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Clinical Case in Community Pharmacy: Appropriate Use of Azithromycin

Authors:
Pantira Parinyarux at Chulalongkorn University
Pantira Parinyarux
Kitiyot Yotsombut at Chulalongkorn University
Kitiyot Yotsombut
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Abstract

ยาต้านจุลชีพกลุ่ม macrolides เป็นยาต้านจุลชีพที่ได้รับความนิยมใช้อย่างแพร่หลาย เนื่องจากมีประสิทธิภาพดีและความปลอดภัยค่อนข้างสูงโดยยา erythromycin เป็นยาชนิดแรกของกลุ่ม macrolides ที่ถูกค้นพบตั้งแต่ ค.ศ. 1952 ซึ่งสกัดแยกได้จาก Streptomyces erythraeus ในระยะแรกที่เริ่มมีการใช้ erythromycin นิยมใช้เป็นทางเลือกของยากลุ่ม penicillins เนื่องจากมีขอบเขตการออกฤทธิ์ใกล้เคียงกัน คือ ครอบคลุมเชื้อแบคทีเรียแกรมบวก เช่น Staphylococci, Pneumococci และ Streptococci จากนั้นจึงเริ่มขยายข้อบ่งใช้ในการรักษาโรคที่เกิดจาก Mycoplasma, Legionella, Campylobacter และ Chlamydia แม้ว่า erythromycin จะมีประโยชน์กว้างขวางในทางคลินิกแต่มีข้อจำกัดในการใช้เนื่องจากตัวยามีความคงตัวต่ำในสภาวะกรดของกระเพาะอาหาร ทำให้ปริมาณยาที่ถูกดูดซึมมีจำกัด อีกทั้งมีค่าครึ่งชีวิตสั้นจำเป็นต้องรับประทานบ่อยครั้ง และสามารถกระตุ้นตัวรับ motilin receptor ทำให้เกิดอาการคลื่นไส้อาเจียน และท้องเสียได้บ่อย ในระยะต่อมาจึงได้มีการพัฒนาต่อยอดได้เป็นยาใหม่ในกลุ่ม macrolides หลายรายการ เช่น clarithromycin และ azithromycin ที่นิยมใช้ในปัจจุบัน
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วารสารสมาคมเภสัชกรรมชุมชน ี่� 20 ฉั่� 117 เือนกรกฎาคม 2564 8
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
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โรคและยา
Clinical case in Community pharmacy:
Practical Points in Azithromycin Dispensing
Clinical case in Community pharmacy: Practical Points in Azithromycin Dispensing
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9วารสารสมาคมเภสัชกรรมชุมชน ี่� 20 ฉั่� 117 เือนกรกฎาคม 2564
Clinical case in Community pharmacy: Practical Points in Azithromycin Dispensing
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

Haemophilus inuenzaeMoraxella
catarrhalisNeisseria gonorrhoeae

2
 Erythromycin Clarithromycin Azithromycin

Streptococcus pyogenes   
Streptococcus pneumoniae   

Haemophilus inuenzae 8 
Moraxella catarrhalis   
Legionella pneumophila   
Neisseria gonorrhoeae   

Chlamydophila pneumoniae   
Mycoplasma pneumoniae   
 





 





วารสารสมาคมเภสัชกรรมชุมชน ี่� 20 ฉั่� 117 เือนกรกฎาคม 2564 10
Clinical case in Community pharmacy: Practical Points in Azithromycin Dispensing Clinical case in Community pharmacy: Practical Points in Azithromycin Dispensing
2
 Erythromycin Clarithromycin Azithromycin
   
   
  
 8 
  


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
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
 
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11 วารสารสมาคมเภสัชกรรมชุมชน ี่� 20 ฉั่� 117 เือนกรกฎาคม 2564
Clinical case in Community pharmacy: Practical Points in Azithromycin Dispensing
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Clinical case in Community pharmacy: Practical Points in Azithromycin Dispensing Clinical case in Community pharmacy: Practical Points in Azithromycin Dispensing
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 
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 
 
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 
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 
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 
13 วารสารสมาคมเภสัชกรรมชุมชน ี่� 20 ฉั่� 117 เือนกรกฎาคม 2564
Clinical case in Community pharmacy: Practical Points in Azithromycin Dispensing
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 
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
Clinical case in Community pharmacy: Practical Points in Azithromycin Dispensing
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 Erythromycin Clarithromycin Azithromycin
 +++ +++
 ++ +
 +++ ++
 ++ ++
 +++ ++++
 ++++ ++++
 +++ +++
  
  
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Comparison of Cardiac Events Associated With Azithromycin vs Amoxicillin
Article
Full-text available
  • Sep 2020
Importance: Conflicting evidence exists on the association between azithromycin use and cardiac events. Objective: To compare the odds of cardiac events among new users of azithromycin relative to new users of amoxicillin using real-world data. Design, setting, and participants: This retrospective cohort study used data from Truven Health Analytics MarketScan database from January 1, 2009, to June 30, 2015. Patients receiving either amoxicillin or azithromycin and enrolled in a health care plan 365 days before (baseline period) the dispensing date (index date) were included in the study. Patients were matched 1:1 on high-dimensional propensity scores. Data were analyzed from October 1, 2018, to December 31, 2019. Exposures: New use of azithromycin compared with new use of amoxicillin. Main outcomes and measures: The primary outcome consisted of cardiac events, including syncope, palpitations, ventricular arrhythmias, cardiac arrest, or death as a primary diagnosis for hospitalization at 5, 10, and 30 days from the index date. Logistic regression models were used to estimate odds ratios (ORs) with 95% CIs. Results: After matching, the final cohort included 2 141 285 episodes of each index therapy (N = 4 282 570) (mean [SD] age of patients, 35.7 [22.3] years; 52.6% female). Within 5 days after therapy initiation, 1474 cardiac events (0.03%) occurred (708 in the amoxicillin cohort and 766 in the azithromycin cohort). The 2 most frequent events were syncope (1032 [70.0%]) and palpitations (331 [22.5%]). The odds of cardiac events with azithromycin compared with amoxicillin were not significantly higher at 5 days (OR, 1.08; 95% CI, 0.98-1.20), 10 days (OR, 1.05; 95% CI, 0.97-1.15), and 30 days (OR, 0.98; 95% CI, 0.92-1.04). Among patients receiving any concurrent QT-prolonging drug, the odds of cardiac events with azithromycin were 1.40 (95% CI, 1.04-1.87) greater compared with amoxicillin. Among patients 65 years or older and those with a history of cardiovascular disease and other risk factors, no increased risk of cardiac events with azithromycin was noted. Conclusions and relevance: This study found no association of cardiac events with azithromycin compared with amoxicillin except among patients using other QT-prolonging drugs concurrently. Although azithromycin is a safe therapy, clinicians should carefully consider its use among patients concurrently using other QT-prolonging drugs.
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Torsades de pointes and QT prolongation Associations with Antibiotics: A Pharmacovigilance Study of the FDA Adverse Event Reporting System
Article
Full-text available
  • Jun 2019
  • Int J Med Sci
Introduction: Macrolides, linezolid, imipenem-cilastatin, fluoroquinolones, penicillin combinations, and ceftriaxone are known to be associated with Torsades de pointes/QT prolongation (TdP/QTP). Other antibiotics may also lead to TdP/QTP, but no study has systemically compared TdP/QTP associations for many available antibiotics. Objectives: The objective of this study was to evaluate the association between TdP/QTP and many available antibiotics using the FDA Adverse Event Report System (FAERS). Methods: FAERS reports from January 1, 2015 to December 31, 2017 were analyzed. The Medical Dictionary for Regulatory Activities (MedDRA) was used to identify TdP/QTP cases. We calculated the Reporting Odds Ratios (RORs) and corresponding 95% confidence intervals (95%CI) for the association between antibiotics and TdP/QTP. An association was considered to be statistically significant when the lower limit of the 95%CI was greater than 1.0. Results: A total of 2,042,801 reports (including 3,960 TdP/QTP reports) were considered, after inclusion criteria were applied. Macrolides had the greatest proportion of TdP/QTP reports. Of the 4,092 reports associated with macrolides, 108 reports (2.6%) were associated with TdP/QTP. Significant TdP/QTP RORs (95%CI) for the antibiotics were (in descending order): macrolides 14.32 (11.80-17.38), linezolid 12.41 (8.52-18.08), amikacin 11.80 (5.57-24.97), imipenem-cilastatin 6.61 (3.13-13.94), fluoroquinolones 5.68 (4.78-6.76), penicillin combinations 3.42 (2.35-4.96), and ceftriaxone 2.55 (1.41-4.62). Conclusion: This study confirms prior evidence for TdP/QTP associations with macrolides, linezolid, imipenem-cilastatin, fluoroquinolones, penicillin combinations, and ceftriaxone. This study also identifies a new association between amikacin and TdP/QTP.
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The Immunomodulatory Effects of Macrolides—A Systematic Review of the Underlying Mechanisms
Article
Full-text available
  • Mar 2018
Background The mechanisms underlying the non-antimicrobial immunomodulatory properties of macrolides are not well understood. Objectives To systematically review the evidence for the immunomodulatory properties of macrolides in humans and to describe the underlying mechanism and extent of their influence on the innate and adaptive immune system. Methods A systematic literature search was done in MEDLINE using the OVID interface from 1946 to December 2016 according to the preferred reporting items for systematic reviews and meta-analysis (PRISMA). Original articles investigating the influence of four macrolides (azithromycin, clarithromycin, erythromycin, and roxithromycin) on immunological markers in humans were included. Results We identified 22 randomized, controlled trials, 16 prospective cohort studies, and 8 case–control studies investigating 47 different immunological markers (186 measurements) in 1,834 participants. The most frequently reported outcomes were a decrease in the number of neutrophils, and the concentrations of neutrophil elastase, interleukin (IL)-8, IL-6, IL-1beta, tumor necrosis factor (TNF)-alpha, eosinophilic cationic protein, and matrix metalloproteinase 9. Inhibition of neutrophil function was reported more frequently than eosinophil function. A decrease in T helper (Th) 2 cells cytokines (IL-4, IL-5, IL-6) was reported more frequently than a decrease in Th1 cytokines (IL-2, INF-gamma). Conclusion Macrolides influence a broad range of immunological mechanisms resulting in immunomodulatory effects. To optimize the treatment of chronic inflammatory diseases by macrolides, further studies are necessary, particularly comparing different macrolides and dose effect relationships.
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Resistance to Macrolide Antibiotics in Public Health Pathogens
Article
Full-text available
  • Aug 2016
Macrolide resistance mechanisms can be target-based with a change in a 23S ribosomal RNA (rRNA) residue or a mutation in ribosomal protein L4 or L22 affecting the ribosome's interaction with the antibiotic. Alternatively, mono- or dimethylation of A2058 in domain V of the 23S rRNA by an acquired rRNA methyltransferase, the product of an erm (erythromycin ribosome methylation) gene, can interfere with antibiotic binding. Acquired genes encoding efflux pumps, most predominantly mef(A) + msr(D) in pneumococci/streptococci and msr(A/B) in staphylococci, also mediate resistance. Drug-inactivating mechanisms include phosphorylation of the 2'-hydroxyl of the amino sugar found at position C5 by phosphotransferases and hydrolysis of the macrocyclic lactone by esterases. These acquired genes are regulated by either translation or transcription attenuation, largely because cells are less fit when these genes, especially the rRNA methyltransferases, are highly induced or constitutively expressed. The induction of gene expression is cleverly tied to the mechanism of action of macrolides, relying on antibiotic-bound ribosomes stalled at specific sequences of nascent polypeptides to promote transcription or translation of downstream sequences.
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Azithromycin and Risk of Sudden Cardiac Death: Guilty as Charged or Falsely Accused?
Article
Full-text available
  • Sep 2013
  • CLEV CLIN J MED
A march 2013 warning by the US Food and Drug Administration that azithromy-cin (Zithromax, Zmax, Z-pak) may increase the risk of sudden cardiac death does not mean we must abandon using it. We should, however , try to determine if our patients have cardio-vascular risk factors for this extreme side effect and take appropriate precautions.
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Blood, Tissue, and Intracellular Concentrations of Azithromycin during and after End of Therapy
Article
Full-text available
Although azithromycin is extensively used in the treatment of respiratory tract infections as well as skin and skin-related infections, pharmacokinetics of azithromycin in extracellular space fluid of soft tissues, i.e. one of its therapeutic target sites, are not yet fully elucidated. In this study, azithromycin concentration versus time profiles in extracellular space of muscle and subcutaneous adipose tissue, but also in plasma and white blood cells were determined at days 1 and 3 of treatment as well as 2 and 7 days after end of treatment. Of all compartments, azithromycin concentrations were highest in white blood cells, attesting for intracellular accumulation. However, azithromycin concentrations in both soft tissues were markedly lower than in plasma both during and after treatment. Calculation of AUC(0-24h)/MIC(90) ratios for selected pathogens suggests that azithromycin concentrations measured in the present study are subinhibitory at all time points in both soft tissues and at the large majority of observed time points in plasma. Hence, it might be speculated that azithromycin's clinical efficacy relies not only on elevated intracellular concentrations but possibly also on its known pleotropic effects including immuno-modulation and influence on bacterial virulence factors. However, prolonged subinhibitory azithromycin concentrations at target site, as observed in the present study, might favor the emergence of bacterial resistance and should therefore be considered with concern. In conclusion, this study has added important information to the pharmacokinetic profile of the widely used antibiotic drug azithromycin and evidentiates the need for further research on its potential for induction of bacterial resistance.
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Mechanistic Study of the Azithromycin Dosage-Form-Dependent Food Effect
Article
Full-text available
  • Apr 2010
  • PHARM RES-DORDR
Azithromycin capsules are known to exhibit a negative food effect, manifest as a decrease in azithromycin bioavailability in the fed state. Azithromycin tablets are known to be bioequivalent to capsules in the fasted state, but do not exhibit a food effect. In the present study, the involvement of gastric degradation of azithromycin to des-cladinose azithromycin (DCA) has been investigated as a possible mechanism for the observed capsule food effect. Healthy volunteers were dosed with azithromycin tablets and capsules, fasted and fed, in a four-way randomized crossover study. Serum levels of DCA were measured as a function of time post-dose. Natural log-transformed PK parameters were statistically analyzed using an ANOVA model appropriate for the study design. When capsules were dosed to fed subjects, the systemic AUC for DCA was 243% of the value observed after fasted-state dosing, and the DCA C(max) was 270% of the value observed after fasted-state dosing. When azithromycin tablets were dosed in the fasted and fed states, there was no significant difference in systemic DCA. Gastric degradation of azithromycin to DCA is the likely mechanism for the observed negative food effect observed for azithromycin capsules. This effect is not observed for tablets. These observations suggest that azithromycin capsules exhibit slow and/or delayed disintegration in the fed stomach, resulting in extended gastric residence and degradation of a portion of the gastrically retained azithromycin.
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Macrolides, Ketolides, and Glycylcyclines: Azithromycin, Clarithromycin, Telithromycin, Tigecycline
Article
  • Dec 2009
The advanced macrolides, azithromycin and clarithromycin, and the ketolide, telithromycin, are structural analogs of erythromycin. They have several distinct advantages when compared with erythromycin, including enhanced spectrum of activity, more favorable pharmacokinetics and pharmacodynamics, once-daily administration, and improved tolerability. Clarithromycin and azithromycin are used extensively for the treatment of respiratory tract infections, sexually transmitted diseases, and Helicobacter pylori-associated peptic ulcer disease. Telithromycin is approved for the treatment of community-acquired pneumonia. Severe hepatotoxicity has been reported with the use of telithromycin.
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Azithromycin and Clarithromycin Overview and Comparison With Erythromycin
Article
  • Jul 1992
Macrolides currently account for 10% to 15% of the worldwide oral antibiotic market.' Erythromycin, the first macrolide antibiotic, was discovered in 1952 from a strain of Streptomyces erythreus obtained from soil samples in the Phillipines. Originally, erythromycin was marketed as an alternative to penicillin because of its activity against gram-positive organisms such as staphylococci, pneumococci, and streptococci. Subsequently, its clinical use broadened to include species of Mycoplasma, Legionella, Campylobacter, and Chlamydia. Although several other macrolides have been marketed in countries other than the United States, they have failed to achieve erythromycin's widespread use. Unfortunately, erythromycin suffers from several drawbacks, including gastrointestinal side effects, a short serum elimination half-life, and only borderline in vitro activity against common gram-negative respiratory pathogens such as Haemophilus influenzae.
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Advanced-generation macrolides: Tissue-directed antibiotics
Article
  • Feb 2001
  • INT J ANTIMICROB AG
The azalide antibiotic azithromycin and the newer macrolides, such as clarithromycin, dirithromycin and roxithromycin, can be regarded as 'advanced-generation' macrolides compared with erythromycin, the first macrolide used clinically as an antibiotic. Their pharmacokinetics are characterized by a combination of low serum concentrations, high tissue concentrations and, in the case of azithromycin, an extended tissue elimination half-life. Azithromycin is particularly noted for high and prolonged concentrations at the site of infection. This allows once-daily dosing for 3 days in the treatment of respiratory tract infections, in contrast to longer dosage periods required for erythromycin, clarithromycin, roxithromycin and agents belonging to other classes of antibiotics. The spectrum of activity of the advanced-generation macrolides comprises Gram-positive, atypical and upper respiratory anaerobic pathogens. Azithromycin and the active metabolite of clarithromycin also demonstrate activity against community-acquired Gram-negative organisms, such as Haemophilus influenzae. Advanced-generation macrolides, and in particular azithromycin, are highly concentrated within polymorphonuclear leucocytes, which gravitate by chemotactic mechanisms to sites of infection. Following phagocytosis of the pathogens at the infection site, they are exposed to very high, and sometimes cidal, intracellular concentrations of antibacterial agent. Pharmacodynamic models and susceptibility breakpoints derived from studies with other classes of drugs, such as the beta-lactams and aminoglycosides, do not adequately explain the clinical utility of antibacterial agents that achieve high intracellular concentrations. In the case of azithromycin, attention should focus on tissue pharmacokinetic and pharmacodynamic concepts.
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