Macrolides

Mechanism of Action

Macrolies inhibit bacterial protein synthesis. The mechanism of action of macrolides revolves around their ability to bind the bacterial 50S ribosomal subunit causing the cessation of bacterial protein synthesis. Once it binds, the drug prevents the translation of mRNA, specifically the growing peptide chain, by preventing the enzyme peptidyltransferase from adding the subsequent amino acid attached to the tRNA. Since the bacterial ribosomal structure is highly conserved across most, if not all, bacterial species, it is considered broad-spectrum.[8] Macrolides are bacteriostatic agents as they only inhibit protein synthesis, although, at high doses, they can be bactericidal.

The anti-inflammatory and immunomodulatory effects of macrolides, particularly azithromycin, are attributed to interactions with phospholipids as well as transcription factors AP-1, NF-kappaB, and other inflammatory cytokines. Later changes seen in macrophages that interact with macrolides include inhibition of cell function, cellular transport, and surface receptor expression regulation. All of these culminate in the immunomodulatory effects of macrolides in the body.[2]

Due to the overprescription of antibiotics, there has been tremendous growth in resistance to many mainstay therapies. Macrolides are no exception to this situation, and many organisms are excessively resistant to them. The primary cause of macrolide bacterial resistance is post-transcriptional methylation of the bacterial 23S ribosomal RNA. This acquired resistance can occur via two mechanisms: it can be plasmid-mediated chromosomal.[9] Studies show a solid link to genetic mutations in bacteria and the ability to spread these genes via transposable elements. The gene in question allows bacteria to be resistant to macrolides, lincosamides, and streptogramin groups of antibiotics at once.[10]

Administration

The formulation of the drug requires discussion with the administering provider. The factors that one needs to consider are strength, dosage, route, clinical goals of treatment, etc. Macrolides come in various forms for administration, depending on the desired medication and the reason for their use. Most commonly used are oral formulations in tablet form, but they also come as topical creams, intravenous formulations, as well as ophthalmic preparations.[4]

The following list includes the most common macrolides and their most common formulations; however, other formulations and dosages do exist:

• Erythromycin
  • Oral tablets: 250 mg / 500 mg
  • Ophthalmic ointment: 0.5%
  • Topical gel or solution: 2%
• Clarithromycin
  • Oral tablets: 125 mg / 250 mg / 500 mg (extended-release) – oral tablets
  • Powder for reconstitution: 125 mg/5mL (oral suspension)
• Azithromycin
  • Oral tablets: 100 mg / 250mg / 500mg / 600mg – oral tablets
  • Powder for injection: 500 mg
  • Powder for reconstitution: 100 mg/5 mL / 200 mg/5 mL, and 1 g dose packet (oral suspension)
• Fidaxomicin
  • Oreal tablets: 200 mg

Adverse Effects

Like any other antibiotic, macrolides carry a certain level of risk from typical adverse effects like nausea, vomiting, abdominal pain, and diarrhea. Abdominal symptoms are largely the result of macrolides being motilin agonists causing an increased risk of gastrointestinal upset and side effects.[11] Besides, the enteric gut flora is susceptible to the effects of macrolides; therefore, it can cause an imbalance between commensal bacteria native to the human gut and pathogenic bacteria to be kept in check.

Another common adverse effect of macrolide use is their propensity to prolong the QT and QTc interval in the cardiac cycle. Erythromycin has the highest tendency, and azithromycin has the lowest. The increase in the intervals puts patients at risk of cardiac arrhythmias like Torsades de pointes, ventricular tachycardia, and ventricular fibrillation. The most common arrhythmia arising from the use of macrolides would be Torsades de Pointes.[12]  

Recent studies on macrolides have also shown that the use of these drugs correlates with sensorineural hearing loss. While the majority of cases were reversible with cessation of the drug, few cases resulted in irreversible sensorineural hearing loss. Studies have shown that hearing loss can occur both at standard doses and increased doses.[13] 

Serious side effects like Stevens-Johnsons syndrome and toxic epidermal necrolysis, although rare, are a possibility and should be kept in mind while prescribing these drugs.[14]  

Erythromycin also has correlations with hepatotoxicity in pregnant women. Moreover, these drugs increase the chances of pyloric stenosis in newborns.[4]

Contraindications

Overall, macrolides are a safe group of antibiotics to take, but relative contraindications exist due to the adverse effects profile and their ability to interact with other drugs. Patients with prolonged QT intervals on electrocardiograms should avoid macrolides due to their arrhythmogenic characteristics. Further, patients with congenital conditions like long QT syndrome type 2 should also avoid these drugs. Patients taking Class Ia and Class III antiarrhythmic agents should also avoid macrolides as both of these drug classes cause an increase in QT interval and induce arrhythmias.[15]

Macrolides can exhibit adverse interactions with some commonly used drugs. Carbamazepine, cyclosporin, terfenadine, astemizole, and theophylline interactions are the most frequently encountered with macrolide antibiotics. As a CYP3A4 inhibitor, erythromycin is more prone to drug-drug interactions mediated by CYP3A4; clarithromycin is much less apt to interact in this manner azithromycin does not participate in these interactions.[16]

Pregnant women should also try to avoid using macrolides, specifically erythromycin, due to possible side effects affecting the mother or the newborn.[17]

Due to the increasing rate of antibiotic resistance, macrolides should be prescribed with caution, and the prescriber should take into account the local resistance status of common pathogens.

Monitoring

When prescribing macrolides, the prescriber should consider the variety of gastrointestinal side effects and cardiac effects that the patient could encounter with macrolide use. In most patients, gastrointestinal side effects will be the most common, and the team should be ready to take proper measures to counter these effects. Due to the risk of QT prolongation, careful monitoring of patients with cardiac conditions as well as those taking antiarrhythmics or drugs known to cause interaction should be carried out. Prescribers should also be aware of possible dermatologic side effects and thus should counsel patients on the side effects. Concerning possible side effects in pregnant women and newborns, patients require counsel on the adverse effects of these drugs in pregnancy, including the probable adverse impact on the newborn when prescribing these drugs.

Toxicity

Due to the severity of the cardiac side effects, monitoring the QT interval on ECG should be done in high-risk patients to avoid the induction of deadly arrhythmias like Torsades de Pointes. Patients at high risk should have electrolytes checked before administering the medications, specifically calcium, potassium, and magnesium.[4] Cessation of the drug is necessary if serious side effects arise in a patient. If possible, another antibiotic should be used over macrolides in these high-risk patients to avoid the chance of inducing arrhythmias.

Enhancing Healthcare Team Outcomes

Although macrolides are a very safe class of antibiotics, proper healthcare administration by the entire interprofessional team should be done to minimize adverse events. All members of the interprofessional healthcare team should monitor patients for the common side effects as well as the uncommon ones. All members need education regarding common gastrointestinal side effects and the serious cardiac effects this drug has. Every healthcare team member shares the responsibility of providing top-notch care to their patients and should always be on the lookout for potential side effects.

When deciding to initiate macrolide therapy, the clinician (MD, DO, NP, or PA) would do well to include a pharmaceutical consult, which would consist of verifying the appropriateness of the agent chosen, verification of proper dosing, and checking for drug-drug interactions. Pharmacists can also assist the patient by answering their questions, warning of signs of adverse events, reinforcing prescriber directions, and reporting any concerns they may have to the clinician. Nursing can monitor and answer patient questions about their therapy and report to the prescriber on treatment progress or lack thereof or the presence of adverse effects. All interprofessional team members should know the most common uses of the macrolide class of antibiotics and exercise collaborative efforts to ensure optimal patient outcomes. [Level 5]