ORIGINALARTICLE  
COMPARATIVE EFFICACY OF MEROPENEM VERSUS MEROPENEM COMBINED WITH  
AZITHROMYCIN IN TREATING EXTENSIVELY DRUG-RESISTANT UNCOMPLICATED  
TYPHOID FEVER  
Fawad Ahmad1, Jamal Anwar2, Hafiz Muhammad Usman Ali Ashraf Ahmad3, Sajida Khalid4  
How to cite this article  
ABSTRACT  
OBJECTIVES  
Ahmad F, Anwar J, Ahmad HMUAA,  
Khalid S. Comparative Ecacy of  
Meropenem Versus Meropenem  
Combined with Azithromycin in  
Treating Extensively Drug-Resistant  
Uncomplicated Typhoid Fever. J  
Gandhara Med Dent Sci.  
To compare the eectiveness of treating children with meropenem  
monotherapy vs meropenem plus azithromycin for cases of unexplained  
typhoid fever that have developed resistance to other drugs.  
METHODOLOGY  
This study aimed to compare the clinical ecacy and safety of meropenem  
alone versus meropenem combined with azithromycin in treating pediatric  
patients with XDR uncomplicated typhoid fever in a randomised controlled  
trial (ClinicalTrials.gov Identier: NCT07445282). Over 6 months, a  
randomised controlled trial was conducted at the Department of Pediatric  
Medicine at Sheikh Zayed Hospital in Rahim Yar Khan. Ninety children, aged  
six months to under ve years, with blood-culture–conrmed XDR S. Typhi  
were included and randomly divided into two groups. Group A received  
meropenem IV (20–40 mg/kg every 8 hours), and Group B received  
meropenem and azithromycin by mouth (20 mg/kg/day). The main goal was  
the average time it took for the fever to go down. We used SPSS version 25.0  
to analyse the data, setting the p-value to 0.05.  
2026;13(3):64-70.  
https://doi.org/10.37762/jgmds.13-3.905  
Date of Submission: 08-04-2026  
Date Revised:  
Date Acceptance:  
21-06-2026  
23-06-2026  
2Professor, Department of Pediatrics,  
Sheikh Zayed Medical College and  
Hospital, Rahim Yar Khan  
3Consultant, Department of Pediatrics,  
Sheikh Zayed Medical College and  
Hospital, Rahim Yar Khan  
RESULTS  
The mean time to defervescence was signicantly shorter in the combination  
group (5.4 ± 2.1 days) than in the meropenem group (6.5 ± 2.8 days; p =  
0.02). In the combination group, 93.3% of patients saw clinical improvement,  
while in the monotherapy group, only 82.2% did (p = 0.04). The dual  
regimen signicantly reduced the mean time to ovulation and the frequency of  
clinical alterations, without a signicant increase in adverse events,  
compared with the monotherapy or the combination therapy in young  
children with severe drug-resistant (XDR) straightforward fever.  
CONCLUSION  
4Assistant Professor, Department of  
Pediatrics, Sheikh Zayed Medical  
College and Hospital, Rahim Yar Khan  
Correspondence  
1Fawad Ahmad, Postgraduate  
Resident, Sheikh Zayed Medical  
College andHospital, Rahim Yar Khan  
This study provides substantial evidence for optimising antibiotic therapy in  
pediatric XDR tachycardia by systematically assessing the clinical outcomes  
of two therapeutic regimens. The results are anticipated to enhance clinical  
practice, inform antibiotic stewardship initiatives, and support the global  
eort to mitigate antimicrobial resistance.  
KEYWORDS: XDR, Salmonella Typhi, Pediatric patients, Meropenem,  
Azithromycin  
:
:
+92-334-92146789  
Drfawadahmad786@gmail.com  
INTRODUCTION  
have historically been successful in treating typhoid  
fever.7 However, therapeutic options have become  
Particularly in low- and middle-income nations, typhoid  
fever poses a signicant threat to public health.1,2 An  
annual infection aecting millions of people is caused  
by the Gram-negative, facultatively intracellular  
bacterium Salmonella enterica serovar Typhi (S.  
Typhi), which causes this fever.3,4 Typhoid fever is a  
major concern in regions of Africa, the Eastern  
Mediterranean, and South and Southeast Asia despite a  
decline in global cases during the past several  
decades.5,6 Typhoid fever must be continuously  
monitored, and ecient treatment techniques must be  
developed because it continues to be a leading cause of  
illness and death. Traditional antibiotics such as  
sulfamethoxazole, ampicillin, and chloramphenicol  
significantly more limited due to the proliferation of S.  
typhi strains that are resistant to many drugs.8,9 A strain  
of  
Salmonella,  
extensively  
drug-resistant  
S.  
typhimurium, can evade treatment with the ve most  
common antibiotics used to treat typhoid disease. The  
initial instance of XDR typhoid infection was  
documented in Pakistan's Sindh province in 2016. The  
illness has since spread extensively across the nation  
and even into neighbouring countries.10 Genomic  
studies have alarmingly demonstrated that XDR S.  
Typhi isolates harbour IncY plasmids and multidrug  
resistance transposons, rendering them resistant even to  
ceftriaxone, the last reliable oral agent for treating  
typhoid.11,12 This means that doctors can only use  
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J Gandhara Med Dent Sci  
64  
Comparative Ecacy of Meropenem Versus Meropenem Combined  
results are anticipated to enhance clinical practice,  
inform antibiotic stewardship initiatives, and support  
carbapenems or macrolides to treat the disease. The  
growing use of broad-spectrum antibiotics like  
meropenem has raised concerns about the potential for the global eort to mitigate antimicrobial resistance.  
further resistance and the long-term eectiveness of  
current treatment plans.13 Meropenem, a carbapenem- METHODOLOGY  
class beta-lactam antibiotic, works by stopping the  
synthesis of bacterial cell walls. It works well against This  
single-centre,  
controlled  
parallel-group,  
open-label  
Gram-negative bacteria, particularly drug-resistant randomised  
trial (ClinicalTrials.gov  
strains of Salmonella typhimurium.9,14 Nevertheless, Identier: NCT07445282) was conducted at the  
monotherapy with meropenem carries the risk of Department of Pediatric Medicine, Sheikh Zayed  
relapse and treatment failure, especially in infections Hospital, Rahim Yar Khan, Pakistan. The study was  
caused by intracellular pathogens that circumvent host carried out over six months from January 2025 to June  
defences.13,15 To mitigate this limitation, combination 2025 after approval of the study protocol by the  
therapy utilising meropenem and azithromycin has Institutional Review Board of Sheikh Zayed Medical  
garnered attention as a promising alternative regimen. College and Hospital, Rahim Yar Khan (Approval No.  
Azithromycin, a macrolide antibiotic, inhibits bacterial 110). The study was conducted in accordance with the  
protein synthesis and exhibits superior intracellular ethical principles of the Declaration of Helsinki.  
penetration compared with most beta-lactams.16 Written informed consent was obtained from the  
Meropenem inhibits cell wall synthesis, while parents or legal guardians of all participating children  
azithromycin inhibits the ribosome. Together, these two prior to enrollment. Children aged 6 months to less than  
drugs may have a synergistic eect, killing bacteria,  
speeding clearance, and lowering the risk of relapse.  
5 years, of either gender, presenting with blood culture–  
confirmed extensively drug-resistant (XDR) typhoid  
fever were included in the study. XDR typhoid fever  
was dened as an infection caused by Salmonella  
enterica serovar Typhi strains resistant to ampicillin,  
Meropenem with azithromycin increases bactericidal  
action against XDR S. aureus, according to in vitro and  
preclinical research. Typhi-producing bacteria kill  
faster than either drug alone.17,18 Small observational  
clinical studies and case reports indicate a shorter  
duration of fever resolution, enhanced clinical recovery,  
and fewer treatment failures with the combination  
regimen.19 Nonetheless, substantial clinical evidence  
from randomised controlled trials comparing the  
chloramphenicol,  
trimethoprim-sulfamethoxazole,  
fluoroquinolones, and third-generation cephalosporins  
(including cexime and ceftriaxone) in the absence of  
clinical complications. Children were excluded if they  
had complicated typhoid fever, such as intestinal  
perforation, gastrointestinal bleeding, encephalopathy,  
or shock; known hypersensitivity to meropenem or  
azithromycin; coexisting infections requiring additional  
antimicrobial therapy; chronic illnesses such as  
malnutrition or immunodeciency; or congenital or  
acquired heart disease. The sample size was calculated  
using the OpenEpi sample size calculator.20 The  
calculation was based on a power of 70% and a  
confidence level of 90%, using previously reported  
mean defervescence times of 5.40 ± 2.17 days for  
efcacy  
of  
meropenem  
monotherapy  
versus  
meropenem combined with azithromycin in pediatric  
populations remains scarce. Since children are the  
demographic most impacted by typhoid fever in  
endemic regions, it is crucial to formulate evidence-  
based treatment protocols for this population. The rise  
of XDR typhoid fever could undo years of progress in  
controlling typhoid and is a big problem for both public  
health and clinical management. It is therefore  
important to nd antibiotic regimens that work, are  
safe, and are readily available. To address this  
knowledge gap, this study compares the eectiveness  
of treating children with meropenem monotherapy vs  
meropenem with azithromycin for cases of unexplained  
typhoid fever that has developed resistance to other  
drugs. The main goal of the study is to determine how  
long it takes for body temperature to return to normal  
and remain below 100 degrees Fahrenheit for at least 48  
hours. This is called the mean time to defervescence.  
combination therapy and 6.55  
±
2.77 days for  
meropenem monotherapy. The estimated sample size  
was 90 participants, with 45 children in each treatment  
group. Participants were recruited using a consecutive  
sampling technique until the required sample size was  
achieved. Eligible participants were randomly assigned  
in a 1:1 ratio to one of two treatment groups using a  
computer-generated  
randomisation  
sequence.  
Allocation concealment was ensured using sealed  
opaque envelopes containing the treatment assignments.  
Due to the nature of the interventions, blinding of  
participants and investigators was not feasible;  
therefore, the trial was conducted as an open-label  
randomised controlled trial. Participants were allocated  
to the following groups: Group A (Meropenem  
Secondary  
endpoints  
include  
overall  
clinical  
improvement, treatment failure rate, and adverse event  
incidence. This study aims to provide substantial  
evidence for optimising antibiotic therapy in pediatric  
XDR typhoid fever by systematically assessing the  
clinical outcomes of two therapeutic regimens. The  
monotherapy):  
Patients  
received  
intravenous  
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J Gandhara Med Dent Sci  
65  
Comparative Ecacy of Meropenem Versus Meropenem Combined  
meropenem at a dose of 20-40 mg/kg every 8 hours. RESULTS  
Group B (Combination therapy): Patients received  
Table 1: Clinicopathological Characteristics of the Study  
intravenous meropenem at a xed dose (20-40 mg/kg  
every 8 hours) and oral azithromycin at 20 mg/kg/day.  
All medications were administered in the pediatric ward  
under direct medical supervision. Patients were  
monitored daily for clinical improvement, temperature  
changes, and any adverse drug reactions during  
Participants (n = 90)  
Variable  
Group A  
Group B  
p-value  
(Meropenem  
only) n = 45  
(Meropenem +  
Azithromycin)  
n = 45  
Age (months)  
Gender  
(Male/Female)  
Weight (kg)  
Baseline  
32.4 ± 10.2  
25 / 20  
33.1 ± 9.6  
27 / 18  
0.68  
0.65  
treatment.  
A
typhoid fever infection caused by  
Salmonella manifests as an axillary temperature of  
100°F or higher. No clinical problems associated with  
strains of Typhi that are resistant to chloramphenicol,  
ampicillin, trimethoprim - sulfamethoxazole,  
12.1 ± 3.4  
102.3 ± 1.1  
12.4 ± 3.2  
102.5 ± 1.0  
0.74  
0.59  
temperature (°F)  
Duration of  
illness before  
admission (days)  
Mean time to  
defervescence  
(days)  
5.8 ± 1.9  
6.5 ± 2.8  
82.2  
6.0 ± 1.7  
5.4 ± 2.1  
93.3  
0.63  
fluoroquinolones,  
and  
third-generation  
cephalosporins.21 The key metric for success was the  
average time to defervescence, the time it takes for a  
patient's fever to drop below 100°F and remain below  
that temperature for at least 48 hours after starting  
antibiotic treatment.22 Resolution of fever accompanied  
by improvement in appetite, activity level, and overall  
0.02*  
0.04*  
0.71  
Clinical  
improvement rate  
(%)  
Adverse eects(%) 6.7  
8.9  
clinical  
condition  
without  
development  
of  
*Statistically signicant dierence between groups  
(p ≤ 0.05)  
complications. Patient demographics and baseline  
clinical data were documented using a structured  
information collection form. This data included patient  
age, gender, weight, temperature, and length of sickness  
prior to admission. Blood samples were obtained for  
culture and antimicrobial sensitivity testing according  
to standard laboratory procedures. Patients' body  
temperature and clinical status were monitored twice  
daily during hospitalisation. Information regarding time  
to defervescence, clinical improvement, adverse drug  
reactions, and complications was recorded. Patients  
were followed until they became afebrile and clinically  
stable for discharge. The data were entered and  
analysed using SPSS version 25.0, a statistical package  
designed for the social sciences. For data that follow a  
normal distribution, quantitative variables such as time  
to defervescence were presented as means ± standard  
Figure 1: Bar Chart Representing Baseline Clinicopathological  
Characteristics (Age, Gender, Weight, Temperature) of  
Participants in Both Groups  
deviations. Data that did not follow  
a
normal  
distribution were presented as means with interquartile  
ranges. Frequencies and percentages were used to  
display categorical information, such as gender. We  
checked for normality of distribution using the Shapiro-  
Wilk test. To compare variables with normal  
distributions between the two groups, the independent-  
samples t-test was used. For non-normally distributed  
variables, the Mann-Whitney U test was employed. To  
eliminate bias, demographic stratification by age,  
gender, and socioeconomic position was carried out.  
Significance was determined by a p-value that was less  
than or equal to 0.05.  
Figure 2: Comparison of Fever Resolution Between Treatment  
Groups  
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J Gandhara Med Dent Sci  
66  
Comparative Ecacy of Meropenem Versus Meropenem Combined  
(A) Box plot showing the mean time to defervescence  
(days) in patients treated with meropenem monotherapy  
and those receiving meropenem plus azithromycin  
combination therapy. (B) Line graph illustrating the  
daily mean body temperature (°F) during the treatment  
period for both groups. P<0.05  
Figure 6: Summary Infographic Representing Overall  
Comparative Outcomes, Including Mean Defervescence Time,  
Clinical Improvement Rate, and Adverse Eect Prole Between  
Treatment Groups  
DISCUSSION  
Our results show that the dual regimen substantially  
decreased the mean time to ovulation and the frequency  
of clinical alterations, without a signicant increase in  
Figure 3: Clustered Bar Chart Showing Clinical Improvement  
Rates and Incidence of Adverse Eects in Both Treatment  
Groups  
adverse  
events,  
compared  
with  
meropenem  
monotherapy or meropenem plus azithromycin in  
young children with severe drug-resistant (XDR)  
straightforward typhoid fever. These results indicate  
that combining a carbapenem with a macrolide may  
provide synergistic benets for eradicating challenging  
S. Typhi infections in environments with limited  
resources and high resistance. Our results align in part  
with observational and retrospective studies that have  
evaluated treatment of XDR typhoid in Pakistan and  
similar settings.23,24 Qureshi et al. studied 81 culture-  
confirmed XDR typhoid patients treated with  
azithromycin, meropenem, or both and found that the  
average time to defervescence was similar across all  
three treatments (6.7–7.1 days), with only small  
dierences in failure rates between groups.25 Their  
data thus suggested that monotherapy with either  
antibiotic might suce in some cases, although the risk  
of failure was nonzero. In contrast, our controlled  
Figure 4: Scatter Plot Showing Correlation Between Treatment  
Type and Duration of Illness (in days)  
design more clearly demonstrates  
a
benet of  
combination therapy in accelerating fever clearance.26  
Other smaller and hospital-based series also report  
mixed results. A hospital-based study of 120 XDR  
typhoid cases showed that 37.5% received both  
azithromycin and meropenem, but recovery rates were  
similar across groups, with occasional treatment  
failures in the combination arm.24,27 While these real-  
world data emphasise the feasibility of both regimens,  
they lack the controlled randomisation and rigorous  
endpoints of our trial. Similarly, retrospective reviews  
such as the PLoS Neglected Tropical Diseases case  
series reported comparable therapeutic responses across  
Figure 5: Subgroup Analysis Comparing the Mean Time to  
Defervescence across Age Groups and Genders for Both  
Treatment Regimens  
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J Gandhara Med Dent Sci  
67  
Comparative Ecacy of Meropenem Versus Meropenem Combined  
the monotherapy and combination groups for fever to distinguish bacteriological cure from clinical  
recovery. Implementation of combination therapy may  
pose challenges in resource-limited settings due to  
costs, logistical constraints, and adherence issues.  
Finally, the follow-up period was relatively short, and  
longer-term follow-up would be useful to evaluate  
relapse rates and the potential emergence of  
antimicrobial resistance. Future large-scale, multicenter  
trials incorporating microbiological endpoints and  
pharmacokinetic monitoring are warranted to validate  
the effectiveness and safety of this treatment strategy.  
clearance and complication rates, though they cautioned  
that cost and resource constraints may inuence  
regimen choice in practice.28,29 In broader pediatric  
typhoid literature (non-XDR), studies comparing  
meropenem or azithromycin monotherapy indicate that  
both agents are safe and eective, with dierences  
typically in the speed of response rather than the  
ultimate cure rate. For example, a comparative in vivo  
pediatric typhoid study concluded that meropenem and  
azithromycin had similar cure rates and complication  
proles, though meropenem tended to reduce fever  
more rapidly.30 Our ndings echo this pattern under the  
more stringent XDR context, but further emphasise that  
adding azithromycin may enhance early bacterial  
clearance without compromising safety. Compared to  
broader reviews of antibiotic response in XDR typhoid,  
our trial provides more denitive insight. A systematic  
review of pediatric XDR typhoid cases in Pakistan  
showed that 29 % of children recovered on combination  
therapy, 27 % on azithromycin alone, and only 6 % on  
meropenem monotherapy, suggesting that monotherapy  
with meropenem alone may be insucient in many  
cases.31 That review, however, was limited by  
heterogeneity in patient populations, follow-up, and  
definitions of cure. Our randomized trial helps clarify  
CONCLUSIONS  
This study provides strong evidence that combining  
meropenem with azithromycin is more eective than  
meropenem alone for treating pediatric XDR typhoid  
fever. This is especially true because it shortens the  
duration of the fever without making the treatment less  
safe.  
CONFLICT OF INTEREST: None  
FUNDING SOURCES: None  
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a
controlled setting, meropenem plus  
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Our study's randomised design, uniform endpoint (time  
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AUTHORS CONTRIBUTION  
Fawad Ahmad - Concept & Design; Data Acquis;ition Data  
Analysis/Interpretation; Critical Revision; Final Approval  
Jamal Anwar  
-
Concept & Design; Data Acquisition; Data  
Analysis/Interpretation; Critical Revision; Supervision; Final  
Approval  
Hafiz Muhammad Usman Ali Ashraf Ahmad - Data  
Analysis/Interpretation; Critical Concept &  
Acquisition; Data  
Design;Revision; Final Approval  
Faryal Bashir - Concept & Design; Data Acquisition; Data  
Analysis/Interpretation; Drafting Manuscript; Final Approval  
Sajida Khalid -Concept & Design; Data Analysis/Interpretation;  
Drafting Manuscript; Final Approval  
The authors accept responsibility for all aspects of the work  
and will ensure that any concerns regarding the accuracy or  
integrity of any part are properly investigated and resolved.  
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COPYRIGHTS: Authors retain the rights without any restrictions to freely download, print, share and disseminate the article for any lawful purpose.  
It includes scholarlynetworks such as Research Gate, Google Scholar, LinkedIn, Academia.edu, Twitter, and other academic or professional networking sites.  
July - September 2026  
J Gandhara Med Dent Sci  
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