Exploring Macrolides: From Bacterial Infections to Anti-inflammatory Benefits || pharmacyteach

 

 Exploring Macrolides: From Bacterial Infections to Anti-inflammatory Benefits

Background 

A class of medications known as macrolides is used to treat and manage a variety of bacterial illnesses. Infections such as tonsillitis, sinusitis, pharyngitis, and pneumonia are frequently treated with azithromycin, clarithromycin, and erythromycin. They also treat pediatric patients' otitis media and simple skin infections. Despite clarithromycin resistance, Helicobacter pylori infections are treated with clarithromycin as part of the usual triple therapy procedure. Macrolides are also frequently used to treat chlamydial and gonococcal infections, two types of sexually transmitted illnesses. This exercise covers the macrolide's mechanism of action, indications, contraindications, and other important aspects (such as off-label applications, dosage, pharmacodynamics, pharmacokinetics, monitoring, and pertinent interactions).

Objective 

• Determine how the antibiotics of the macrolide class work.
• Explain the possible side effects of the antibiotics of the macrolide class.
• Examine the proper monitoring required for patients using antibiotics of the macrolide class.
• Explain how an interprofessional team can improve how macrolide antibiotics are administered and managed.

History of macrolides

Erythromycin was the first macrolide to be found, used for the first time in 1952. Erythromycin was frequently used in place of penicillin when patients had penicillin-resistant diseases or were allergic to the antibiotic. Erythromycin was chemically modified to produce later macrolides, such as azithromycin and clarithromycin, which were intended to be more readily absorbed and have less adverse effects (a considerable percentage of users experienced gastrointestinal side effects from erythromycin).

Macrolides include the following:

• Azithromycin
• Clarithromycin
• Erythromycin
• Fidaxomicin

Introduction

Natural substances called macrolides are made up of a lactone ring to which deoxy sugars are bonded. Pharmaceutical antimicrobial therapy uses some macrolides because of their antifungal or antibiotic qualities. Erythromycin was the first macrolide to be used in this way in 1952; it was frequently used to treat infections in people who were allergic to penicillin or whose infections were resistant to the antibiotic.

For a broad range of bacterial illnesses, the FDA has authorized the use of macrolide antibiotic medicines. Specifically, infections such as tonsillitis, sinusitis, pharyngitis, and pneumonia are frequently treated with azithromycin, clarithromycin, and erythromycin. Additionally, the FDA has authorized its usage for treating young patients' otitis media and simple skin infections. Furthermore, regardless of the presence of clarithromycin resistance, the usual triple therapy approach uses clarithromycin to treat Helicobacter pylori infections. Macrolides are also frequently used to treat chlamydial and gonococcal infections, two types of sexually transmitted illnesses. Like other antibiotics, the sensitivity and resistance status of the organism being targeted determines the majority of macrolide use. One of the main medications used to treat atypical pneumonia, which is typically brought on by bacteria like Mycoplasma pneumoniae, Legionella, and Chlamydia pneumoniae, is macrolides.

Recent research has demonstrated that macrolide maintenance medication improves spirometry results and quality of life in both adults and children with non-cystic fibrosis bronchiectasis. Additionally, it has been demonstrated that these medications lessen the frequency of exacerbations of bronchiectasis. These trials did not, however, show a decrease in hospitalizations related to exacerbations.

Macrolides continue to be a crucial component of chronic obstructive pulmonary disease (COPD) exacerbation therapy plans. These medications are used to treat COPD because of their immunomodulation and anti-inflammatory properties.

Mechanism of action of macrolides:

Antibacterial Activities:

Bacterial protein production is inhibited by macrolides. The capacity of macrolides to bind the 50S ribosomal subunit of bacteria and stop bacterial protein synthesis is the basis of their mode of action. By blocking the enzyme peptidyltransferase from adding the next amino acid linked to the tRNA, the medication stops the translation of mRNA, more especially the expanding peptide chain, after it has bound. The bacterial ribosomal structure is regarded as broad-spectrum since it is largely conserved throughout the majority of bacterial species if not all of them. Although they can be bactericidal at large dosages, macrolides are bacteriostatic agents since they simply prevent the synthesis of proteins. 

Anti-inflammatory and immunomodulatory Activities :

Interactions with phospholipids, transcription factors AP-1, NF-kappaB, and other inflammatory cytokines are thought to be responsible for the anti-inflammatory and immunomodulatory properties of macrolides, especially azithromycin. Subsequent alterations in macrophages interacting with macrolides include cellular transport, surface receptor expression modulation, and suppression of cell activity. These all lead to the body's immunomodulatory reactions to macrolides.

The overprescription of antibiotics has led to a massive increase in resistance to many mainstay therapies, including macrolides, to which many organisms are overly resistant. Post-transcriptional methylation of the bacterial 23S ribosomal RNA is the main cause of macrolide bacterial resistance, which can be acquired through two mechanisms: plasmid-mediated chromosomal. Research indicates a strong correlation between genetic variations in bacteria and the capacity to spread these genes via transposable components. The gene in question enables bacteria to be resistant to the streptogramin groups of antibiotics, lincosamides, and macrolides simultaneously.

Administration

The administering provider must be consulted regarding the drug's formulation. Strength, dosage, method, clinical treatment goals, etc. are all important considerations.  Depending on the intended prescription and the purpose of use,  macrolides can be administered in a variety of ways. Although oral formulations in tablet form are the most often utilized, they are also available as topical creams, intravenous formulations, and ocular preparations.The most popular macrolides and their most popular formulations are listed here, but there are other formulations and dosages available.

Adverse Effects

Similar to other antibiotics, macrolides are susceptible to common side effects such as diarrhea, vomiting, nausea, and stomach pain. Since macrolides are motilin agonists, they increase the risk of gastrointestinal distress and adverse effects, which are primarily responsible for abdominal symptoms. Additionally, because the enteric gut flora is vulnerable to the effects of macrolides, it may result in an imbalance between pathogenic bacteria and commensal bacteria that are naturally present in the human gut.

The combination of some macrolides and statins (used to decrease cholesterol) is not recommended and can result in crippling myopathy, according to a 2008 British Medical Journal report. This is because certain macrolides, specifically erythromycin and clarithromycin, but not azithromycin, are strong cytochrome P450 system inhibitors, especially of CYP3A4.

The tendency of macrolides to lengthen the QT and QTc intervals in the cardiac cycle is another frequent side effect. The two antibiotics with the highest and lowest tendencies are erythromycin and azithromycin. Patients are at risk for cardiac arrhythmias such as ventricular fibrillation, ventricular tachycardia, and Torsades de pointes due to the increase in intervals. Torsades de Pointes is the most frequent arrhythmia brought on by the usage of macrolides. 

Additionally, recent research on macrolides has demonstrated a correlation between the usage of these medications and sensorineural hearing loss. Few cases resulted in irreversible sensorineural hearing loss, although most cases were curable after drug withdrawal. According to studies, hearing loss can happen at both normal and elevated dosages.

Even though they are uncommon, serious adverse effects such as toxic epidermal necrolysis and Stevens-Johnsons syndrome can occur and should be considered when administering these medications.

Additionally, erythromycin has been linked to hepatotoxicity in expectant mothers. Additionally, these medications raise the risk of pyloric stenosis in infants.

Contraindication

Although macrolides are generally considered a safe class of antibiotics, there are some relative contraindications because of their adverse effect profile and potential for medication interactions. Because of their arrhythmogenic properties, macrolides should be avoided by patients having extended QT intervals on ECGs. Furthermore, these medications should be avoided by people who have congenital disorders such as long QT syndrome type 2. Macrolides should also be avoided by patients on Class Ia and Class III antiarrhythmic medications because they both lengthen the QT interval and cause arrhythmias.

Certain regularly used medications may interact negatively with macrolides. The most common interactions with macrolide antibiotics are those involving carbamazepine, cyclosporin, terfenadine, astemizole, and theophylline. Erythromycin is more likely to have CYP3A4-mediated drug-drug interactions than clarithromycin, which is a CYP3A4 inhibitor; azithromycin does not take part in these interactions.

Because macrolides, particularly erythromycin, might have negative effects on both the mother and the unborn child, pregnant women should also attempt to avoid taking them.

Macrolides should be used cautiously due to the rising rate of antibiotic resistance, and the prescriber should consider the local resistance status of common infections.

Interaction

The liver enzyme CYP3A4 is responsible for the metabolism of several medications. Because macrolides inhibit CYP3A4, they lower its activity and raise the blood levels of medications that rely on it for excretion. Negative consequences or drug-drug interactions may result from this.

  Macrolides are cyclic compounds with sugar moieties and a lactone ring. By creating reactive metabolites that bind to the enzyme covalently and irreversibly, they can block CYP3A4 through a process known as mechanism-based inhibition (MBI), which makes the enzyme inactive. Since new enzyme molecules must be synthesized to restore activity, MBI is more severe and persistent than reversible inhibition.

The size and structure of the lactone ring of macrolides determine the extent of MBI. The 14-membered lactone ring of clarithromycin and erythromycin are more vulnerable to CYP3A4's demethylation, which results in the production of nitroalkanes, the reactive metabolites that induce MBI. However, the 15-membered lactone ring of azithromycin makes it less vulnerable to nitrosoalkene production and demethylation. As a result, clarithromycin and erythromycin are powerful inhibitors of CYP3A4, increasing the area under the curve (AUC) value of co-administered medications by more than five times, but azithromycin is a modest inhibitor. AUC is a measurement of the body's cumulative exposure to drugs. The AUC of medications that rely on CYP3A4 for clearance can be considerably raised by macrolide antibiotics like erythromycin and clarithromycin, but not azithromycin, by blocking it. This can raise the risk of side effects or drug-drug interactions. Unlike other macrolide antibiotics, azithromycin is a weak CYP3A4 inhibitor that has no discernible effect on the AUC value of medications taken together.

For instance, patients taking statins, which are cholesterol-lowering medications primarily processed by CYP3A4, may experience clinical ramifications due to the variation in CYP3A4 inhibition by macrolides. Clarithromycin or erythromycin taken along with statins may raise the risk of statin-induced myopathy, a disorder that damages and pains muscles. However, azithromycin is seen to be a safer substitute because it has no discernible effect on the pharmacokinetics of statins. Using fluvastatin is an additional choice, a statin that is metabolized by the enzyme CYP2C9, which is not blocked by clarithromycin.

Colchicine toxicity may result when taking macrolides, such as azithromycin, with colchicine. Organ failure, fever, myalgia, pancytopenia, and gastrointestinal distress are signs of colchicine toxicity.

Monitoring

The variety of cardiac and gastrointestinal adverse effects that a patient may experience from taking macrolides should be considered by the physician when writing a prescription. The majority of patients will experience gastrointestinal side effects, thus the team should be prepared to take the appropriate precautions to mitigate these symptoms. Patients with heart problems, those using antiarrhythmics, and those taking medications known to induce interactions should all be closely monitored due to the possibility of QT prolongation. Prescribers should advise patients about potential dermatological adverse effects as they should be aware of them. Regarding potential side effects in expectant mothers and babies, patients need advice on the negative consequences of these medications during pregnancy, including the likely negative influence on the unborn child, when these medications are prescribed.

Toxicity

Given the severity of the cardiac adverse effects, high-risk patients should have their QT interval on their ECG monitored to prevent the induction of fatal arrhythmias such as Torsades de Pointes. Before giving the drugs to high-risk patients, electrolyte levels—specifically calcium, potassium, and magnesium—should be assessed. If a patient experiences severe side effects, the medication must be stopped. To reduce the danger of causing arrhythmias, macrolides should ideally be replaced with another antibiotic in these high-risk patients.

Enhancing Healthcare Team Outcomes

Even though macrolides are a fairly safe class of antibiotics, side effects should be minimized by the full interprofessional team administering them properly. Every member of the interprofessional healthcare team should keep an eye out for both typical and unusual side effects in patients. Every member needs to be informed about the serious cardiac effects of this medication as well as common gastrointestinal side effects. Each member of the healthcare team is accountable for giving their patients the best care possible and should constantly be aware of any possible negative impacts.

A pharmaceutical consult should be included by the physician (MD, DO, NP, or PA) when deciding to start macrolide therapy. This would entail confirming that the agent selected is suitable, confirming that the dosage is correct, and looking for drug-drug interactions. In addition, pharmacists can help patients by responding to their inquiries, alerting them to potential negative consequences, reiterating prescription instructions, and communicating any worries they may have to the physician. Nurses can keep an eye on patients' therapy, respond to their inquiries, and inform the prescriber of any negative side effects or treatment progress. To guarantee the best possible patient outcomes, all members of the interprofessional team should be aware of the most typical applications for the macrolide class of antibiotics and work together.

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