operating theatre services, serving an estimated population of 300,000 individuals in the region. With a capacity of 200 beds, the hospital accommodates an average of 1000 inpatients per month. A total of 123 nurses, 25 pharmacists, and 29 physicians are working at the hospital.

2.2 Eligibility criteria

2.2.1 Inclusion criteria

  • Pharmacists, physicians, and nurses directly involved in patient care and pharmaceutical services at Pawi General Hospital during the study period were included.

  • Pharmacists, physicians, and nurses who voluntarily agree to participate in the study were included.

2.2.2 Exclusion criteria

  • Healthcare Professionals not directly involved in patient care and/or pharmaceutical services at Pawi General Hospital

  • Pharmacists, physicians, and nurses on temporary assignments or internships at Pawi General Hospital.

  • Pharmacists, physicians, and nurses who decline to participate in the study voluntarily.

2.3 Sample size calculation and sampling method

The sample size was calculated with GPower statistical software version 3.1.9.4, with a 0.3 effect size, 95% significance level, α = 0.05 and 95% actual study power, reaching a total sample size of 111 individuals.

2.4 Data collection procedures and analysis

The dependent variable in this study is the Practice and Perception of Healthcare Professionals. This variable encompasses the collective understanding, awareness, and perspectives of healthcare professionals at Pawi General Hospital regarding the contribution of pharmaceutical compounding to ADEs and AMR. Sociodemographic characteristics of professionals (profession, gender, age, educational level, work experience and training experience of professionals on compounding medications) were the independent variables.

A self-administered questionnaire was developed from different literature [2, 14, 15] that assess practice and perceptions regarding pharmaceutical compounding, ADEs, and AMR. The questionnaire is available as a supplementary file [Supplementary file 1: Questionnaire]. It has 24 questions. The questionnaire has four sections. The first section contained six questions which focused on socio-demographic characteristics of the participants.

The second section contained six questions which focused on the practices related to compounded medications and AMR. The third section had six questions which focused on the perception of healthcare practitioners on the contributions of compounding to antimicrobial resistance. The fourth part had six questions which evaluated healthcare practitioners’ knowledge of extemporaneous compounding and its contribution to antimicrobial resistance. The questionnaire was pre-tested for clarity on nine healthcare professionals before the actual data collection at Injibara General Hospital and adjusted accordingly. A pharmacist who received training on the study's objectives, ethical considerations, and data collection tools conducted the data collection process. The data collection took place at Pawi General Hospital, where healthcare professionals including pharmacists, physicians, and nurses were approached during their working hours. They were invited to participate voluntarily by filling out the questionnaire during their free time. All questionnaires were distributed and collected by the trained pharmacist after gaining a half day training, ensuring that participants had sufficient opportunity to respond thoughtfully. STATA version 17 was used for analysis. Descriptive Analysis was used to summarize demographic characteristics of participants. The normality of continuous variables was evaluated using the Shapiro–Wilk test, a statistical method designed to determine if a dataset follows a normal distribution. For normally distributed data, variables are reported as means with standard deviations (SD). If the data does not follow a normal distribution, variables are reported as medians with interquartile ranges (IQR). A p-value greater than the significance level of 0.05 suggests that the data does not significantly deviate from normality. Conversely, a p-value below 0.05 indicates a significant deviation from normality. The mean \(\pm \) standard deviations (SD) and percentages (%) of the variables were calculated.

2.5 Ethical approval

Ethical approval was received from obtained Pawi Health Science College. Ethical guidelines were strictly followed to protect the rights and privacy of study participants. Informed consent was obtained from each participant before involvement in the study, ensuring confidentiality, and written consent was acquired before data collection.

3 Results

3.1 Socio-demographic information

About 145 health care professionals were approached, of which 120 completed the questionnaire, resulting in a response rate of 82.75%. Among the respondents, nurses constituted the largest group, accounting for 70.00% of the total participants, followed by pharmacists and physicians comprising 17.50% and 12.50%, respectively. In terms of gender distribution, the majority were males, representing 59.17%, while females accounted for 40.83%. The mean age of the respondents was 32.22 years, with a standard deviation of 0.46. Regarding educational level, the majority held a degree (55.00%) or diploma (42.50%), with smaller proportions having specialty qualifications (1.67%) or master's degrees (0.83%). The average work experience among respondents was 6.38 years, with a standard deviation of 0.36. When queried about their training experience on compounding medications, 22.50% reported having received training, while the majority (77.50%) had not undergone such training (Table 1).

Table 1 Socio-demographic characteristics of respondents (n = 120)
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3.2 Practice of health professionals on compounded medications and AMR

The finding of the study shows that over half of the participants (55.93%) reported having prescribed or dispensed compounded medications. Of those, all respondents believed their practice was appropriate. Nearly half of the respondents (39.17%) felt that their education and training adequately prepared them for prescribing or dispensing compounded medications, highlighting a perceived gap in training adequacy among a substantial portion of the cohort. However, despite their involvement and perceived preparedness, a concerning finding is that a notable proportion of respondents (43.33%) reported experiencing adverse effects or patient harm related (Table 2).

Table 2 Practice of health professionals on compounded medications towards AMR and ADE (n = 120)
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3.3 Sources of information for professionals consult when prescribing or dispensing compounded medications

When prescribing or dispensing compounded medications, healthcare professionals often rely on a variety of sources to ensure accuracy and safety. Among the sources mentioned, guidelines 31.67% are the most frequently consulted. Journals (15.83%) also play a significant role as a source of information. Furthermore, there are respondents (30.83%) who utilize all mentioned sources, including journals, guidelines, online resources, and colleagues (Fig. 1).

Fig. 1
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Sources of information for professionals consult when prescribing or dispensing compounded medications (n = 120)

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3.4 Perception of healthcare practitioners on the contributions of compounding to AMR

3.4.1 Importance of compounded medications in patient care

The majority, constituting 91 respondents or 75.83% of the total, deemed compounded medications in patient care as "Very Important." Another portion, comprising 27 respondents or 22.50%, regarded it as "Somewhat Important." Only a small minority, representing 2 respondents or 1.67%, categorized it as "Not Very Important." Notably, no respondents indicated that the variable was "Not at All important." This distribution highlights a consensus among the majority of respondents regarding the significance of the variable, with a clear emphasis on its importance, as indicated by the overwhelming majority rating it as either "Very Important" or "Somewhat Important." (Table 3).

Table 3 Perception of health professionals on the importance of compounded medications in patient care (n = 120)
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3.4.2 Concerns about contribution of inappropriately compounded medication to AMR and ADEs

A significant majority (61.67%) of respondents, expressed being "Very Concerned" about the contribution of inappropriately compounded medication to AMR and ADEs. Additionally, 31.67% of respondents reported being "Somewhat Concerned,". However, a smaller proportion, representing 3.33% of respondents, reported being "Not Very Concerned". Furthermore, 3.33% of respondents expressed being "Not at All Concern" (Table 4).

Table 4 Concerns about contribution of inappropriately compounded medication to AMRand ADEs (n = 120)
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3.4.3 Responsibility in preventing AMR and ADEs

In this study, a majority of respondents (65.83%), believed that as having "A Lot of Responsibility." in preventing AMR and ADEs from inappropriately compounded medications. Additionally, 25.83% of respondents reported as having "Some Responsibility". However, a smaller proportion, representing 8.33% of respondents, indicated a "Little Responsibility" in preventing AMR and ADEs from inappropriately compounded medications. Notably, no respondents reported having no responsibility (Table 5).

Table 5 Perception of health professionals of their responsibility in preventing AMRand ADEs from inappropriately compounded medications (n = 120)
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3.4.4 Statements for perception evaluation of the contribution of compounded medication to AMR

The survey responses indicate varying levels of agreement on the impact of different compounding practices on antimicrobial resistance (AMR). A significant majority, comprising 52.50%, agreed that cautious use of antimicrobials in compounding can decrease AMR, highlighting the recognition of prudent antimicrobial usage as a key strategy. Similarly, 45.83% of respondents strongly agreed that inappropriate compounding contributes to AMR, emphasizing the importance of proper compounding practices in mitigating resistance development. About 46.67% of respondents agreed appropriate use of broad-spectrum antimicrobials in compounding can reduce resistance (Table 6).

Table 6 Statements for perception evaluation of the contribution of inappropriately compounded medication to AMR (n = 120)
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3.4.5 Statements for knowledge evaluation of the factors contribution to AMR development

Several factors contribute to AMR, as indicated by the percentages of respondents who identified each factor. Under dose administration was recognized by 83.33% of respondents as a contributing factor, while contamination was identified by 71.67%. Moreover, 66.67% of respondents highlighted the ineffectiveness of compounded preparations, and 83.33% pointed to inappropriate preparation processes due to the lack of standard operating procedures. Additionally, incompatibility between drugs and excipients was acknowledged by 79.17% of respondents, and 75.83% indicated the misuse of drugs beyond their use-by date as a factor. These findings underscore the multifaceted nature of AMR and the importance of addressing various contributing factors to combat this global health threat (Table 7).

Table 7 Factors contribution of inappropriately compounded medication to AMR development (n = 120)
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4 Discussion

The present study indicates that a significant portion of participants, over half (55.93%), have prescribed or dispensed compounded medications, suggesting widespread use of these formulations in clinical practice. All respondents who engaged in prescribing or dispensing compounded medications believed their practice was appropriate, reflecting confidence in their abilities in this regard. About 67.50% of professionals are familiar with the concept of AMR associated with compounded medications. However, disparities exist in training and education, with 60.83% of professionals expressing concerns about the adequacy of their preparation for prescribing or dispensing compounded medications. In comparison to the study by Smith et al., our findings align with the global trend where healthcare professionals’ express concerns about the adequacy of their education in addressing issues related to compounded medications and antimicrobial resistance [4].

Lee et al.'s research highlights the importance of continuous education, and our study supports this by emphasizing the need for targeted interventions to enhance healthcare professionals' knowledge [5]. In the current study, about 43.33% of the professionals revealed their experience in the development of adverse effects or patient harm related to compounded medications. Studies also show that the risk of patients experiencing significant harm from substandard medications compounded by pharmacies is considerable. Healthcare providers must acknowledge the potential legal ramifications when prescribing or administering compounded treatments. Patients harmed by compounded medications failing to meet Food and Drug Authority (FDA) standards may litigate against the pharmacy, citing product deficiencies. Additionally, they may pursue legal action against prescribing physicians and medical facilities, alleging professional negligence due to a breach in the expected standard of care [6, 7].

In developing nations, where compounding practices are prevalent, government guidance is urgently needed to mitigate risks associated with extemporaneous preparations and reduce adverse drug reactions (ADRs), particularly in infants who are physiologically immature [14, 16, 17]. The safety and efficacy of such preparations heavily rely on pharmacist professionalism [18].

Unlike licensed drugs, extemporaneous preparations lack clinical evaluation for efficacy and safety, posing risks of adverse events, microbial contamination, calculation errors, patient acceptance issues, and therapeutic risks [19]. Errors during compounding, such as grinding or dilution mistakes, can affect efficacy, safety, and patient acceptance [20]. Establishing standards for compounding processes, including standardized formulas, appropriate equipment, and trained personnel, is crucial to mitigate these risks [21].

The majority of healthcare professionals consider compounded medications to be very important in-patient care. This underscores the significance of these formulations in addressing specific patient needs. Cordina et al. emphasize the crucial role of compounded medications in patient care, and our findings resonate with this by showcasing that 40% of healthcare professionals consider compounded medications to be "Very Important." [10].

Antimicrobial resistance (AMR) poses a significant health challenge worldwide, impacting both developed and developing countries [22]. While the emergence of AMR is a natural occurrence, its progression is exacerbated by the inappropriate utilization of antibiotics [23]. Epidemiological research indicates a clear correlation between antibiotic misuse and overuse and the proliferation of AMR. Overuse and misuse of antibiotics can induce bacterial resistance by either eliminating drug-sensitive receptors or triggering the production of enzymes that counteract the drugs [24, 25].

A considerable number of healthcare professionals express varying levels of concern about the potential contribution of compounded medications to AMR. This highlights a shared apprehension within the healthcare community. The concerns expressed by healthcare professionals in our study regarding the potential contribution of compounded medications to antimicrobial resistance align with Laxminarayan et al.'s call for global solutions to address antibiotic resistance [11]. A substantial portion of respondents acknowledged having a lot of responsibility in preventing AMR related to compounded medications. The distribution of responses on the level of responsibility is consistent with the World Health Organization's global strategy, emphasizing shared responsibility among healthcare professionals in preventing antimicrobial resistance [9].

Professionals generally agree that cautious use of antimicrobials in compounding can decrease AMR. However, opinions are more divided regarding the use of broad-spectrum antimicrobials in place of narrow-spectrum ones and the role of inappropriate compounding in AMR development.

In recent times, there has been a surge in antibiotic resistance, denoting the capability of microorganisms to withstand the effects of one or more drugs used to combat infections they cause. This phenomenon can lead to severe health implications for patients and poses a significant public health concern [26]. Improper use or incorrect dosing of antibiotics may contribute to the development of bacterial resistance.

The present study indicates a varied level of knowledge among healthcare professionals regarding compounded medications and their potential contribution to ADEs and AMRs. The misuse of antibiotics, especially when administered in high or inappropriate doses, can lead to antibiotic resistance [27]. This resistance not only impacts patients' clinical conditions but also carries economic implications, as it may result in worsened or unresolved diseases, leading to increased healthcare costs for patients [28]. Furthermore, the presence of other drugs mixed with antibiotics in suspension dosages can compromise the quality and stability of concurrently prescribed active substances, potentially affecting the therapeutic effects of the medications given to patients [29].

Comparing our findings on cautious use of antimicrobials with European Medicines Agency guidelines reveals a convergence in the understanding that careful and judicious use of antimicrobials is crucial to minimizing resistance [30].

While compounding is considered a traditional method of drug preparation, it continues to be practiced today. However, it still poses challenges due to various issues such as medication errors, compounding quality issues, and the risk of bacterial contamination in compounded dosage forms [29].

Responses to specific knowledge questions indicate a spectrum of understanding. While a majority is aware of factors like contamination and incompatibility contributing to AMR, there's a need for further education, as a significant number still express uncertainty or lack of awareness on these aspects.

The identification of factors such as contamination and incompatibility align with the guidelines provided by the ASHP, emphasizing the importance of quality control measures in compounding practices [13].

The Food and Drug Administration (FDA) acknowledged quality issues with prescribed drugs, including contamination. Contamination in drug compounding was due to the proliferation of pathogenic and non-pathogenic microorganisms, including bacteria and fungi. Significant microbial contamination, particularly of pathogenic bacteria, mold, and yeast, could compromise the safety, aesthetics, therapeutic potential, and drug release of the dosage form [31]. Some instances of contamination not only posed risks to patients but also caused damage to the drug dosage form [32]. Inadequate handling during the compounding and repackaging processes likely contributed significantly to microbial contamination. The presence of microbes in the dosage form not only poses hazards but could also induce physical, chemical, and organoleptic changes in the dosage, alter the content of active substances, and even convert them into toxic products [33].

The identified problems, such as under-dose administration and contamination, align with existing literature on factors contributing to AMR. Addressing these issues requires a multifaceted approach involving education, training, and stringent quality control measures.

Regulatory agencies remain highly concerned about the application of quality standards in extemporaneous compounding. This is because substandard compounding practices can lead to severe contamination that poses life-threatening risks or produce products lacking the necessary strength, quality, and purity [34].

Using pharmaceutical compounded preparations beyond their expiry date can compromise their efficacy, increase the risk of contamination, and contribute to the development of antimicrobial resistance [35,36,37,38]. It is essential to adhere to expiry dates and proper storage conditions to ensure the effectiveness and safety of compounded medications.

Interprofessional collaboration in prescribing and dispensing pharmaceutical compounding is crucial for ensuring safe and effective patient care. Through effective communication and teamwork among pharmacists, physicians, nurses, and allied health professionals, healthcare systems can optimize the compounding process. This collaboration involves obtaining accurate patient information, implementing standardized protocols, and conducting interdisciplinary education and training programs to promote a shared understanding of compounding practices and safety measures. By leveraging the expertise of various healthcare professionals and fostering a culture of collaboration, institutions can enhance medication safety, prevent adverse events, and improve overall patient outcomes in pharmaceutical compounding [39].Overall, the study emphasizes the need for targeted educational interventions to enhance healthcare professionals' knowledge and awareness regarding inappropriately compounded medications and their potential role in AMR. Healthcare professionals demonstrate varying levels of concern and responsibility, indicating the complexity of perceptions within the healthcare community. The findings underscore and gives an implication for the development of standardized training programs, regular updates on best practices, and collaborative efforts among healthcare professionals to address the identified knowledge gaps and concerns.

Strengths of the study include its comprehensive examination of healthcare professionals' perceptions and practices regarding compounded medications and their potential contribution to ADEs and AMR. The study provides valuable insights into knowledge gaps and concerns among healthcare professionals, highlighting areas for targeted interventions to improve patient safety. Additionally, the study's alignment with global trends and existing literature enhances its relevance and significance in the field of pharmaceutical compounding and patient care.

However, the study also has limitations that should be acknowledged. Firstly, the study's sample size and demographic characteristics may limit the generalizability of its findings to broader populations of healthcare professionals. Additionally, self-reported data on perceptions and experiences may be subject to recall bias and social desirability bias, potentially influencing the accuracy and reliability of the results. Moreover, the study's cross-sectional design may restrict its ability to establish causal relationships or capture changes in perceptions and practices over time.

5 Conclusions

This study provides valuable insights into the practice and perceptions of healthcare professionals regarding compounded medications and their potential contribution to antimicrobial resistance. The nuanced understanding gained from this research can inform targeted interventions aimed at improving patient safety and fostering responsible compounding practices within healthcare settings. Recommendations include the development of standardized training programs, regular updates on best practices, and collaborative efforts among healthcare professionals to address the identified knowledge gaps and concerns. By emphasizing the development of standardized training programs, regular updates on best practices, and collaborative efforts among healthcare professionals, this research offers tangible strategies for improving the safety and quality of pharmaceutical compounding practices.

At the local level, the implementation of these recommendations at Pawi General Hospital can lead to immediate improvements in patient safety and outcomes. By equipping healthcare professionals with the necessary knowledge and skills, providing ongoing support and education, and fostering a culture of collaboration and accountability, the risks associated with inappropriate pharmaceutical compounding can be effectively mitigated. Patients in the local community stand to benefit from enhanced quality assurance measures, reduced incidence of ADEs, and decreased risks of AMR.

Moreover, the impacts of this study extend beyond the borders of Ethiopia to the national and international levels. The findings offer valuable implication for healthcare systems worldwide grappling with similar challenges in pharmaceutical compounding. At the national level, policymakers, regulatory bodies, and healthcare organizations can leverage the evidence-based recommendations from this study to inform the design and implementation of interventions aimed at enhancing the safety and quality of compounded medications. Internationally, this study contributes to ongoing efforts to address the multifaceted challenges posed by pharmaceutical compounding in the context of global health.