Acute febrile illness (AFI) constitutes one of the most common reasons for emergency and outpatient department visits across tropical and subtropical regions of the Indian subcontinent. The aetiological spectrum is diverse, encompassing bacterial, viral, parasitic, and rickettsial pathogens, often co-existing in the same geographical milieu [1]. Among these, enteric fever caused by Salmonella typhi and Salmonella paratyphi, scrub typhus due to Orientia tsutsugamushi, rickettsial spotted fever group infections, and leptospirosis collectively account for a substantial proportion of AFI admissions in tertiary care hospitals across southern India [2].

The clinical presentation of these illnesses frequently overlaps, rendering aetiological differentiation at the bedside challenging. Fever, headache, myalgias, and constitutional symptoms are common to all these entities, and confirmatory serological or microbiological diagnosis is often delayed by 3–7 days in routine clinical practice [3]. This diagnostic uncertainty, compounded by the risk of rapid clinical deterioration and multi-organ dysfunction if treatment is delayed, necessitates early empirical antibiotic therapy based on the local epidemiological pattern [4].

Intracellular pathogens such as Orientia tsutsugamushi and Rickettsia spp. are inherently resistant to beta-lactam antibiotics but highly susceptible to tetracyclines, particularly doxycycline [5]. Conversely, gram-negative enteric pathogens including Salmonella typhi require antibiotics with excellent intracellular and biliary penetration, such as fluoroquinolones, third-generation cephalosporins, or azithromycin [6]. The rising prevalence of fluoroquinolone-resistant Salmonella strains across the Indian subcontinent has, however, significantly limited the utility of this antibiotic class [7].

Cefixime, an oral third-generation cephalosporin, has demonstrated reliable efficacy against enteric fever and other gram-negative bacterial infections in the outpatient setting and has a favourable safety profile suitable for a broad patient population [8]. The oral bioavailability and convenient once-daily dosing of cefixime make it particularly attractive for management of tropical febrile illnesses in low- and middle-income country settings [9].

The empirical combination of doxycycline and cefixime theoretically provides complementary bactericidal and bacteriostatic activity against the most common pathogens responsible for AFI in tropical India, namely intracellular organisms (doxycycline) and gram-negative enteric bacteria (cefixime). However, robust prospective clinical evidence supporting this specific combination in undifferentiated AFI is limited, and no dedicated study from Karnataka has been reported to date [10].

Against this background, the present study was designed to prospectively evaluate the clinical efficacy, safety, and pharmacodynamic outcomes of doxycycline–cefixime combination therapy compared to standard empirical monotherapy in hospitalised patients with acute febrile illness at Shri Atal Bihari Vajpayee Medical College and Research Institute, Bangalore.

2. OBJECTIVES

Primary Objective: To compare the time to defervescence and clinical cure rates at Day 7 and Day 14 between doxycycline–cefixime combination therapy (Group A) and standard empirical therapy (Group B) in patients with acute febrile illness.

Secondary Objectives: (i) To assess the safety and tolerability profile of the combination regimen; (ii) to evaluate the effect of treatment on inflammatory markers (CRP, ESR, and total leucocyte count); (iii) to determine the hospital length of stay and treatment failure rates; and (iv) to compare outcomes stratified by aetiological diagnosis.

3.1 Study Design and Setting This was a prospective observational cohort study conducted in the Department of General Medicine at Shri Atal Bihari Vajpayee Medical College and Research Institute, Bangalore, Karnataka, India, a 750-bed tertiary care teaching hospital with a defined catchment area encompassing both urban and peri-urban populations. The study period extended from January 2025 to December 2025. 3.2 Eligibility Criteria Inclusion Criteria: (i) Age ≥18 years; (ii) Documented fever ≥38.5°C (axillary) for 3–14 days prior to admission; (iii) Clinically diagnosed acute febrile illness as the primary presenting complaint; (iv) Willingness to provide written informed consent and comply with follow-up. Exclusion Criteria: (i) Known allergy to doxycycline, tetracyclines, cephalosporins, or penicillins; (ii) Pregnancy or lactation; (iii) Age <18 years; (iv) Malaria diagnosed on peripheral blood smear or rapid antigen test; (v) Confirmed dengue haemorrhagic fever with platelet count <50,000/µL requiring ICU admission at baseline; (vi) Severe immunosuppression (HIV/AIDS with CD4 <200 cells/µL, organ transplant recipients, or patients on systemic corticosteroids ≥20 mg prednisolone equivalent for >4 weeks); (vii) Severe renal impairment (eGFR <30 mL/min/1.73 m²) or hepatic failure (Child-Pugh Class C); (viii) Prior antibiotic therapy for >48 hours before admission; (ix) Diagnosed bacterial meningitis, infective endocarditis, or other conditions requiring parenteral antibiotic therapy for indications beyond AFI. 3.3 Sample Size Calculation Sample size was estimated using the formula for comparison of two proportions. Based on a prior study reporting clinical cure rates of 88% with combination antibiotic therapy and 70% with standard monotherapy in tropical AFI [11], with α = 0.05 (two-tailed) and power (1-β) = 80%, a minimum of 66 patients per group was required. Accounting for a 12% dropout rate, 75 patients per group were enrolled, for a total of 150 participants. 3.4 Treatment Protocol Eligible patients were allocated into two groups based on the treating physician's clinical judgement guided by institutional protocol and patient preference: Group A (Combination therapy, n=75): Doxycycline hyclate 100 mg (Doxt-SL®) orally twice daily PLUS Cefixime 400 mg (Cefix-400®) orally once daily for 14 days. Both drugs were administered with meals to reduce gastrointestinal adverse effects. Patients were instructed to avoid sun exposure and use sunscreen owing to photosensitivity risk with doxycycline. Group B (Standard empirical therapy, n=75): Patients received either azithromycin 500 mg orally once daily for 7 days (for suspected enteric or atypical infections) or ceftriaxone 2 g intravenously once daily for 7–10 days (for patients requiring parenteral therapy or suspected gram-negative infections), as per the institutional empirical antibiotic protocol and attending physician discretion. The choice was individualised based on clinical severity, tolerability, and evolving diagnostic information. 3.5 Outcome Measures Primary outcomes: (i) Time to defervescence, defined as the first day on which oral temperature fell below 37.5°C and remained so for at least 48 consecutive hours; (ii) Clinical cure rate at Day 7, defined as complete resolution of fever, improvement of ≥2 points on a 5-point symptom severity scale, and no requirement for antibiotic escalation; (iii) Clinical cure rate at Day 14. Secondary outcomes: (i) Hospital length of stay; (ii) Treatment failure, defined as persistence of fever after Day 7 requiring change in antibiotic regimen; (iii) Relapse at 28 days; (iv) Requirement for ICU admission; (v) Adverse drug events; (vi) Serial inflammatory marker trends (CRP, ESR, WBC). 3.6 Data Collection and Follow-up A structured case record form (CRF) was used to collect demographic data, clinical history, examination findings, investigation reports, treatment details, and outcome data at baseline (Day 0), Day 3, Day 7, Day 14, and Day 28 (telephonic follow-up). Temperature was recorded four times daily (morning, afternoon, evening, night) using a standardised digital thermometer. Axillary temperature ≥37.5°C was considered febrile. Blood specimens were collected at baseline, Day 7, and Day 14 for complete blood count, CRP, ESR, liver function tests, and renal function tests. 3.7 Microbiological and Serological Investigations All patients underwent a standardised diagnostic workup at admission, including: blood culture and sensitivity (two sets from separate venipuncture sites, 10 mL each, processed using BacT/ALERT® automated system); peripheral blood smear and rapid malarial antigen test (SD Bioline Malaria Ag P.f/Pan®); dengue NS1 antigen and IgM/IgG ELISA (PANBIO®); scrub typhus IgM ELISA (InBios®, cut-off OD ≥0.5); Widal agglutination test (Tulip Diagnostics®); leptospira IgM ELISA (PanBio®); and chest radiograph. Rickettsial fever was serologically confirmed using Weil-Felix agglutination (OX-2, OX-19, OX-K titres ≥1:160). Aetiological attribution was based on the first positive test result meeting predefined diagnostic criteria. 3.8 Statistical Analysis Data were entered into Microsoft Excel 2019 and analysed using IBM SPSS Statistics version 26.0 (IBM Corp., Armonk, NY, USA). Continuous variables were expressed as mean ± standard deviation (SD) and compared using the independent samples t-test (for normally distributed data) or Mann-Whitney U test (for non-normal data). Normality was assessed using the Shapiro-Wilk test. Categorical variables were expressed as frequencies and percentages, and compared using the Chi-square test or Fisher's exact test as appropriate. Serial laboratory values within groups were compared using the paired t-test. Time to defervescence was analysed by Kaplan-Meier survival curves with log-rank testing. A two-tailed p-value of <0.05 was considered statistically significant. Relative Risk (RR) with 95% confidence intervals (CI) was calculated for dichotomous outcomes. All analyses followed the intention-to-treat principle.

4.1 Patient Enrolment and Baseline Characteristics

During the study period (January–December 2025), a total of 218 patients were screened for eligibility. Of these, 68 patients were excluded for the following reasons: malaria confirmed on blood smear (n=19), dengue haemorrhagic fever (n=14), age <18 years (n=8), prior antibiotic therapy >48 hours (n=13), refusal to consent (n=7), and severe immunosuppression (n=7). The remaining 150 patients were enrolled: 75 in Group A (doxycycline+cefixime) and 75 in Group B (standard therapy). Six patients in Group A and eight in Group B were lost to follow-up; however, data from all 150 enrolled patients were included in the intention-to-treat analysis (Figure 1 – CONSORT Flowchart).

The two groups were well-matched at baseline with no statistically significant differences in age, sex, duration of fever before admission, vital parameters, or co-morbidity burden (Table 1). The mean age was 34.2 ± 11.8 years in Group A and 33.9 ± 12.1 years in Group B. Males constituted 56.0% and 58.7% of Groups A and B respectively.

Table 1: Baseline Demographic and Clinical Characteristics of Study Participants

Values expressed as mean ± SD or n (%). SD: Standard Deviation; BP: Blood Pressure. p-values derived from independent samples t-test (continuous) or Chi-square test (categorical).

4.2 Aetiological Distribution

Aetiological diagnosis was established in 118/150 (78.7%) patients by Day 14. Enteric fever was the most common diagnosis, accounting for 37.3% of Group A and 34.7% of Group B patients. Scrub typhus was the second most frequent aetiology (24.0% and 25.3% respectively), followed by undifferentiated fever (18.7% and 17.3%), rickettsial fever (12.0% and 13.3%), and leptospirosis (8.0% and 9.3%). The aetiological distribution did not differ significantly between the two groups (Table 2).

Table 2: Aetiological Distribution of Acute Febrile Illness by Treatment Group

Values expressed as n (%). p-values derived from Chi-square or Fisher's exact test as appropriate.

4.3 Baseline Laboratory Parameters

Baseline haematological and biochemical parameters were comparable between both groups. Mild thrombocytopaenia (platelet count 100–150 × 10³/µL) was noted in 24 (32.0%) patients in Group A and 22 (29.3%) in Group B. Transaminase elevation less than twice the upper limit of normal was observed in approximately 28% of patients in both groups at baseline, consistent with the hepatotropic nature of many tropical febrile illnesses (Table 3).

Table 3: Baseline Laboratory Parameters of Study Participants

Values expressed as mean ± SD. CRP: C-reactive protein; ESR: Erythrocyte sedimentation rate; ALT: Alanine aminotransferase; AST: Aspartate aminotransferase; ULN: Upper limit of normal.

4.4 Primary Outcomes

The mean time to defervescence was significantly shorter in Group A (3.1 ± 1.2 days) compared to Group B (5.4 ± 1.8 days; p<0.001). Kaplan-Meier analysis demonstrated a statistically significant difference in fever clearance curves between the two groups (log-rank p<0.001), with Group A achieving 50% defervescence by Day 3 compared to Day 5 in Group B (Figure 2).

Clinical cure at Day 7 was achieved in 68/75 (90.7%) patients in Group A versus 52/75 (69.3%) in Group B (RR 1.31, 95% CI 1.10–1.56; p=0.002). By Day 14, the cure rates were 97.3% (73/75) and 84.0% (63/75) respectively (p=0.009). Treatment failure was significantly less common in Group A (2.7% vs 16.0%; p=0.007). The mean hospital length of stay was significantly shorter in Group A (5.2 ± 1.4 vs 7.8 ± 2.1 days; p<0.001) (Table 4).

Table 4: Primary and Secondary Clinical Outcomes by Treatment Group

RR: Relative Risk; CI: Confidence Interval. p-values derived from Chi-square test (proportions) or independent t-test (continuous). ICU: Intensive Care Unit.

4.5 Inflammatory Marker Trends

Serial measurements of CRP, ESR, and total leucocyte count demonstrated a more rapid and sustained decline in Group A compared to Group B. Mean CRP fell from 52.4 ± 21.3 mg/L at baseline to 14.2 ± 8.6 mg/L at Day 7 and 5.1 ± 3.2 mg/L at Day 14 in Group A, compared to 51.8 ± 19.7 mg/L to 28.9 ± 14.1 mg/L to 11.8 ± 6.4 mg/L in Group B (Figure 3). The between-group difference in CRP at Day 7 was statistically significant (p<0.001). ESR normalisation was also more rapid in Group A. Total leucocyte count showed a statistically significant improvement within Group A between baseline and Day 14 (p=0.008), whereas the change in Group B did not reach significance (p=0.071) (Table 5).

Table 5: Serial Inflammatory Marker Trends During Treatment (Mean ± SD)

WBC: White Blood Cell count; CRP: C-reactive protein; ESR: Erythrocyte Sedimentation Rate. p-values represent within-group significance (baseline vs Day 14) by paired t-test.

4.6 Safety and Tolerability

Adverse drug events were reported in 45 (60.0%) patients in Group A and 29 (38.7%) in Group B (p=0.009). However, the majority of events in both groups were mild to moderate in severity and self-limiting. The most common adverse effect in both groups was gastrointestinal disturbance (nausea, vomiting, diarrhoea, and epigastric discomfort). Photosensitivity was reported exclusively in Group A (5 patients, 6.7%; p=0.022) and was managed with topical emollients and avoidance of sun exposure; none required drug discontinuation. Drug discontinuation due to adverse events occurred in 2 (2.7%) patients in Group A and 1 (1.3%) in Group B (p=0.557), and these patients were switched to an alternative regimen. No deaths occurred in either group during the study period (Table 6).

Table 6: Adverse Drug Events by Treatment Group

Values expressed as n (%). AE: Adverse Event; ULN: Upper limit of normal. p-values from Chi-square or Fisher's exact test.

4.7 Graphical Representations

Figure 1: CONSORT flow diagram showing screening, enrolment, allocation, follow-up, and analysis of study participants. ITT: Intention-to-treat.

Figure 2: Kaplan-Meier curves illustrating time to defervescence in Group A (doxycycline+cefixime, solid line) and Group B (standard therapy, dashed line). Log-rank test p<0.001.

Figure 3: Serial serum CRP levels (mean ± SD) at baseline, Day 7, and Day 14 in Group A and Group B. *Statistically significant between-group difference at Day 7 (p<0.001).

Figure 4: Clinical cure rates (%) in Group A and Group B at Day 7 and Day 14. **p=0.002; *p=0.009 (Chi-square test).

Figure 5: Aetiological distribution of acute febrile illness in Group A and Group B. No significant between-group differences were observed (p>0.05 for all categories).

Figure 6: Hospital length of stay (days) in Group A and Group B. Box represents IQR; whiskers represent full range; horizontal line = median. ***p<0.001 (Mann-Whitney U test).

This prospective observational study evaluated the clinical efficacy and safety of doxycycline–cefixime combination therapy versus standard empirical therapy in hospitalised adults with acute febrile illness at a tertiary care centre in Bangalore, southern India. The principal findings indicate that the combination regimen is associated with significantly shorter time to defervescence, higher clinical cure rates at Day 7 and Day 14, reduced hospital length of stay, and lower treatment failure rates compared to standard empirical therapy, without a significant increase in serious adverse events. Acute febrile illness in tropical India occupies a unique epidemiological niche characterised by the co-existence of intracellular pathogens (Orientia tsutsugamushi, Rickettsia spp., Anaplasma spp.) and gram-negative enteric bacteria (Salmonella typhi, Salmonella paratyphi A, and gram-negative urinary pathogens) in the same geographic region [12]. The challenge for the clinician lies in selecting an empirical regimen that provides adequate coverage for both categories of pathogen while the diagnostic workup is awaited. Doxycycline, a semisynthetic tetracycline, is bacteriostatic and exerts its action by inhibiting bacterial protein synthesis at the 30S ribosomal subunit. Its unique ability to penetrate macrophages and achieve intracellular bactericidal concentrations against obligate intracellular organisms renders it the drug of choice for scrub typhus, rickettsial infections, Q fever, and leptospirosis [13]. Multiple studies from southern India have confirmed the efficacy of doxycycline in reducing mortality and morbidity from scrub typhus, where the case fatality rate can reach 30–35% without appropriate treatment [14]. Cefixime, a third-generation oral cephalosporin, inhibits bacterial cell wall synthesis by binding penicillin-binding proteins and is stable against most plasmid-mediated beta-lactamases. It demonstrates reliable in vitro activity against Salmonella typhi and has been validated in clinical trials as an effective oral treatment for uncomplicated enteric fever in adults and children [15]. Compared to fluoroquinolones, cefixime maintains its efficacy against nalidixic acid-resistant Salmonella strains that frequently demonstrate reduced fluoroquinolone susceptibility [16]. Crucially, cefixime's oral bioavailability of approximately 40–50% and once-daily dosing regimen facilitate compliance and enable step-down therapy from parenteral regimens in the inpatient setting [17]. The synergistic pharmacological rationale for combining doxycycline with cefixime is thus compelling: while doxycycline provides coverage for intracellular organisms that are inherently beta-lactam-resistant, cefixime ensures adequate coverage for gram-negative enteric pathogens that are doxycycline-resistant. This approach mirrors the established practice of combining doxycycline with a beta-lactam in community-acquired pneumonia to cover both typical and atypical pathogens [18]. However, direct evidence for this specific combination in tropical febrile illness has been sparse. Our finding of a significantly shorter time to defervescence in Group A (3.1 ± 1.2 days vs 5.4 ± 1.8 days; p<0.001) is consistent with the rapid in vitro killing kinetics of doxycycline against intracellular pathogens, which comprised over 36% of the aetiological diagnoses in our cohort. Rahi et al. (2019) reported mean defervescence times of 3.4 days with doxycycline monotherapy in scrub typhus, comparable to our combination group outcomes [19]. The superior cure rate at Day 7 (90.7% vs 69.3%) likely reflects the broader aetiological coverage afforded by the combination, particularly in cases where aetiological diagnosis remained pending. The rapid decline in serum CRP observed in Group A mirrors the clinical response and suggests more efficient suppression of the systemic inflammatory response. CRP is a sensitive but non-specific acute phase reactant that correlates well with the severity and resolution of bacterial infections [20]. The between-group difference at Day 7 (14.2 vs 28.9 mg/L; p<0.001) suggests that the combination therapy more effectively controlled the inflammatory cascade, possibly by achieving earlier bacteriological cure. The significantly shorter hospital length of stay in Group A (5.2 vs 7.8 days; p<0.001) has important health-economic implications. In a resource-limited setting, reducing bed occupancy for AFI patients can facilitate better allocation of inpatient resources and reduce the financial burden on patients and healthcare systems. Cost-effectiveness analyses were beyond the scope of the present study but warrant future investigation. The safety profile of doxycycline–cefixime combination therapy was broadly acceptable. The higher total adverse event rate in Group A (60.0% vs 38.7%) was primarily attributable to mild gastrointestinal effects of doxycycline, which are well-recognised and dose-dependent [21]. Administering doxycycline with food significantly reduces oesophageal irritation and nausea without impairing bioavailability [22]. Photosensitivity, observed exclusively in Group A (6.7%), is a known class effect of tetracyclines and can be effectively managed with sun avoidance counselling and topical protection. No cases of severe photosensitivity requiring drug discontinuation occurred. The low rate of drug discontinuation (2.7%) reflects satisfactory overall tolerability. Importantly, no deaths or serious anaphylactic reactions were recorded in either group, affirming the safety of this regimen in an appropriately selected patient population. The present study has several limitations that must be acknowledged. First, as a prospective observational study, treatment allocation was non-randomised, introducing the possibility of selection and confounding biases, despite the well-matched baseline characteristics. A randomised controlled trial design would provide higher-level evidence. Second, aetiological diagnosis could not be established in all patients (21.3%), which is consistent with the sensitivity limitations of available serological assays in routine practice. Third, the relatively small sample size may have been insufficient to detect differences in lower-frequency outcomes such as relapse and ICU admission. Fourth, drug compliance was assessed by patient self-report and pill counts rather than pharmacokinetic monitoring. Fifth, the study was conducted at a single centre in urban Bangalore, potentially limiting generalisability to rural or different geographical settings within India. Notwithstanding these limitations, the study contributes clinically relevant prospective evidence supporting the use of doxycycline–cefixime combination therapy as an effective empirical strategy for AFI in tropical tertiary care settings. Future multicentre randomised controlled trials with adequate power and rigorous aetiological characterisation are needed to confirm these findings and establish optimal treatment duration.

Doxycycline–cefixime combination therapy demonstrated clinically meaningful and statistically significant superiority over standard empirical monotherapy in hospitalised adults with acute febrile illness, with significantly shorter time to defervescence, higher Day-7 and Day-14 clinical cure rates, reduced treatment failure, and shorter hospital length of stay. The safety profile was acceptable, with adverse effects being predominantly mild and self-limiting. The combination provides rational dual coverage for the most prevalent tropical pathogens implicated in acute febrile illness in southern India. Pending confirmation by a multicentre randomised controlled trial, doxycycline–cefixime may be considered as an empirical therapeutic option for acute febrile illness in resource-limited tropical settings, particularly where diagnostic facilities are limited and mixed infections are epidemiologically plausible.

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