Potential Antibiotic-Drug Interactions: Analysis of Pediatric Patient

Prescriptions at Omnia Farma Pharmacy Purwokerto

Esti Dyah Utami , Farah Ayu Maharani , Heny Ekowati , Masita Wulandari Suryoputri
1* 2 1 1

1. Laboratory of Pharmacology and Clinical Pharmacy, Faculty of Health Sciences, Universitas Jenderal
Soedirman, Purwokerto
2. Department of Pharmacy, Faculty of Health Sciences, Universitas Jenderal Soedirman, Purwokerto
ARTICLE INFO ABSTRACT
Submitted : Background: The use of drugs in pediatric patients requires special
Revised : attention because pediatrics have physiological and anatomical
Accepted : differences with adults. Children are more susceptible to infectious
diseases, and often get antibiotic therapy and other symptomatic drugs to
Published :
support recovery, thus increasing the potential for drug interactions.
Objectives: The study aimed to analyze the incidence of potential
Corresponding Author:
antibiotic drug interactions prescribed to pediatric patients at Omnia
Esti Dyah Utami
Farma Pharmacy Purwokerto.
Corresponding Author
Methods: This observational study was conducted retrospectively by
Email:
collecting prescription data of pediatric patients aged 0-18 years at
esti.utami@unsoed.ac.id
Omnia Farma Pharmacy Purwokerto during January-December 2023
using simple random sampling method. Data were analyzed descriptively
using standard of the Lexicomp Interaction Checker database and other
scientific literature.
Results: There were 286 patient prescriptions that met the inclusion
criteria, the majority of patients were male, aged 1-5 years, with the
most prescribed antibiotic being amoxicillin (73.13%). The results of the
study only found potential drug interactions in 12 antibiotic prescriptions
(4.20%), of which 50% were interactions between azithromycin and
salbutamol. Most of the potential antibiotic-drug interactions found
were of minor severity (91.67%), with pharmacodynamic interaction
mechanisms (83.33%).
Conclusion: Antibiotic prescribing in pediatric patients at Omnia Farma
Pharmacy is quite good in terms of the minimal number of potential drug
interactions found. Special attention to the therapy of pediatric patients
through the collaboration of doctors and pharmacists needs to be done
so that patients get optimal therapy.

Keywords: Potential Drug Interactions; Antibiotics; Pediatrics;

Prescriptions; Pharmacy.
INTRODUCTION
Infectious diseases are still an important public health problem. Antibiotics are drugs used to treat
infections due to bacteria. Antibiotics have the ability to kill bacteria (bactericidal) or inhibit the proliferation of
bacteria (bacteriostatic)1. The use of antibiotics in Indonesia has increased along with the increase in infection
cases. Previous research reported that non-surgical pediatric patients at Sulianti Saroso Jakarta Infection Hospital
received empirical antibiotics at 99.4% with an accuracy rate of 40.9% 2. Antibiotics that are not used wisely or
rationally can trigger resistance problems 1. Antibiotic resistance is one of the global public health threats, which is
directly responsible for 1.27 million global deaths in 2019 3. Antibiotic resistance arises due to overprescribing
antibiotics, inaccurate doses, types and duration of antibiotic administration, thus reducing their therapeutic
benefits4.
Children are generally more susceptible to disease than adults 5. The treatment needs of pediatric patients
are not the same as adult patients, so special attention is needed for the selection of drug types and doses 6.
Pediatric patients have different physiological and anatomical conditions than adults because the organs of the
child's body are still developing, causing differences in drug pharmacokinetics 7. Antibiotic prescriptions are usually
given together with other drugs, 80% of these prescription patterns have the potential for drug interactions 8.
Pediatric patients diagnosed with infection at least get more than two drugs, because in addition to antibiotics to
treat the infection, patients also get symptomatic therapy 9, so it is not uncommon to find antibiotic interactions
with other drugs that are minor, moderate, or major 10. Previous research reported the possibility of antibiotic drug
interactions in pediatrics with major severity between rifampicin and isoniazid by 42.85% 10. The incidence of drug
interactions in children can be a potential that can cause unwanted effects7.
Drug interactions occur when the effect of a drug is altered by the presence of another drug, herbal
medicine, food, drink, or other environmental chemical agent. Drug interactions can be harmful if they result in
increased toxicity or decreased efficacy of a drug 11. The different pharmacokinetics of drugs in children cause drug
interactions in children to require more attention12. Recommendations that are often used as a reference for drug
interactions in pediatrics are guidelines in the adult population, but extrapolation of drug interaction data from the
adult population to pediatrics can result in over- or under-prediction of drug interactions 13. Therefore, it is
important to study potential drug interactions in pediatrics. Some previous studies on drug interactions in
pharmacies examined all types of drugs in pediatric prescriptions 14–17. Meanwhile, studies of potential antibiotic
interactions in children are mostly conducted in hospitals as reported in previous studies 10,18–21. Omnia Farma
Pharmacy has a clinic with pediatricians, so it is one of the pharmacies in Purwokerto that receives the most
prescriptions for pediatric patients. This study focuses on the study of antibiotic drug interactions that have the
potential to occur in pediatric patient prescriptions, so that the results can be a source of evaluation for health
workers in improving the rationality of selecting antibiotic therapy in pediatrics.

METHODS
Study design
This study is a descriptive observational study with a cross-sectional design. Data collection was carried out
retrospectively, with random sampling techniques, namely data collection techniques by giving equal opportunities
to each member of the population to be taken as a research sample. Randomization was carried out by numbering
each recipe, which was then randomized using Microsoft Excel.
Population and samples
The population of this study were all pediatric patient prescriptions at Omnia Farma Pharmacy Purwokerto
during January to December 2023. The research sample is the entire population that meets the inclusion criteria.
The minimum sample size was calculated using the Slovin formula, which amounted to 286 prescriptions. The
inclusion criteria in this study are:
a. All prescriptions for pediatric patients (aged 0-18 years) served at Omnia Farma Pharmacy between January
and December 2023.
b. Prescriptions consist of 2 or more drugs
c. Prescriptions containing antibiotics
d. Prescription contains drugs that are administered orally
e. A complete prescription that contains the name of the drug, dosage, and instructions for use.
Study instruments
The study was conducted by taking data from pediatric patient prescriptions, which were then collected
using an instrument in the form of a Case Report Form containing information about patient identity and a list of
prescribed drugs.
Data collection
This study has obtained eligibility and ethical approval from the Research Ethics Commission of the Faculty
of Health Sciences Universitas Jenderal Soedirman with letter number 1340/EC/KEPK/XII/2023 and permission
from Omnia Farma Pharmacy Purwokerto. Data collection was carried out for 4 months, by collecting data in the
form of patient identity (name, gender, age), as well as data on prescribed drugs (number of drugs, drug names,
doses, and intervals of use).
Data Analysis
The data obtained were then processed and analyzed descriptively to determine patient characteristics,
patterns of antibiotic prescribing in pediatrics, and the incidence of potential antibiotic drug interactions. Analysis
of the incidence of potential drug interactions between antibiotics and other antibiotic or non-antibiotic drugs was
identified using databases such as Lexicomp Interaction Checker and Drug Interaction Checker, as well as other
scientific literature such as Stockley's Drug Interaction , Drug Interaction Facts and scientific journals on related
11 21

drug interactions. The potential drug interactions found were then further reviewed to determine the severity,
mechanism, and clinical effects or manifestations of the drug interactions.

RESULTS AND DISCUSSION

In this study, data from 286 prescriptions of pediatric patients who met the inclusion criteria were obtained.
Patient characteristics based on gender and age are presented in Table I. Most of the pediatric patients who
received antibiotics were male (60.48%). Boys are more susceptible to disease because their immune system is not
yet fully formed. Biologically, the immune systems of males and females are different. The hormone estrogen
makes the female immune system stronger, making it more resistant to infection 22. The results of this study also
showed that patients who most often received antibiotics were in the age range of 1-5 years, with a frequency of
120 (41.96%) patients. Previous research also reported the same thing that pediatric patients hospitalized at
Semarang City Hospital who received antibiotic therapy were mostly male (50.78%) and 67.97% aged 1-4 years 23.
The results of another study at Bukit Sari Semarang Pharmacy found that 58.5% of pediatrics patients were male
with the most age aged 0-5 years 17. The age of 1-5 years, also known as toddlers, is a stage of child development
that is very vulnerable to disease. This is one of the reasons why prevalence is quite high. This is due to the fact
that toddlerhood is a period of transition to an adult diet, which can disrupt a child's nutritional status and increase
the risk of disease24.

Table I. Patient Characteristics

Characteristic Frequency Percentage (%)
n=268
Gender
Male 173 60.49
Female 113 39.51
Age (years)
1. 25 8.74
5. 120 41.96
10. 81 28.32
18. 60 20.98

Table II shows the pattern of antibiotic prescribing in pediatric patients at Omnia Farma Pharmacy
Purwokerto. The results show that the majority of pediatric patients (97.2%) get 1 type of antibiotic and only 2.8%
of patients get a combination of 2 types of antibiotics. So that the total antibiotics prescribed to all patients were
294 antibiotics. The most prescribed antibiotic combination was amoxicillin with cotrimoxazole. Based on the
results of this study, the most prescribed type of antibiotic compared to other antibiotic drugs was amoxicillin
(73.13%). Meanwhile, co-amoxiclav which is a combination of amoxicillin and clavulanic acid was given to 8
patients (2.72%). Amoxicillin is a penicillin class antibiotic that has a beta-lactam ring. Amoxicillin is a broad
spectrum antibiotic and has high oral bioavailability, with plasma concentrations within 1-2 hours so it is often
prescribed to children and adults. Clavulanic acid is one of the beta lactamse inhibitor compounds commonly
combined with amoxicillin, to increase penicillin activity including on bacteria producing beta lactamase enzymes
that can inactivate penicillin25.
Previous study reported that the administration of amoxicillin antibiotics is a more effective treatment
alternative compared to other antibiotics, because amoxicillin antibiotics have a broad spectrum and are more
affordable . Amoxicillin is also the first generation used for the management of treatment of respiratory tract
26

infections in children26,27. Other antibiotics that were widely prescribed in this study were cotrimoxazole in 21
patients and cefixime in 17 pediatric patients. The results of previous research on pediatric patients hospitalized at
Ananda Hospital Purwokerto also mostly (94.44%) received beta lactam antibiotics, especially the cephalosporin
group, namely ceftriaxone (43.52%). Cefixime antibiotics were prescribed in 11.11% of patients, while penicillin
group drugs, namely ampicillin, were given to 14.81% of pediatric patients19.

Table II. Antibiotic Prescribing Patterns in Pediatric Patients

Frequenc Percentage
Number of Antibiotics y (%)
n=268
1 type of antibiotic (single) 278 97.2
2 types of antibiotics (combination) 8 2.80
Frequenc Percentage
Type of Antibiotics y (%)
n=294
Amoxicillin 215 73.13
Cotrimoxazole 21 7.14
Cefixime 17 5.78
Nifuroxazide 14 4.76
Ciprofloxacin 9 3.06
Co-amoxiclav 8 2.72
Azithromycin 7 2.38
Clindamycin 2 0.68
Clarithromycin 1 0.34

The selection of antibiotics in infants and children must pay attention to the maturity of organ function and
its effects on growth and development. The use of azithromycin in neonates requires special attention because
there is no safety data, as well as the use of cotrimoxazole in children less than 6 weeks. Ciprofloxacin also needs
special attention in pediatric patients less than 12 years of age because of the risk of damaging cartilage (cartillage
dysgenesis) . In this study, azithromycin antibiotics were still found in 7 children, but all of them were relatively
1

safe because they were prescribed to children aged 3-13 years. Co-trimoxazole in this study was given to 21
children, all of whom were aged 1-15 years so it is also relatively safe. Meanwhile, the antibiotic ciprofloxacin was
prescribed to 9 children, with 3 of them aged 12-13 years. However, the other 6 children who received
ciprofloxacin were less than 12 years old, so health workers need to pay special attention to these patients.
The incidence of potential drug interactions between antibiotics and other antibiotic or non-antibiotic drugs
found in this study can be seen in Table III. Of the 286 pediatric prescriptions analyzed, only 12 prescriptions
(4.20%) of antibiotics were found to have potential drug interactions, while 274 prescriptions (95.80%) did not
have potential drug interactions. The percentage of potential drug interactions obtained in this study is lower and
relatively different from some previous studies. The results of identifying drug interactions in antibiotic
prescriptions in pediatric patients at Ananda Hospital Purwokerto obtained as many as 55% of prescriptions that
experienced drug interactions. The potential for drug interactions occurs more in prescriptions with the number of
drugs ≥5 (62.5%)19. Previous study14 in Bandung Pharmacies reported 15.00-21.29% of potential drug-drug
interactions (DDI), while another research found 36.7% of potential drug interactions in prescriptions for pediatric
patients in the Semarang area 17. Another study in Surakarta City pharmacies found 52.14% of drug interactions 15,
and 63.50% of potential drug interactions in prescriptions in Bandung pharmacies16.

Table III. Results of Analysis of Potential Antibiotic Drug Interaction Events in Pediatric Patients
Number of Prescriptions Percentage
Potential Drug Interactions
(n=286) (%)
Drug interactions present 12 4.20
No drug interaction 274 95.80
Number of Cases Percentage
Severity of Potential Drug Interactions
(n=12) (%)
Minor 11 91.67
Moderate 1 8.33
Major 0 0.00
Number of Cases Percentage
Mechanisms of Potential Drug Interactions
(n=12) (%)
Pharmacokinetics 2 16.67
Pharmacodynamics 10 83.33

Based on the severity, drug interactions are divided into three groups, namely minor, moderate and major
severity. Antibiotic prescribing in pediatrics is generally accompanied by drugs to treat symptoms of the disease, so
it is not uncommon to find antibiotic interactions with other drugs that are minor, moderate or major 10.
Differences in the effect of drug interactions on the pharmacokinetic profile between pediatric patients and adult
patients can occur. This is due to age-dependent physiological processes that can affect pharmacokinetic and
pharmacodynamic outcomes13. Several variables may influence the potential for drug interactions in pediatric
patients compared to adult patients. For example, physiological changes such as intragastric pH, gastric emptying,
intestinal motility, protein binding and transporters in each phase of pediatric development may affect drug-
metabolizing enzymes. In addition, there can also be differences in the relationship between drug exposure and
response due to changes in the expression and function of proteins that mediate drug effects 13. Changes in
excretion and elimination processes can extend the half-life of metabolized drugs and can cause toxicity12.
Table III shows that of the 12 cases of potential drug interactions found in the prescriptions of pediatric
patients at Omnia Farma Pharmacy, 11 interactions (91.67%) were drug interactions with minor severity and 1
interaction (4.20%) was a moderate interaction. Minor drug interactions do not require special treatment due to
the insignificant risk of clinical effects or side effects. Then, drug interactions that occur at a moderate level can
cause moderate interaction effects in patients, which can reduce the patient's clinical status or the effectiveness of
the drug administered. As a result, in order to reduce the risk, medication monitoring may be performed, such as
monitoring for adverse effects. An example of a moderate interaction in this study is between clindamycin and
kaolin pectin, which can cause increased absorption in the gastrointestinal tract by kaolin pectin, which can reduce
the effectiveness of clindamycin. From the results of this study, it was found that interactions with minor severity
were more common than moderate interactions, and no interactions with major severity were found. Concomitant
administration of drugs should be avoided if a major interaction occurs because it can endanger the patient's
life28,29.
 Based on the mechanism, drug interactions are generally divided into two types, namely, pharmacokinetic
interactions and pharmacodynamic interactions. Pharmacokinetic interactions occur when a drug affects the
absorption, distribution, metabolism and excretion of another drug. Pharmacodynamic interactions occur when
the pharmacological effect of a drug is altered by the presence of another drug at its target of action. Some drugs
may compete directly at the same receptor, or sometimes react indirectly by involving interference with
physiological mechanisms11. Based on Table III, the potential for pharmacodynamic drug interactions is higher than
drug interactions that occur pharmacokinetically. Of the 12 potential drug interactions, 10 (83.33%) occurred
through pharmacodynamic mechanisms and 2 (16.67%) were interactions with pharmacokinetic mechanisms. In a
previous study16, similar results were obtained that the mechanism of pharmacodynamic drug interactions
occurred more frequently (90.34%) compared to pharmacokinetic interactions (9.66%). This occurs because some
drugs work on the same receptor system, site of action, or physiological system, so they can cause synergistic or
opposing effects11. An example of a drug interaction that occurs in pharmacodynamic interactions is between
azithromycin and salbutamol, which is a stimulant of beta-2 adrenergic receptors in the respiratory tract.
Salbutamol can also affect beta-1 adrenergic receptors, causing prolongation of the QT interval on the ECG and
causing cardiac arrhythmias. On the other hand, azithromycin also has side effects on the cardiovascular system
such as palpitations, post-marketing reports also found torsades de pointes, arrhythmias, QT prolongation on the
ECG, hypotension, and cardiovascular death30. The solution that can be taken is to monitor and adjust the patient's
dose if symptoms of heart disease or chest pain occur 31,32. Cases of potential interaction between azithromycin and
salbutamol in this study were found in 6 patients, which included minor severity (Table IV).

Table IV. Overview of Potential Antibiotic Drug Interactions that Occur in Pediatric Patients
Drug-Drug Frequency Severity
Mechanisms of Potential Drug Interactions Clinical Manifestations
Interactions (%) Levels
Stimulation of beta-2 Prolongs the QT
adrenergic receptors in the interval on the ECG
Azithromycin respiratory tract by and causes
and 6 (50.00%) Minor Pharmacodynamics salbutamol; reduces arrhythmia
Salbutamol bacterial infections of the
respiratory tract by
azithromycin
Prolongation of the QT Increased QT interval;
Ciprofloxacin interval by ciprofloxacin risk of heart disease;
and 4 (33.33%) Minor Pharmacodynamics ondansetron inhibits
electrolyte
Ondansetron potassium ions in the heart disturbances
(hypokalemia)
Clindamycin Increased absorption in the Decreased
and Kaolin 1 (8.33%) Moderate Pharmacokinetics digestive tract by kaolin effectiveness of
Pectin pectin clindamycin
Inhibition of the CYP3A4 QT prolongation;
Klaritomisin
enzyme by clarithomycin; gastrointestinal
dan 1 (8.33%) Minor Pharmacokinetics
inhibited metabolism of disorders;
Omeprazole
omeprazole hepatotoxicity

Concomitant use of ciprofloxacin and ondansetron can also cause drug interactions in the
pharmacodynamic phase with minor severity, which was found in 4 patients in this study. Ciprofloxacin is an
antibiotic in the floroquinolone class which has a mechanism of action by inhibiting the mechanism of action of the
DNA gyrase enzyme which plays a role in bacterial division. Meanwhile, ondansetron is a selective 5-HT3
(serotonin) receptor antagonist which has antiemetic effects through 5-HT3 receptor antagonists 33. In pediatrics,
ondansetron is used to treat vomiting induced by gastroenteritis. Ondansetron is an antiemetic that is safe and
effective compared to other antiemetics. Ondansetron has the side effect of QT prolongation which can result in
the risk of arrhythmia or irregular pulse depending on the dose given 34. The combination of antibiotics
ciprofloxacin and ondansetron results in drug interactions, namely that both can increase the prolongation of the
QT interval if given simultaneously 35. Therefore, it is necessary to provide a 2 hour gap between administering the
medication to minimize the risk of side effects from the interaction of ciprofloxacin and ondansetron36.
The mechanisms of drug interaction that occurred in the pharmacokinetic phase with moderate severity
was found when administering a combination of clindamycin and kaolin pectin. There is 1 patient who has the
potential to experience an interaction between these drugs. The combination of administering clindamycin with an
absorbent such as kaolin pectin (which is commonly used to treat diarrhea by adsorbing infectious agents or
toxins), could potentially experience pharmacokinetic drug interactions 37. Clindamycin is a macrolide antibiotic
which has a mechanism of action, namely inhibiting bacterial protein synthesis at the 5OS ribosome level which
causes a bacteriostatic effect . Giving a combination of kaolin pectin with clindamycin can reduce the effectiveness
25

of clindamycin. Therefore, consumption of the drug clindamycin can be given 2 hours after administration of kaolin
pectin to reduce the risk of drug interactions38, or adjust the dose of clindamycin if necessary39.
Interactions between antibiotics and other drugs that occur in the absorption phase can occur due to
complex formation. In this study, interactions in this phase occurred with clarithomycin and omeprazole. This
interaction is in the minor severity category and was found in 1 patient in this study. Claritomycin is a macrolide
antibiotic that is active against gram-positive bacteria. Claritomycin is absorbed orally by 55% and will increase if
given with food. This drug will be widely distributed to the lungs, liver, phagocyte cells and soft tissue 40.
Omeprazole is a PPI class of drug which is used to treat gastritis and is a stronger drug that inhibits gastric acid
secretion. Omeprazole works by blocking the H+/K+-ATPase enzyme in gastric parietal cells, thereby suppressing
the secretion of hydrogen ions into the gastric lumen and resulting in inhibited gastric acid secretion 41. Drug
interactions between omeprazole and CYP3A inhibitors such as clarithomycin can reduce the effects of
omeprazole. Inhibition of CYP3A by clarithomycin will increase the effectiveness of omeprazole in plasma so that it
can cause side effects such as diarrhea, pneumonia and nausea or vomiting. Therefore, giving a combination of
claritomycin and omeprazole can be done by giving a minimum of 2 hours between drug administration and
monitoring the patient to identify possible side effects42.
Based on the data of potential drug interactions obtained in this study, antibiotic prescribing for pediatric
patients at the Omnia Farma Pharmacy is good when viewed from the minimum number of potential drug
interactions found in this study. Apart from that, there were no drug interactions of major severity found in drug
prescribing in pediatric patients. However, this still needs to be a concern, because drug-drug interactions should
not occur in therapy given to patients, considering that clinical manifestations or undesirable effects can arise due
to drug interactions . Pharmacists need to intervene through discussions with doctors and provide evidence-based
14

solutions to potential drug-drug interactions, especially in pediatric patients. Communication with the prescribing
doctor is very necessary to minimize the occurrence of drug interactions, so that the pharmacist can provide
considerations regarding the risks and benefits that the patient will receive. This can increase collaboration
between pharmacists and clinicians in the management of drug therapy for patients. In addition, the ability of
pharmacists as a source of drug-related knowledge among health workers will be increasingly recognized, which is
an important factor in improving the integrity of pharmacists 43. Attention to pediatric patient prescriptions through
collaboration between doctors and pharmacists must always be increased. There are several general management
measures to prevent or overcome drug interactions that can be recommended by pharmacists, namely by avoiding
the use of drug combinations that have the potential to cause interactions, adjusting the dose of the drug given to
the patient, or recommending a 2-hour or 4-hour gap between drugs if there is potential drug-drug interactions
occur during the absorption phase. In addition, monitoring of clinical symptoms or side effects that may occur can
also be carried out (so that they can be followed up with dose adjustments). Providing information to the patients
regarding drug interactions and the effects that may occur is also an important role that pharmacists can play.
The limitations of this research include that it was only carried out in 1 (one) pharmacy, and did not analyze
potential interactions between non-antibiotic drugs because it only focused on interactions between antibiotics
and other drugs. Analysis of potential drug interactions in this study was also carried out theoretically based on
scientific literature, and did not look at clinical manifestations in patients due to limited data that could be
collected at pharmacies, so it is not known whether these drug interactions have clinical implications. Further
research needs to be carried out in a wider scope by including data collection on patient clinical manifestations, so
that the study of the drug interactions can be more comprehensive.
CONCLUSION
The results of this study showed that from 286 pediatric prescriptions at the Omnia Farma Pharmacy in
Purwokerto, only 12 prescriptions (4.20%) of antibiotics were found to have the potential drug interactions,
consisting of 11 incidents of minor interactions and 1 incident of moderate interactions. The majority of drug
interaction mechanisms found in this study were pharmacodynamic interactions, namely 10 cases, with the most
interactions occurring being between azithromycin and salbutamol. Antibiotic prescribing for pediatric patients at
the Omnia Farma Pharmacy is good in terms of the minimal number of potential drug interactions and no
interactions of major severity. Further research is needed to examine the incidence of drug interactions and their
clinical manifestations in pediatric patients with a wider population coverage.

ACKNOWLEDGEMENT
We are grateful to Jenderal Soedirman University’s Institute for Research and Community Service (LPPM
Unsoed), which funded this study under the Unsoed Basic Research 2024 grant no.
26.428/UN23.35.5/PT.01/II/2024. We also are grateful to Omnia Farma Pharmacy for allowing us to carry out this
research.

STATEMENT OF ETHICS
This research has received ethical approval from the Research Ethics Commission of the Faculty of Health
Sciences Unsoed with letter no. 1340/EC/KEPK/XII/2023.

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