Antibiotics remain one of the most significant therapeutic discoveries of the twentieth century, revolutionizing the management of infectious diseases and drastically reducing morbidity and mortality worldwide [1]. However, the widespread and often indiscriminate use of these agents has contributed to the alarming rise of antimicrobial resistance (AMR), now recognized as a global public health crisis [2-4]. In this context, fixed-dose combinations (FDCs) of antibiotics have emerged as a common prescribing practice in many regions, particularly in low- and middle-income countries [5]. These formulations, which combine two or more active antimicrobial agents in a single dosage form, are intended to enhance therapeutic efficacy, broaden antimicrobial coverage, and improve patient compliance [5]. Yet, their rationality, safety, and long-term impact on resistance patterns remain subjects of considerable debate. The rationale for antibiotic FDCs is multifaceted. By combining agents with complementary mechanisms of action, FDCs may provide synergistic effects, reduce the risk of therapeutic failure, and potentially delay the emergence of resistant strains [6, 7]. They may also simplify dosing regimens, thereby improving adherence in patients with complex or prolonged treatment courses. In certain clinical scenarios—such as tuberculosis, HIV, or malaria—FDCs have demonstrated clear benefits in terms of treatment outcomes and public health impact [8, 9]. However, the extension of this concept to antibacterial therapy outside these well-established indications has raised concerns. Many antibiotic FDCs are marketed and prescribed without robust evidence of efficacy, pharmacokinetic compatibility, or safety. Inappropriate combinations may expose patients to unnecessary toxicity, increase treatment costs, and accelerate the development of multidrug-resistant organisms [5]. India, like several other countries, has witnessed extensive use of antibiotic FDCs across both hospital and community settings [10]. Regulatory authorities have periodically attempted to restrict irrational formulations, yet their availability and prescription remain widespread. Studies have highlighted that a significant proportion of these combinations lack approval from major international regulatory agencies, and some are not recommended by standard treatment guidelines [10]. The persistence of such practices reflects a complex interplay of factors, including prescriber habits, patient demand, pharmaceutical marketing, and gaps in regulatory enforcement. Understanding the patterns of use and clinical outcomes associated with these FDCs is therefore critical for informing stewardship initiatives and guiding rational prescribing. Retrospective analyses provide valuable insights into real-world prescribing behaviors and patient outcomes. By examining medical records, prescription data, and treatment results, such studies can identify trends in utilization, highlight areas of irrational use, and assess the clinical consequences of FDC therapy [11]. They also offer an opportunity to evaluate the safety profile of these combinations, including adverse drug reactions, treatment failures, and recurrence of infections. Importantly, retrospective evidence can serve as a foundation for prospective investigations and policy interventions aimed at optimizing antibiotic use. The present study was undertaken to systematically evaluate the patterns of use and outcomes of fixed-dose antibiotic combinations in a tertiary care setting. Specifically, it aims to analyze the frequency and types of FDCs prescribed, the clinical indications for which they were utilized, and the outcomes observed in terms of efficacy, safety, and compliance. By identifying both rational and irrational prescribing trends, this study seeks to contribute to the growing body of evidence on antibiotic stewardship. Furthermore, it intends to highlight the potential risks associated with inappropriate FDC use, thereby underscoring the need for stricter regulatory oversight and prescriber education. This study will seek to answer the research question: What are the patterns of use and the clinical outcomes associated with fixed dose combinations (FDCs) of antibiotics in a tertiary care hospital setting? The present study aims to evaluate the prescribing patterns and clinical outcomes associated with fixed-dose combinations (FDCs) of antibiotics in a tertiary care setting by analyzing the frequency, types, indications, and therapeutic outcomes of prescribed antibiotic FDCs in terms of efficacy, safety, and patient compliance. The study also assesses the rationality of FDC use with respect to standard treatment guidelines and determines their impact on hospital stay, readmission rates, and treatment costs.

The study was conducted as a retrospective, observational analysis of fixed-dose combinations (FDCs) of antibiotics prescribed in a tertiary care hospital. The study was undertaken in the Department of Pharmacology, SKMCH, Muzaffarpur, Bihar, India. The study period covered a three-month data-collection phase during which hospital records, prescription registers, pharmacy dispensing records, and relevant patient case files pertaining to prescriptions issued between January 2024 and December 2025 were reviewed. The study was conducted only after obtaining approval from the Institutional Ethics Committee. Study Population The study population comprised patients of all age groups and both sexes who had received at least one antibiotic FDC during hospitalization or an outpatient visit during the defined study period. Eligible records were those in which the prescribed FDC, clinical indication, dosage regimen, and duration of treatment were sufficiently documented. Patients receiving only single-agent antibiotic therapy without an FDC were excluded. Records that were incomplete, illegible, or lacked adequate documentation of treatment outcome or follow-up were also excluded. Each eligible patient record served as the principal unit of analysis, while individual FDC prescriptions were additionally characterized according to their components, indication, dose, route, frequency, and duration. Sampling Method & Sample Size A retrospective record-based sampling approach was used. The sample size was calculated using the single-proportion formula (n=Z2pq/d2), where (Z) was 1.96 for a 95% confidence level, (p) represented the anticipated proportion of irrational antibiotic FDC use as 80% from Bortone B et al. (2021), (q=1-p), and (d) represented the desired relative precision of 5% [11]. The calculated sample size was 246, which was further adjusted to 274 with 10% attrition rate. Outcome Parameters The primary outcome parameters were the prescribing frequency and types of antibiotic FDCs, their clinical indications, and therapeutic outcomes, including documented clinical efficacy, safety, and compliance. Clinical efficacy was assessed from the recorded resolution or improvement of the presenting infection following FDC therapy. Safety was assessed from documented adverse drug reactions and other treatment-related complications, whereas compliance was assessed from available documentation regarding completion of therapy, missed doses, discontinuation, or treatment interruption. Secondary outcome parameters included the occurrence of adverse drug reactions, treatment failure, recurrence of infection, duration of hospital stay, readmission following treatment, and direct treatment cost. The rationality of each prescribed antibiotic FDC was also evaluated in relation to applicable standard treatment recommendations and national regulatory information. These outcomes were consistent with the prespecified objectives of the study. Methodology A structured data-collection proforma was developed before extraction of information from the records. Demographic variables including age and sex were recorded along with the clinical diagnosis, relevant comorbidities, treating department, admission status, and prescriber-related information where available. Details of every antibiotic FDC were extracted, including generic composition, brand name when documented, strength of individual components, dosage form, route of administration, dose, dosing frequency, duration, and indication. Concomitantly prescribed antibiotics and other relevant medicines were also recorded to identify potential duplication or inappropriate combination therapy. Clinical outcome information was obtained from progress notes, investigation reports, discharge summaries, follow-up records, and treatment charts. Treatment was considered clinically successful when the available records documented resolution or substantial improvement of the infection without the need for unplanned escalation of antimicrobial therapy. Treatment failure was considered when infection persisted or worsened, antimicrobial therapy had to be changed because of inadequate response, or a documented complication was attributed to failure of treatment. Recurrence was defined as a documented reappearance of the same or a clinically related infection after apparent resolution. Hospital stay was calculated from admission to discharge, while readmission was identified from subsequent hospital records when available. The rationality of each FDC was assessed systematically by examining its regulatory status and clinical appropriateness. Prescriptions were compared with the relevant CDSCO-approved or restricted/banned FDC information and with accepted standard treatment guidelines applicable to the underlying infection [12]. ADR information was obtained from documented clinical notes and formal ADR reporting forms whenever available, as specified in the original protocol. Data were anonymized at the time of extraction and coded using unique study identifiers, and double data entry or cross-checking was performed to reduce transcription errors. Statistical Analysis The collected data were entered into Microsoft Excel and subsequently analyzed using IBM SPSS 26. Categorical variables were summarized as frequencies and percentages, whereas continuous variables were presented as mean with standard deviation. The distribution of antibiotic FDCs was described according to individual combinations, therapeutic indications, departments, demographic groups, duration of therapy, and regulatory or rationality classification. The chi-square test or Fisher’s exact test, as appropriate, was used for comparison of categorical variables such as FDC rationality, treatment success, ADR occurrence, and recurrence across different groups. Student’s independent-samples t-test or one-way analysis of variance was used for normally distributed continuous variables such as duration of hospital stay and treatment cost. Multivariable logistic regression was performed, where the number of events permitted, to identify independent predictors of treatment success, treatment failure, ADRs, or other clinically relevant binary outcomes. Effect estimates were reported with 95% confidence intervals, and a two-sided p-value of <0.05 was considered statistically significant.

Among the 274 patients, β-lactam + β-lactamase inhibitor combinations were the most frequently prescribed FDCs (96, 35.0%), mainly for pneumonia, UTI and intra-abdominal infections. This was followed by fluoroquinolone + nitroimidazole combinations (61, 22.3%), predominantly for gastrointestinal and intra-abdominal infections. Macrolide + β-lactam combinations accounted for 14.2% (39 patients), while cephalosporin + β-lactamase inhibitor combinations accounted for 11.7% (32 patients). Fluoroquinolone + cephalosporin/other antibiotic combinations and other FDCs constituted 7.7% and 9.1%, respectively [Table 1]. Table 1. Distribution of patients according to commonly prescribed antibiotic FDCs and clinical indications (n = 274) Antibiotic FDC category No. of patients Percentage (%) Common clinical indications β-lactam + β-lactamase inhibitor 96 35.0 Pneumonia, UTI, intra-abdominal infection Fluoroquinolone + nitroimidazole 61 22.3 Gastrointestinal and intra-abdominal infections Macrolide + β-lactam 39 14.2 Respiratory tract infections Cephalosporin + β-lactamase inhibitor 32 11.7 Respiratory and urinary infections Fluoroquinolone + cephalosporin/other antibiotic 21 7.7 Complicated bacterial infections Other antibiotic FDCs 25 9.1 Miscellaneous indications The figure 1 shows that respiratory tract infections were the most common clinical indication for antibiotic FDC use (33.9%), followed by urinary tract infections (22.6%) and gastrointestinal/intra-abdominal infections (17.2%). Skin and soft-tissue infections accounted for 10.6%, while other infections (8.0%) and post-operative/surgical infections (7.7%) constituted smaller proportions. Of the 274 prescriptions, only 55 (20.1%) were classified as rational, whereas 219 (79.9%) were potentially irrational. Regarding regulatory status, only 30 (10.9%) were approved/recognized by the CDSCO, while 244 (89.1%) were not approved. Similarly, only 48 (17.5%) were compatible with WHO Essential Medicines recommendations, compared with 226 (82.5%) that were not compatible/recommended. Adequate supporting evidence was available for only 71 prescriptions (25.9%), while 203 (74.1%) had limited or insufficient evidence, indicating a high prevalence of potentially inappropriate FDC use [Table 2]. Table 2. Assessment of rationality and regulatory status of prescribed antibiotic FDCs (n = 274) Parameter No. of prescriptions Percentage (%) Overall rationality classification Rational FDC 55 20.1 Potentially irrational FDC 219 79.9 Regulatory status Approved/recognized by CDSCO 30 10.9 Not approved by CDSCO 244 89.1 Compatibility with WHO Essential Medicines recommendations Compatible/recommended 48 17.5 Not compatible/not recommended 226 82.5 Presence of adequate evidence supporting combination Adequate evidence 71 25.9 Limited/insufficient evidence 203 74.1 Clinical treatment success was higher with rational FDCs than potentially irrational FDCs (87.3% vs 76.3%; p=0.0978), although the difference was not statistically significant. Treatment failure (12.7% vs 23.7%) and recurrence (3.6% vs 10.0%; p=0.1831) were numerically lower with rational FDCs, while ADRs were similar (7.3% vs 9.6%; p=0.7945). Importantly, treatment completion/compliance was significantly higher with rational FDCs (90.9% vs 78.5%; p=0.0357). The requirement for antimicrobial escalation/change was also lower with rational FDCs (14.5% vs 23.3%; p=0.1996), although this difference was not statistically significant [Table 3]. Table 3. Clinical efficacy, treatment failure, recurrence, safety and compliance according to FDC rationality Outcome Rational FDC (n=55) Potentially irrational FDC (n=219) p-value (Fisher’s Exact Test) Clinical treatment success, n (%) 48 (87.3) 167 (76.3) 0.0978 Treatment failure, n (%) 7 (12.7) 52 (23.7) Infection recurrence, n (%) 2 (3.6) 22 (10.0) 0.1831 Adverse drug reaction, n (%) 4 (7.3) 21 (9.6) 0.7945 Treatment completion/compliance, n (%) 50 (90.9) 172 (78.5) 0.0357 Antimicrobial escalation/change required, n (%) 8 (14.5) 51 (23.3) 0.1996 Patients receiving rational FDCs had a significantly shorter hospital stay than those receiving potentially irrational FDCs (5.24 ± 2.17 vs 6.79 ± 3.48 days; p=0.0018). The mean treatment cost was also significantly lower with rational FDCs (₹4,860 ± 1,940 vs ₹6,420 ± 3,180; p=0.0006). Mean duration of antibiotic therapy was significantly shorter in the rational group (6.18 ± 2.05 vs 7.49 ± 3.13 days; p=0.0035). Readmission (7.3% vs 13.7%; p=0.2551) and additional antibiotic therapy (16.4% vs 24.7%; p=0.2141) were numerically lower with rational FDCs but did not reach statistical significance [Table 4]. Table 4. Comparison of hospital stay, readmission and treatment cost according to FDC rationality Outcome variable Rational FDC (n=55) Potentially irrational FDC (n=219) p-value Duration of hospital stay, mean ± SD (days) 5.24 ± 2.17 6.79 ± 3.48 0.0018* Treatment cost, mean ± SD (₹) 4,860 ± 1,940 6,420 ± 3,180 0.0006* Readmission within follow-up, n (%) 4 (7.3) 30 (13.7) 0.2551** Additional antibiotic therapy required, n (%) 9 (16.4) 54 (24.7) 0.2141** Mean duration of antibiotic therapy, mean ± SD (days) 6.18 ± 2.05 7.49 ± 3.13 0.0035* *Unpaired t test, **Fisher’s exact test Multivariable logistic regression identified rational FDC use (adjusted OR 1.96, 95% CI: 1.01–3.82; p=0.047), good treatment compliance (adjusted OR 3.28, 95% CI: 1.61–6.69; p=0.001), and targeted therapy based on clinical/microbiological indication (adjusted OR 2.41, 95% CI: 1.29–4.49; p=0.006) as independent predictors of treatment success. In contrast, inpatient treatment, ≥2 comorbidities, treatment duration >7 days, age ≥60 years, and documented ADR were not statistically significant predictors (p>0.05) [Table 5]. Table 5. Multivariable logistic regression analysis of factors associated with treatment success Dependent variable: Clinical treatment success Predictor Adjusted OR 95% CI p-value Rational FDC use 1.96 1.01–3.82 0.047 Good treatment compliance 3.28 1.61–6.69 0.001 Targeted therapy based on clinical/microbiological indication 2.41 1.29–4.49 0.006 Inpatient treatment 0.79 0.45–1.39 0.412 Presence of ≥2 comorbidities 0.58 0.32–1.04 0.068 Treatment duration >7 days 0.71 0.39–1.29 0.260 Age ≥60 years 0.76 0.43–1.35 0.349 Presence of documented ADR 0.54 0.24–1.22 0.139

The present retrospective study evaluated the prescribing patterns, rationality, regulatory status, and clinical outcomes of antibiotic fixed-dose combinations (FDCs) in 274 patients. A major finding was the high prevalence of potentially irrational prescribing, with 79.9% of FDCs classified as potentially irrational, while only 20.1% were considered rational. Furthermore, 89.1% were not approved by the CDSCO, 82.5% were not compatible with WHO Essential Medicines recommendations, and 74.1% had limited or insufficient supporting evidence. Treatment completion was significantly better with rational FDCs (90.9% vs. 78.5%; p=0.0357), and rational prescribing was associated with significantly shorter hospital stay, lower treatment cost, and shorter antibiotic duration. The predominance of β-lactam + β-lactamase inhibitor FDCs in the present study is clinically understandable because these combinations are commonly used for respiratory, urinary, and intra-abdominal infections, which were also the leading indications in our cohort. The observed emphasis on respiratory infections is consistent with the findings of Lee J et al. (2025), who studied patients with carbapenem-resistant Acinetobacter baumannii (CRAB) nosocomial pneumonia and demonstrated superior outcomes with a high-dose ampicillin/sulbactam-based regimen compared with colistin. Their study reported markedly lower 28-day mortality (20% vs. 61%; aRR=0.16, 95% CI 0.08–0.32) and higher 28-day clinical success (55% vs. 32%; aRR=2.71, 95% CI 1.14–5.20) [13]. Although the clinical setting and antibiotic combinations differ from the present study, these findings support the concept that an appropriately selected combination can improve therapeutic outcomes when there is a clear microbiological or clinical rationale. A particularly important finding in our study was the 79.9% prevalence of potentially irrational FDC use. This closely parallels the concerns raised by Bortone B et al. (2021), who reported that 92% of antibiotic FDCs included in their international consumption analysis were not CDSCO-approved and more than 80% were not compatible with the WHO Essential Medicines List [11]. Our findings were strikingly similar, with 89.1% not approved by the CDSCO and 82.5% not compatible with WHO recommendations. The high proportion of non-recognized combinations in our tertiary-care setting may therefore reflect the broader availability and continued use of antibiotic FDCs despite limited international regulatory or guideline support. The prominence of India in Bortone et al.'s analysis further provides a relevant regional context [11]. Similarly, Wirtz VJ et al. (2013) found that among antibacterial FDCs marketed in Latin America, 21% were unsafe, 70% lacked sufficient evidence for efficacy, and only 9% were rational [14]. Our finding that 74.1% of prescriptions had limited or insufficient evidence is highly comparable and reinforces the concern that commercial availability does not necessarily indicate an adequately supported therapeutic combination. Differences in prescribing regulations, availability of branded formulations, physician preference, and local prescribing culture may partly explain the persistence of such combinations. The present study demonstrated better treatment outcomes with rational FDCs, although the difference in overall clinical success did not reach statistical significance (87.3% vs. 76.3%; p=0.0978). This finding is broadly compatible with evidence showing that the clinical advantage of FDC therapy is context-dependent. Mahadeo R et al. (2014) found no significant difference in treatment outcomes between FDC and single-drug preparations, while Albanna AS et al. (2013) reported no clear advantage of FDCs for bacterial conversion, acquired resistance, or adverse drug reactions [15,16]. In contrast, Lai JML et al. (2019) reported significantly higher 2-month sputum conversion with FDC therapy (96.3% vs. 94.3%; p<0.001), although this difference disappeared at 6 months [17]. These varying findings suggest that the benefit of an FDC depends largely on disease, combination quality, treatment duration, and appropriateness of drug selection rather than the fixed-dose formulation itself. An important strength of our results was the significant improvement in treatment completion/compliance with rational FDCs (90.9% vs. 78.5%; p=0.0357). This agrees with Wei Q et al. (2023), whose meta-analysis of 61 studies showed significantly improved medication compliance with FDC therapy compared with free-equivalent combination therapy (1.29-fold improvement; 95% CI 1.23–1.35; p<0.00001) [18]. Ki MS et al. (2023) similarly demonstrated higher treatment completion among FDC-treated tuberculosis patients (83.9% vs. 78.9%; p<0.01; adjusted OR 1.45, 95% CI 1.34–1.56) [19]. The improved adherence may be attributable to simplification of the dosing regimen and reduction in pill burden. However, our findings additionally suggest that rationality matters, because simplification alone does not make an inappropriate antibiotic combination therapeutically justified. The significantly shorter hospital stay (5.24±2.17 vs. 6.79±3.48 days; p=0.0018), lower treatment cost (₹4,860±1,940 vs. ₹6,420±3,180; p=0.0006), and shorter antibiotic duration (6.18±2.05 vs. 7.49±3.13 days; p=0.0035) observed with rational FDCs indicate potentially important clinical and economic benefits. These findings are consistent with the regression analysis, in which rational FDC use, good compliance, and targeted therapy independently increased the likelihood of treatment success. They also complement Dalfino L et al. (2023), who demonstrated that an appropriate cefiderocol-based strategy and timely targeted treatment significantly reduced clinical failure in CRAB ventilator-associated pneumonia [20]. Overall, the present findings indicate that FDC therapy should not be judged solely on the convenience of combining antibiotics; its value depends on rational composition, evidence of efficacy, regulatory acceptability, and appropriateness to the clinical indication. The study had several limitations. Its retrospective, observational design limited control over data quality and prevented establishing causal relationships between FDC rationality and clinical outcomes. The study was conducted in a single tertiary-care hospital, which may limit the generalizability of the findings to other healthcare settings.

In conclusion, this study demonstrates a high prevalence of potentially irrational antibiotic FDC prescribing in the tertiary-care setting, with respiratory tract infections being the most common indication and β-lactam + β-lactamase inhibitor combinations the most frequently used. Rational FDC use was associated with better treatment completion, shorter hospital stay, lower treatment cost, and shorter antibiotic duration, while differences in treatment success, recurrence, ADRs, and readmission were not statistically significant. Multivariable analysis further identified rational FDC use, good compliance, and targeted therapy as independent predictors of treatment success. These findings emphasize that antibiotic FDCs should be prescribed selectively on the basis of clinical indication, supporting evidence, regulatory status, and standard treatment guidelines, with strengthened antimicrobial stewardship, prescription auditing, and prescriber education to minimize irrational use and promote safe, effective, and cost-conscious antibiotic therapy.

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