Potential Drug-drug Interactions in COVID-19 patients treated with Azithromycin

Heny Ekowati, Nur Intan Aditya Muninggar, Nialiana Endah Endriastuti,

Hanif Nasiatul Baroroh*

Department of Pharmacy, Faculty of Health Sciences, Jenderal Soedirman University, Purwokerto, Indonesia.

ABSTRACT:

The SARS-COV-2 virus is the cause of COVID-19, a disease that has spread to many countries. The COVID-19 Management Guidelines in Indonesia include azithromycin as one of the antibiotics used to treat COVID-19. Antibiotics are needed in patients with possible co-infection. This study aimed to determine the potential drug interaction of azithromycin with other therapy in hospitalized COVID-19 patients at the Banyumas Regional General Hospital. The study was descriptive observational research. The data was collected retrospectively based on medical records of hospitalized COVID-19 patients at the Banyumas Regional General Hospital from July 2020 to June 2021. The Lexi-Interact™ and Drugbank online is used to identify potential drug interactions. A total of 221 patients were included, with 122 patients (55.21%) being women. The number of patients experiencing potential-drug interactions was 199 patients (90%), with a number of potential drug interactions were 289 cases. The most potential drug interaction was azithromycin with omeprazole (85 cases - 29.41%). Most cases were moderate severity with pharmacokinetic interaction. This study concluded that the administration of azithromycin with other drugs for COVID-19 patients at the Banyumas Hospital has the potential for interactions that could be prevented by monitoring related side effects.

INTRODUCTION: 

Severe Acute Respiratory Syndrome Coronavirus (SARS-CoV-2), also known as the Coronavirus Disease 2019 (COVID-19) virus, is the cause of the disease. Patients with COVID-19 frequently experience fatigue, aches in their muscles, sneezing, sore throats, dry coughs, high fevers, respiratory disorders like pneumonia, dyspnea, and even mortality. These symptoms appear within 14 days after infection^1,2,3,4,5. Drugs for COVID-19 therapy include antivirals, corticosteroids, multivitamins, supplements, and antibiotics such as Azithromycin⁶. The effectiveness and safety of antibiotics as medications for treating COVID-19 disease have been studied⁷.

Antibiotics prescription is for COVID-19 patients suspected of a bacterial infection with symptoms of pneumonia⁸. Azithromycin is one of the antibiotics used in COVID-19 therapy, according to Guidelines for the Management of COVID-19 in Indonesia. Azithromycin was administered 500mg/24 hours for 5-7 days⁹. Azithromycin is the treatment of choice for COVID-19 associated with pneumonia. In the elderly it can be fatal, which is characterized by increased CRP and decreased lymphocytes¹⁰. COVID-19 patients in Indonesia also needed drug therapy for their comorbid condition¹¹. Thus, this situation caused polypharmacy which increases drug-related problems such as drug interaction and affects the patient's clinical condition¹². The occurrence of drug interactions can cause a decrease in drug effects so that the desired therapeutic results are not maximal¹³. Drug interactions that often occur with antihypertensive drugs, diuretics, proton pump inhibitors and antibiotics¹⁴.

Drug bio-availability is depending on the dosage, quality of manufacture, and other factors such as drugs or food consumed simultaneously. So apart from other drugs, interactions can also occur with food^15,16. Drug-drug interactions in COVID-19 patients receiving azithromycin therapy were investigated. For example, azithromycin interaction with hydroxychloroquine will prolong the QT interval^17,18. Azithromycin and remdesivir will increase liver function disorder; azithromycin with ondansetron and levofloxacin prolongs the QT interval¹⁹. COVID-19 patients with polypharmacy conditions increase the possibility of drug-drug interaction. Azithromycin is an antibiotics-choice for children, adults, geriatric, and pregnant women. Therefore, we investigated the potential of azithromycin interaction with other medications in COVID-19 individuals. This study is significant for evaluating medication therapy and optimizing azithromycin therapy efficacy in COVID-19 patients.

MATERIALS AND METHODS:

Materials:

Subject:

At Banyumas Hospital, Banyumas Regency, Central Java, a retrospective analysis was carried out on hospitalized patients with confirmed COVID-19 between July 2020 and June 2021, Indonesia using a total sampling technique on all members of the population who fulfilled both the inclusion and exclusion requirements. Our inclusion requirements were confirmed. Patients with or without comorbidities with COVID-19, hospitalized patients using azithromycin as COVID-19 therapy, and complete medical record data. We collected data including drug therapy information (name, type of preparation, dose, route of administration, the timing of drug administration, and frequency of drug administration). The exclusion criteria in this study were pregnant patients.

Data collection and Analysis:

Patient characteristics such as age, gender, comorbidities, and profile of azithromycin were collected from medical records and analyzed univariately. The database used in this study is a literature study obtained from various sources, namely using the Interaction Checker on drugbank.com and Lexi-Interact™ available on the uptodate.com website. We also use supporting literature such as e-books and journals to analyze data on potential drug interactions, mechanisms, severity, and treatment of drug interactions.

Ethical Consideration:

This recent study has received ethical approval from the Health Research Ethics Committee at RSUD Banyumas under number 116/EPK-RSUDBMS/VI/2021.

RESULT:

Patient demographic data describes the profile of COVID-19 patients hospitalized at the Banyumas Hospital from 2020 to 2021. Of the 221 patients, 122 were women (55.21%) and 99 were men (44.79%). Gender factors influence the distribution and severity of COVID-19. Patients in the early elderly age range (46-55 years) were 56(25.34%) (Table 1). Patients classified into comorbidities such as hypertension 26 patients (29.21%), diabetes mellitus 53 patients (59.55%), congestive heart failure 15 patients (16.85%), and others. There are 36 patients (40.45%) with other comorbidities such as dyslipidemia (2 patients), gastritis (4 patients), asthma (4 patients), bronchitis (1 patient), tuberculosis (6 patients), chronic kidney disease (4 patients), six patients with ischemic heart disease, one with hypertensive heart disease, cancer (1 patient), gout (2 patients), rheumatoid arthritis (1 patient), stroke (1 patient), and low-back pain (1 patient).

Azithromycin prescribed to 221 patients with confirmed COVID-19 at the Banyumas Hospital. Azithromycin used in COVID-19 patients with indications of bacterial co-infection as empirical antibiotic therapy in Banyumas Hospital. Azithromycin is an antibiotic to treat possible bacterial co-infection in patients with pneumonia8. The results showed potential drug interaction in 199(90%) of 221 patients (Table 2). Meanwhile, in 22 patients (10%), there are no potential drug interactions. Patients were using drugs without azithromycin's interaction. Based on severity, drug interactions classified into three groups, major, moderate, and minor. 

Our study found one major interaction event (0.35%), 264 moderate interaction events (91.35%), and 24 minor interaction events (8.30%). We found 126 pharmacodynamic interactions (44%), and 163 pharmacokinetic interactions (56%) (Table 2).

Table 1. The demographic features of COVID-19 patients receiving azithromycin treatment

^aDyslipidemia, gastritis, bronchitis, tuberculosis, renal failure, Ischemic Heart Disease (IHD), Hypertension Heart Disease (HHD), gout, rheumatoid arthritis, stroke, low-back pain

Figure 1. The prescribed azithromycin in COVID-19 patients, and percentages of Drug-Drug Interaction (DDI) that have been detected in all prescriptions (n = 221)

Table 2. The mechanism and severity categories of potential Drug-Drug Interaction (DDI) in COVID-19 patients treated with Azithromycin

DISCUSSION:

Azithromycin is a therapy for COVID-19 patients who are co-infected with bacterial pneumonia. Azithromycin antibiotics have a wide range to affect the number of patients. In addition, azithromycin is safe for pregnant and pediatric patients. Azithromycin dose 500mg for adult patients and 10mg/kg body weight for pediatric patients⁹. Azithromycin is administered orally every 24 hours and divided into three doses. The three doses are classified based on the patient's condition. Patients under teen years dose of azithromycin 10mg/Kg BW. Based on the patient's medical record data, azithromycin 250mg for four years old patients with a body weight of 26kg. Azithromycin 100mg was administered to patients one to two years old with a body weight of 9-10kg.

A total of 59.37% of patients had no comorbidities. The most comorbid disease suffered by COVID-19 patients is diabetes mellitus. Diabetes mellitus is a comorbid disease that is commonly experienced by COVID-19 patients and is referred to as a risk factor for the severity of COVID-19²⁰. Prevention of drug interaction events requires knowledge of the molecular mechanisms of drug interactions, classification of severity, management of drug interactions²¹.

Among these patients, the highest potential interaction is between azithromycin and omeprazole (moderate interaction)²². Omeprazole metabolism inhibits by azithromycin. Azithromycin inhibits the action of the CYP3A4 enzyme, as a substrate for omeprazole^22,23,24. These interactions are overcome by monitoring possible toxic effects such as nausea, abdominal pain, and diarrhea^22,25. Paracetamol is for symptomatic therapy for COVID-19 patients. Azithromycin has interaction with paracetamol 17.99%. Azithromycin inhibits paracetamol metabolism by inhibiting the CYP3A4 enzyme and acts as a weak substrate for CYP3A4 enzyme^22,26. These two interactions, azithromycin with omeprazole or paracetamol are moderate events²². This interaction was overcome by monitoring the hepatotoxic effect of paracetamol's impaired liver function.

The other potential interactions are azithromycin with levofloxacin, chloroquine, hydroxychloroquine, ondansetron, moxifloxacin, and domperidone. These drugs interact with azithromycin by pharmacodynamic mechanism. The mechanism is by increasing QT prolongation. Both azithromycin and the drug are causative agents of QT prolongation by blocking calcium channels in cell membranes. The K channel involved in this mechanism is the rapid component cardiac K-channel (IKr). This channel plays a role in regulating the heart rate²⁷. This inhibitory mechanism increases the accumulation of K+ ions in the intracellular and causes an extension of ventricular repolarization. The event occurs as a prolonged of the QT interval on electrocardiograms^28,29,30.

QT prolongation in the combination of these drugs included in the adverse drug reaction that will occur synergistically³¹. QT prolongation monitored through pharmacokinetic parameters. There is a possibility of inhibition of the CYP3A4 enzyme by azithromycin. However, these drugs are not involved in pharmacokinetic interactions³². According to Lexi-Interact™, interactions between azithromycin and other drugs caused adverse drug reaction prolongation of the QT interval. This adverse drug reaction augments and classified as a synergistic pharmacodynamic drug interaction. There is a possibility these drugs will exacerbate the effects³³. Pharmacodynamic drug interactions have a minor chance of occurrence. However, this potential drug interaction is considered for patient safety³².

Morphine, digoxin, and risperidone also have potential interaction with azithromycin. These interactions are moderate severity with pharmacokinetic mechanisms. The mechanism of interaction between azithromycin and these three drugs is increasing the levels of these three drugs. It is related to azithromycin as an inhibitor of P-glycoprotein. P-glycoprotein is an efflux transporter that plays a role in transporting drugs from intracellular to extracellular. The role of P-glycoprotein is to absorb toxic substances and pass on the metabolic process in the liver^34,35. P-glycoprotein transporters are distributed in many cells in the body with different functions. P-glycoprotein is found in the blood-brain barrier, intestinal cells and the apical membranes of excretory cells (liver cells and proximal renal tubules)³⁶. Liver and intestinal cells express the most P-glycoprotein transporters with an abundance of CYP3A4 metabolizing enzymes. It is made the metabolic cycle repeat through absorption and efflux processes. Drugs that work as P-Glycoprotein inhibitors are CYP3A4 inhibitors. Therefore, if the transporter inhibits by inhibitors such as azithromycin, the absorption, and metabolism are also inhibited. This can occur when azithromycin is used together with morphine and risperidone. While azithromycin concomitantly uses with morphine or risperidone, the concentration of the drugs in the blood increase and causes a toxic effect^37,38. To overcome the interaction between morphine and azithromycin is by monitoring the presence of toxic effects caused by morphine (respiratory depression). When these effects occur, it is necessary to decrease the dose of the drugs.

The P-glycoprotein transporter has different roles in several drugs. P-glycoprotein plays a role in preventing the distribution of loperamide to the brain. When this transporter at the blood-brain barrier inhibited, it will cause the entry of the drug into the intracranial fluid. This process cause side effects such as respiratory depression. P-glycoprotein also plays a role in the absorption of digoxin. P-glycoprotein located in intestinal epithelial cells affects the process of absorption and reduces drug bioavailability. Azithromycin acts as a P-glycoprotein inhibitor when concomitantly administered with digoxin. This causes an increase in digoxin levels³³.

Overcome interactions between azithromycin and digoxin by monitoring dizziness, weakness, gastrointestinal disturbances, and arrhythmias³³. Management in overcoming the interaction of azithromycin with risperidone is monitoring the occurrence of toxic effects of risperidone, namely prolongation of the QT interval³³. Drug interactions between azithromycin and simvastatin cause rhabdomyolysis. Rhabdomyolysis is a condition in which skeletal muscle tissue injury occurs with symptoms such as pain, swelling, muscle dysfunction, stiffness, tingling, weakness, and cloudy urine³⁹. The potential interaction between azithromycin and warfarin occurs at 0.69%. This interaction has a similar interaction mechanism as azithromycin and simvastatin. Warfarin consists of two enantiomeric, S-warfarin and R-warfarin. R-warfarin metabolized by the CYP3A4 enzyme⁴⁰. Concomitant use of azithromycin and warfarin increases the serum concentration of warfarin due to inhibition of the CYP3A4 enzyme. It caused an increase in adverse drug reactions to warfarin. The management to overcome this event is maintaining a check on the bleeding^33.

The potential interactions between azithromycin with colchicine occurred in one event (0.35%). It is related to the role of azithromycin as a P-glycoprotein inhibitor and will increase colchicine-serum concentration⁴¹. Kidney abnormalities and the development of pancytopenia effects may occur. Several critical conditions manifest in autoimmune diseases, anemia, and malnutrition⁴². Overcome drug interaction by reducing the dose of colchicine. For patients with liver and kidney disorders, colchicine is contraindicated³³. In addition to the drug interactions mentioned above, there are several interactions between azithromycin and other drugs with minor severity, namely metoclopramide, metronidazole, loperamide, terbutaline, salbutamol and remdesivir. Remdesivir is reported to shorten patient hospitalization but had no statistical relevance impact of death⁴³. Adverse drug reactions that occur due to drug interactions in patients can be prevented by monitoring drug therapy⁴⁴. This method can detect known and unknown associations between drug exposure and ADR. This relates to early detection and alert monitoring the safety profile of the drug prescribed⁴⁵. There are many possibilities for interactions between COVID-19 drugs and other drugs. These facts will be useful for screening and identifying potentially harmful DDI consequences, and thus adopt a prevention and management approach to avoid them⁴⁶. This research has limitations since it only studies relevant literature to assess azithromycin's possible potential interactions with other COVID-19 drugs; it fails to evaluate the actual occurrence of drug interactions. It also ignores the mode of administration.

Table 3. List of potential interactions associated with Azithromycin by drug, severity, frequency, interaction mechanism, effect, and recommendation

Monitoring the toxic effects of omeprazole

Monitor for QT prolongation and presence of arrhythmias

Monitoring the toxic effects of opioid (respiratory depression); dose reduction may be required

Monitoring of digoxin serum concentrations and toxic effects (gastrointestinal disturbances, weakness, dizziness, arrhythmias)

Monitor risk QT interval prolongation and presence of arrhythmias

The serum concentration of warfarin is increased due to the CYP3A4 inhibitory activity by macrolide antibiotics

Monitor for an increase in the therapeutic effect of warfarin (bleeding)

Individuals with a high risk of prolonged QT intervals should be monitored

Individuals with a high risk of prolonged QT intervals should be monitored

Individuals with a high risk of prolonged QT intervals should be monitored

CONCLUSION:

The highest use of azithromycin was in June 2021, with as many as 25 patients (11.32%). Potential drug interactions occurred in 199(90%) of 221 patients, with 289 cases of drug interactions. Based on the severity level, the most potential drug interactions occurred with a moderate degree of 264 events (91.35%), and based on the mechanism, the most potential drug interactions occurred pharmacokinetic with a total of 163 events (56%) so that the way to handle it is by monitoring the toxicity effects. The highest potential drug interactions occurred between azithromycin and omeprazole. Total drug interaction 85 events (29.41%), moderate severity, and pharmacokinetic mechanism.

CONFLICT OF INTEREST:

There are no conflict of interest for the authors in relation to this study.

ACKNOWLEDGMENTS:

We appreciate the funding provided by the Jenderal Soedirman University, Research and Community Service Institute (LPPM) under the Basic Research Grant for this project (Number: T/654/UN23.18/ PT.01.03/2021).

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Accepted on 16.07.2024           © RJPT All right reserved

Research J. Pharm. and Tech 2024; 17(9):4486-4492.