Paediatrica Indonesiana

p-ISSN 0030-9311; e-ISSN 2338-476X; Vol.58, No.1(2018). p. 51-5 ; doi: http://dx.doi.org/10.14238/pi58.1.2018.51-5

Original Article

Prescribing antibiotics to pediatric dengue:

increasing risk of bacterial resistance
Dhanunjaya Sandopa1, Sree Keerthi Nethi1, Sai Charitha Sreeram1,
Narasimha Kumar Godlaveti Vijay2, Vyshnavi Biradavolu1, Jagadeesh Vijay Kakimani1

I
Abstract n the field of medicine, the battle between
Background Use of antibiotics to treat self-limiting viral infections bacteria and mankind can be explained in three
like dengue fever (DF) without any co-morbid conditions in pedi- phases: the pre-antibiotic era, the antibiotic
atric patients is common practice in India, and a major contribution
of the inappropriate use of antibiotics in the country.
era, and the post-antibiotic era. The period
Objective To provide an analysis of diagnosis, grading, and prescrib- before the introduction of sulfa drugs and penicillin
ing of antibiotics in pediatric inpatients with DF in a tertiary care is considered to be the ‘pre-antibiotic era.’ Bacteria
teaching hospital in India. dominated mankind and bacterial infections were
Methods Data from case sheets of all pediatric inpatients (n=370)
diagnosed with DF without co-morbid conditions were collected the leading cause of death.1 Discovery of penicillin
with regards to diagnosis, grading, presence, and appropriateness by Sir Alexander Fleming in 1928 laid the foundation
of antibiotic usage according to the 2009 WHO Guidelines, the and hope of controlling bacterial infections. Since
National Vector Borne Disease Control Program (NVBDCP) of India that time, the ‘antibiotic era’ has seen the discovery
Guidelines, and the Hospital Infection Society (HIS) Guidelines.
Results Platelet count determination (50% of the cases) was the of many antibiotics, which has transformed modern
major diagnostic method for dengue. Inappropriate grading of DF medicine and saved millions of lives. 2 These
was seen in 20% of patients. Almost 75% of the 370 dengue cases discoveries gave hope that mankind would rein over
were prescribed antibiotics for the expressed purpose of avoiding bacterial infections forever. However, the foremost
hospital-acquired infections. A single antibiotic was given in 225
prescriptions (60.81%), 2 antibiotics in 33 (8.91 %) cases, and 3 driving force for discovering newer antibiotics was the
antibiotics in 9 (2.43%) cases. development of resistance to the existing antibiotics.
Conclusions Prescribing one or more antibiotics to treat self-limiting Eventually, the antibiotic pipeline began to dry
viral infections is considered as inappropriate and may lead to the up, because the pharmaceutical industry considers
development of multidrug resistance. Furthermore, excess use of
antibiotics in infancy may induce imbalances in gut and microbiota, investment in antibiotic study to be unprofitable,
called dysbiosis, and increases the probability of occurrence of
diseases such as obesity, diabetes, and asthma in later life. These
findings can inform the development of antibiotic stewardship in
the treatment of dengue. [Paediatr Indones. 2018;58:53-7 ; doi:
http://dx.doi.org/10.14238/pi58.1.2018.53-7 ].
From the Department of Clinical Pharmacology, Sri Padmavathi School
of Pharmacy, Tirupathi, Andhrapradesh 1, and the Department of
Keywords: antibiotics; bacterial resistance; Pharmacology, Siddha Central Research Institute, Chennai, Tamilnadu2,
dengue; inappropriate use India.

Reprint requests to: Mr. Dhanunjaya Sandopa, Assistant Professor,

Department of Clinical Pharmacology, Sri Padmavathi School of Pharmacy,
Tirupathi, Andhrapradesh, India 517503. Telp. +91-9177392747; Fax.
0877 – 2237732; Email: [email protected].

Paediatr Indones, Vol. 58, No. 1, January 2018 • 51

 Dhanunjaya Sandopa1 et al.: Prescribing antibiotics to pediatric dengue: increasing risk of bacterial resistance

fearing a possible lack of returns. This approach of the the curriculum of Pharm. D. course in the pediatric
pharmaceutical industry is due to the short period of ward, we observed the use of antibiotics to treat
antibiotic usage compared to other drugs used to treat diseases which are generally self-limiting, to avoid
metabolic, cardiovascular, and central nervous system hospital-acquired infections in Sri Venkateswara
disorders. Hence, bacterial resistance to antibiotics is Ramnarayana Ruia Government General Hospital
inevitable, as newer antibiotics may be outdated in a (SVRRGGH), Tirupathi. Hence, we aimed to evaluate
short span of time.2 the extent of inappropriate prescribing of antibiotics in
In response to antibiotics, bacteria change in treating dengue fever (DF) in pediatric patients.
ways that reduce or eliminate drug effectiveness.
These changes are due to the evolution of antibiotic
resistance genes by spontaneous mutations and Methods
furthered by natural selection of resistant strains over
sensitive ones.3 Once a strain develops resistance, the This cross-sectional, observational study was carried
once-effective antibiotic will no longer inhibit the out for 6 months (July to December 2016) in the
bacteria. If this continues, mankind will eventually inpatient Department of Pediatrics, SVRRGGH,
face a cataclysmic condition. In view of this, the US Tirupathi, India. The minimum required sample
Centers for Disease Control and Prevention (CDC) size (n=370) used was based on the pilot study that
declared in 2013 that the human race is now in the was performed in the early weeks of July 2016 on 50
‘post-antibiotic era.’ Moreover, the World Health patients.
Organization (WHO) warned of a dreadful antibiotic The study was approved by the Institutional
resistance crisis.2 This situation is comparable to the Review Board, Sri Padmavathi School of Pharmacy,
pre-antibiotic era, in that irrational use of antibiotics Tiruchanoor, Tirupathi, India. All patients admitted
has led to the emergence of resistant strains and to the pediatric inpatient ward of SVRRGGH with
infections which are not yet recognized and the re- dengue fever during the study period were included
emergence of virulent forms of previous infections.1 in the study, except for those with other infections
Resistance development is an evolutionary process, and co-morbid conditions.
with unpredictable times. Resistance requires constant A specially designed pro forma was used for
exposure of bacteria to the antibiotic. Hence, the collecting data, including patient demographics, past
rational or irrational use of antibiotics drives the medical history, family and surgical history, traveling
evolution of bacterial resistance. As such, the greater and transfusion history, signs and symptoms, diagnosis,
the exposure of bacteria to antibiotics, the faster the and medications presently prescribed for each patient.
evolution of resistance.3 The data were obtained from patient case profiles after
Dengue and chikungunya are the third and obtaining parental informed consent. All prescriptions
fourth most common monsoon diseases in India. were analyzed for the appropriate diagnosis, grading,
They are mosquito-borne (Aedes aegypti) viral diseases and presence of antibiotics, according to the 2009
associated with urban environments. Dengue manifests WHO Guidelines5 and NVBDCP Guidelines of India.6
as sudden onset of fever and severe headache; it In addition, the presence of appropriate antibiotics for
occasionally produces shock and hemorrhage leading hospital-acquired infection was also assessed based on
to death. Chikungunya is characterized by pain HIS Guidelines of India.7-9
usually lasting 3-7 days and, in some cases, results
in persistent arthritis. These diseases share common
symptoms of a typical bacterial infection, and mislead Results
health workers to use antibiotics unnecessarily. In
addition, illicit prescribing of antibiotics by medical In this study, we observed more DF cases (Table 1) in
practitioners is increasing the condition of resistance, children between the age group 5-10 years (52.97%),
due to improper diagnosis, lack of understanding of followed by 0-4 years (37.29%) and 11-15 years
the potential dangers of inappropriate use, costs, and (9.23%). This may be because of children playing
outcomes of therapy.4 During our hospital visit as per in unsanitary places or field areas where there is risk

52 • Paediatr Indones, Vol. 58, No. 1, January 2018

 Dhanunjaya Sandopa1 et al.: Prescribing antibiotics to pediatric dengue: increasing risk of bacterial resistance

of being bitten by mosquitoes. There is no existing antibiotics to 33 (8.91%) cases, and 3 antibiotics to
scientific reason for high prevalence of dengue in 9 (2.43%) cases, at a time (Figure 1). Triple therapy
children, but the rate of mortality in pediatrics is high antibiotics included cefotaxime in all prescriptions
due to secondary infections, developing immunity, with cefixime, azithromycin, amoxyclav, doxycycline,
and exposure to virulent strains, while most children and ceftriaxone in different combinations. Antibiotics
remain asymptomatic.10 given as dual therapy were ceftriaxone with doxycycline,
cefotaxime, or amoxyclav, and cefotaxime with
Table 1. Age distribution of dengue fever patients doxycycline, cefixime, or metronidazole.
Age group No. of cases (N=370)
0-4 years 138
5-10 years 196
11-15 years 36

Out of 370 cases, 181 (48.91%) cases were

diagnosed based on platelet count, followed by NS1
antigen (36.75%), IgM (12.7%) and IgG (1.62%)
antibodies, while only 4.4% of cases were diagnosed
solely based on symptoms (Table 2).

Table 2. Diagnostic parameters used to diagnose dengue

fever
Figure 1. Distribution of antibiotics
Parameters No. of cases (N=370)
PLT, n (%) 181 (48.91)
NS1AG, n (%) 136 (36.75)
Among the antibiotics prescribed, cefotaxime
IgM, n (%) 47 (12.7)
and ceftriaxone were most commonly used (96 cases;
35.90% for each drug), followed by doxycycline
IgG, n (%) 6 (1.62)
(13.8%), amoxyclav (8.6%), cefixime (2.6%),
amikacin (1.5%), azithromycin (0.75%), as well as
In this study, 315 (85.13%) cases were ciprofloxacin and metronidazole (0.38%) (Table 4).
appropriately graded and 72 cases (19.45%) were
inappropriately graded (Table 3). Of the 315 Table 4. Antibiotic prescribing pattern
appropriately-graded cases, mild dengue was observed Antibiotic No. of prescription (N=267)
in 132 cases (41.9%), moderate dengue in 176 cases Cefotaxime, n(%) 96 (35.9)
(55.87%), and severe dengue in 7 cases (2.22%). Ceftriaxone, n(%) 96 (35.9)
Among the moderate and severe cases, DHF Doxycycline, n(%) 37 (13.8)
prevalence was 49.45% (183 subjects) in which DHF1 Amoxyclav, n(%) 23 (8.6)
contributed to the highest percentage (48.63%; 89 Cefixime, n(%) 7 (2.6)
cases), followed by DHF 2 (47.54%), and DHF 3
Amikacin, n(%) 4 (1.5)
(3.82%).
Azithromycin, n(%) 2 (0.75)
Ciprofloxacin, n(%) 1 (0.38)
Table 3. Appropriateness in grading dengue fever
Metronidazole, n(%) 1 (0.38)
Grading No. of cases (N=370)
Inappropriate, n (%) 72 (19.45)
Appropriate, n (%) 315 (85.13)

Of 370 confirmed dengue cases, 267 (74.6%)

cases were prescribed antibiotics. A single antibiotic
was prescribed to 225 cases (60.81% of all cases), 2

Paediatr Indones, Vol. 58, No. 1, January 2018 • 53

 Dhanunjaya Sandopa1 et al.: Prescribing antibiotics to pediatric dengue: increasing risk of bacterial resistance

Discussion status of the patient requires assessment, for the basis

of the physician to decide between a bolus of 20 mL/
The most common monsoon diseases in India are kg in 15 minutes or maintenance with IV fluids at a
malaria, diarrhea, dengue, chikungunya, typhoid, rate of 5 to 10 mL/kg/hr over 1 hour. Otherwise, DF
viral fevers, and cholera. They all share some common may be fatal after entering into the phases like shock
symptoms and present challenges for the physician. and coma.5,6
Antibiotics are of no use in management of dengue and In our observation, 75% of the cases were
chikungunya, as they are viral, infections. According prescribed with antibiotics, under the guise of avoiding
to the WHO Clinical Guidelines 5 and the 2014 hospital-acquired infections. However, antibiotics
NVBDCP Guidelines,6 no drug of choice for dengue are not necessary to treat dengue, according to the
exists, as drugs that directly act against dengue virus guidelines. Empiric antibiotics are being prescribed
are still in the pipeline.11 Hence, therapy is solely based for suspected infections to avoid hospital-acquired
on the management of symptoms. Accurate diagnosis infections. However, this empiric use of antibiotics
of dengue can be confirmed based on serum positivity for treating nosocomial infections should be according
for NS1 antigen, IgM, and IgG antibodies. The NS1 to the HIS guidelines. In addition, antibiotics like
antigen can be determined by ELISA, which is highly amikacin, doxycycline, and amoxyclav should not
sensitive, specific,12 and helpful in the early diagnosis be used without performing susceptibility tests, while
of acute infection. In our study, we observed that ceftriaxone and cefixime cannot be used prior to
platelet count determination had been used in most performing hypersensitivity tests.13-16 Azithromycin,
(50%) of the cases to diagnose dengue infection. This ceftriaxone, and metronidazole can only be used
approach is not appropriate because thrombocytopenia for the prophylaxis of endocarditis and sexually
occurs due to destruction of platelets, mediated by transmitted diseases (STDs).17,18 In addition, usage
antiplatelet-antibodies observed from the 3rd day to of amoxyclav in dengue can further increase the risk
the 7th day of illness. Moreover, platelet count may also of bleeding.14
fall in other infections like HIV, HHV-6, ehrlichiosis, The prescribing of antibiotics is an art requiring
Rickettisia, malaria, hepatitis-C, cytomegalovirus, skill in using the appropriate antibiotic for the
Epstein-Barr syndrome, Helicobacter pylori, and particular infection. Inappropriate usage of more than
E. coli. Hence, platelet count is not an ideal diagnostic one antibiotic increases the chances of developing
parameter to diagnose dengue fever. However, it can multidrug resistance, which is a serious issue to be
be considered for prognosis of the disease. These considered. Though there are many policies describing
implementations can make the physician clear and the appropriate indications for use of antibiotics, these
confident regarding usage of antibiotics and further drugs are often used inappropriately. Furthermore,
allows him to follow strict regimen recommended by if this scenario continues, the list of organisms
WHO and HIS of India and thus reduce the need for developing resistance will increase. More powerful
antibiotic use and cost burden on the patient. and costlier antibiotics must be prescribed for simple
Once the dengue diagnosis has been confirmed, infections, which may have many adverse effects and
grading plays a major role in the success of the can present an economic burden to patients.
treatment. Inappropriate grading may result in failure In conclusion, prescribing one or more antibiotics
of therapy, and the need for advanced assessment to treat self-limiting viral infections is considered as
of complications. As manifestations of DF vary by inappropriate, and leads to the development of
grades, different treatment approaches are required, as multidrug resistance. Furthermore, excess use of
mentioned in the WHO Guidelines. Mild dengue does antibiotics in infancy may induce imbalances in gut
not require therapy with IV fluids, while moderate and microbiota, called dysbiosis, and increase the
and severe dengue requires IV fluid maintenance. probability of diseases such as obesity, diabetes, and
Moderate dengue can be managed with IV fluids at a asthma in later life.19 These findings can be used to
rate of 2 to 3 mL/kg/hr, with reassessment of complete improve antibiotic stewardship in the treatment of
blood count (CBC) to increase the rate up to 5 to 10 dengue.
mL/kg/hr for 2 hours. In severe dengue, hemodynamic

54 • Paediatr Indones, Vol. 58, No. 1, January 2018

 Dhanunjaya Sandopa1 et al.: Prescribing antibiotics to pediatric dengue: increasing risk of bacterial resistance

Acknowledgments 8. World Health Organization. Prevention of hospital-acquired

The authors are grateful to all who have contributed to the infections: a practical guide. Malta: WHO; 2002. p.1-64.
success of this study. We especially acknowledge the Department 9. Mohammed M, Mohammed A, Mirza M, Ghori A.
of Pediatrics, Sri Venkateswara Ramnarayana Ruia Government Nosocomial infections: an overview. Int Res J Pharm.
General Hospital (SVRRGGH), Tirupathi, India for assistance in 2014;5:7-12.
procuring data. It has been a privilege and wonderful experience 10. Murray NE, Quam MB, Wilder-Smith A. Epidemiology of
to be part of this esteemed institution and we owe our sincere dengue: past, present and future prospects. Clin Epidemiol.
thanks to our Principal, Dr. D. Ranganayakulu, Sri Padmavathi 2013;5:299-309
School of Pharmacy (SPSP), Tirupathi. We would also like to 11. Ghazala Z, Anuradha HV, Shivamurthy MC. Pattern of
express our profound gratitude to Mrs. P. Sulochana, BA, LLB, management and outcome of dengue fever in pediatric in-
Chairperson, SPSP, Tirupathi who provided the facilities to patients in a tertiary care hospital: a prospective observational
execute this work. study. International Journal of Basic & Clinical Pharmacology.
2014; 3:534-8. DOI: http://dx.doi.org/10.5455/2319-2003.
ijbcp20140623.
Conflict of Interest 12. Bisordi I, Rocco IM, Suzuki A, Katz G, Silveira VR, Maeda
AY, et al. Evaluation of dengue NS1 antigen detection for
None declared. diagnosis in public health laboratories, São Paulo State, 2009.
Rev Inst Med Trop São Paulo. 2011;53:315-20.
13. HL Sharma, KK Sharma. Penicillins, cephalosporins and
References other b-lactam antibiotics. In: Kothari Divyesh A, editors.
Principles of pharmacology. 2nd ed. New Delhi: Paras Medical
1. Yoneyama H, Katsumata R. Antibiotic resistance in bacteria Publisher; 2103. p. 722-8.
and its future for novel antibiotic development. Biosci 14. Sharma HL, Sharma KK. Aminoglycosides. In: Kothari
Biotechnol Biochem. 2006;70:1060-75.C. Divyesh A, editor. Principles of pharmacology. 2nd ed. New
2. Ventola CL. The antibiotic resistance crisis: part 1: causes Delhi: Paras medical publisher; 2103. p. 738.
and threats. P T. 2015;40:277-83. 15. Harvey RA. Protein synthesis inhibitors. In: Clark MA,
3. Read AF, Woods RJ. Antibiotic resistance management. Evol editor. Pharmacology. 6th ed. New Delhi: Lippincott's
Med Public Health. 2014;2014:147. Illustrated Reviews Series; 2012. p. 395-404.
4. Eandi M, Zara GP, Della Pepa C. Application of 16. Sharma HL, Sharma KK. Broad spectrum antibiotics:
pharmacoeconomics to the use of antibiotics. Clin Microbiol tetracyclines and chloramphenicol. In: Kothari Divyesh A,
Infect. 2000;6:90-2. editor. Principles of pharmacology. 2nd ed. New Delhi: Paras
5. World Health Organization. Dengue: guidelines for diagnosis, medical publisher; 2103. p. 748-50.
treatment, prevention and control. Geneva: World Health 17. Sharma HL, Sharma KK. Macrolides, ketolides, lincosamides,
Organization; 2009. p.1-147. oxazolidones and other antibacterial drugs. In: Kothari
6. National vector borne disease control programme. National Divyesh A, editor. Principles of pharmacology. 2nd edition.
guidelines for clinical management of dengue fever. 2014 Dec; New Delhi: Paras medical publisher; 2103. p. 741-3.
[cited 2016 March 17] Available from: https://www.scribd. 18. Sharma HL, Sharma KK. Antiamoebic and other
com/document/347257604/Dengue-National-Guidelines- antiprotozoal drugs. In: Kothari Divyesh A, editor. Principles
2014-Compressed. of pharmacology. 2nd ed. New Delhi: Paras Medical Publisher;
7. Hospital Infection Society guidelines. Nosocomial Infection 2103. p. 819-21.
– Prevention and Management. 1-10; [cited 2016 March 15]. 19. Vangay P, Ward T, Gerber JS, Knights D. Antibiotics, pediatric
Available from: http://www.apiindia.org/pdf/pg_med_2008/ dysbiosis, and disease. Cell Host Microbe. 2015;17:553-64.
Chapter-08.pdf.

Paediatr Indones, Vol. 58, No. 1, January 2018 • 55