Macrolide Antibiotics

They belong to macrolide antibiotics compounds that contain macrocyclic lactone attached to various deoxy-sugars.

From: xPharm: The Comprehensive Pharmacology Reference, 2007

Therapeutic Areas II: Cancer, Infectious Diseases, Inflammation & Immunology and Dermatology

T. Kaneko, ... T.V. Magee, in Comprehensive Medicinal Chemistry II, 2007

Macrolide antibiotics such as erythromycin, clarithromycin, and azithromycin have been used widely to combat primarily respiratory diseases caused by Gram-positive pathogens and fastidious Gram-negative pathogens. The popularity of this class of antibiotics is largely due to their spectrum of activity and their relative safety. The second-generation macrolides, clarithromycin and azithromycin, are derived from erythromycin, and have a broader spectrum of activity and improved pharmacokinetic properties. Macrolide antibiotics inhibit bacterial protein synthesis by interfering with ribosome function, and details of the inhibitory mechanisms have been clarified by recent advances in the x-ray structure of the ribosome–macrolide complexes. The widespread use of these antibiotics had catalyzed the emergence of macrolide-resistant strains, especially among Streptococcus pneumoniae, Streptococcus pyogenes, and Staphylococcus aureus. In response to these resistant pathogens, third-generation macrolides, represented by the ketolide telithromycin, are being developed. These derivatives have increased affinity for the bacterial ribosome and a reduced propensity to be efflux pump substrates compared with the first- and second-generation macrolides. Discovery of telithromycin and its introduction into the market triggered a renewed interest in the chemistry of macrolide antibiotics in recent years. As a result, a large number of novel and potent analogs were synthesized and are under investigation. In this chapter, the major classes of macrolide antibiotics as well as the newer analogs are reviewed. Included are descriptions of their syntheses, their mechanism of action, resistance mechanisms, structure–activity relationship (SAR), and their pharmacokinetic and safety properties.

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Macrolide antibiotics

In Meyler's Side Effects of Drugs (Sixteenth Edition), 2016

Long-term effects

Drug tolerance

An area of increasing concern and clinical importance is the increasing macrolide resistance that has been reported over the last several years with some of the common pathogens, particularly Streptococcus pneumoniae, group A streptococci, and Haemophilus influenzae, and may result in failure of therapy of pneumonia, pharyngitis, and skin infections [55]. High rates of resistance of several groups of streptococci to macrolides have been reported from all parts of the world [56–65].

Resistance to erythromycin can develop rapidly and is usually associated with bacterial cross-resistance to the other macrolide antibiotics, and also to the chemically unrelated lincosamides. Resistance has been detected in strains of staphylococci, Group A hemolytic streptococci, viridans streptococci, Streptococcus pyogenes, Neisseria gonorrhoeae, Bacteroides fragilis, and Clostridium difficile [66,67]. It has tended to occur in hospitals, where either erythromycin or the lincosamides were used extensively, but can also result from multiple drug resistance when other antibiotics are used. Subinhibitory concentrations of erythromycin can cause resistance in staphylococci.

In combination with proton pump inhibitors and other antibiotics, macrolides are still successfully used for the eradication of H. pylori infection [68,69]. However, resistance of H. pylori to macrolides has emerged in a number of countries. The first case of H. pylori resistance to clarithromycin has now also been documented in Denmark and follows increased use of this macrolide in eradication regimens [70].

Clinical isolates of N. gonorrhoeae with reduced susceptibility to azithromycin are commonly found in Uruguay, and one of the mechanisms involved included mutations in the mtrR gene [71].

Resistance of H. pylori to clarithromycin appears to have increased in proportion to clarithromycin use. Clarithromycin resistance arises through mutations that lead to base changes in 23S ribosomal RNA subunits. A rapid PCR hybridization assay with a sensitivity of 97% for the detection of clarithromycin resistance of strains of H. pylori has been described [72]. Resistance to clarithromycin has a serious impact on the efficiency of eradicating regimens that include clarithromycin [73–75]. The reported incidences of primary resistance of H. pylori to clarithromycin are 6.1% in the USA, 8% in Austria, 8.7% in Bulgaria, 9.5% in Japan, 10% in Spain, 11% in France, 13% in Nigeria, and 23% in Italy [76–83].

Among strains of Enterococcus faecium, resistance against tylosin was mainly detected in strains from poultry, but also in some strains from pork. Among strains of E. faecium and Enterococcus faecalis isolated from pigs and poultry in Denmark, resistance to tylosin was often observed among isolates from places in which these antimicrobials had been widely used, but rarely among isolates from places in which their use had been limited [84].

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Drug Allergy

Anca M. Chiriac, Pascal Demoly, in Pediatric Allergy: Principles and Practice (Third Edition), 2016

Macrolides

Macrolide antibiotics are considered to be one of the safest antibiotic treatments available, with a DHR prevalence of 0.4% to 3% of all treatments.45,63 Their chemical structure is characterized by a large lactone ring, which can vary from 12 to 16 atoms, with one or more sugar chains attached. Cross-reactivity among different macrolides has not been extensively studied, but when it was tested, a majority of patients with a demonstrated DHR to a certain macrolide could tolerate another macrolide with a different number of atoms in the lactone ring. Moreover, macrolide antibiotics are unlikely to cross-react with macrolide immunosuppressants such as 23-C tacrolimus and 29-C sirolimus. Published series reveal that, after performing DPT, DHRs to macrolides are confirmed in only 2.7% to 17% of cases.45,63

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Advances in antibiotic measurement

Amitava Dasgupta, in Advances in Clinical Chemistry, 2012

12 Therapeutic Drug Monitoring of Macrolide Antibiotics

The macrolide antibiotics contain a large macrocyclic lactone ring to which one or more deoxysugar may be attached. These antibiotics inhibit bacterial protein biosynthesis by binding reversibly to the subunit 50S of the bacterial ribosome and preventing translocation of peptidyl-tRNA. Erythromycin was one of the first drugs of this type used in clinical practice, but subsequent broader spectrum drugs, such as clarithromycin and azithromycin, have been developed more recently and are widely utilized. Macrolide antibiotics are most frequently used to treat infections of the upper and lower respiratory tract and skin and soft tissue infections. The antimicrobial spectrum of macrolides is broader than that of penicillins (and comparable to many late-generation cephalosporins); therefore, macrolide antibiotics have been successfully used as a substitute in treating patients with known penicillin allergy [3].

Adverse reactions with macrolide antibiotics are relatively rare, and therefore, therapeutic drug monitoring is not usually necessary during therapy with macrolide antibiotics. Only chromatographic methods are available for determination of serum or plasma levels of these antibiotics. Macrolide antibiotics, such as erythromycin, azithromycin, and clarithromycin, can be readily analyzed using chromatographic techniques with solid phase or liquid–liquid extraction. UV, electrochemical, and fluorescence (following derivatization with agents like 9-fluorenylmethyl chloroformate) detection methods have been used successfully. Sensitive methods using liquid chromatography–tandem mass spectrometry have also been introduced in recent years which eliminate time-consuming pretreatment and derivatization steps and show greater reproducibility and less interference than the conventional HPLC methods [65–67].

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Pharmacology of Specific Drug Groups

Purnima Kumar, in Pharmacology and Therapeutics for Dentistry (Seventh Edition), 2017

Chemistry and classification (Table 33-7; Fig. 33-8)

Macrolide antibiotics are characterized by large 14-membered, 15-membered, or 16-membered lactone rings. Erythromycin, as derived from Streptomyces erythreus, was introduced in 1952, and azithromycin and clarithromycin were introduced in 1991 and 1992, respectively. Azithromycin is a 15-membered macrolide with an added nitrogen and N-methylation (making it technically an azalide), whereas clarithromycin is formed by the alkylation of a hydroxyl group of erythromycin (a 14-membered ring). Troleandomycin is a synthetic derivative of oleandomycin, dirithromycin is a prodrug yielding erythromycylamine in the intestine, and telithromycin is a derivative of erythromycin A and a 14-membered macrolide with a 3-keto group substitution.

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Methadone

In Meyler's Side Effects of Drugs (Sixteenth Edition), 2016

Macrolide antibiotics

Macrolide antibiotics inhibit CYP3A4 and might therefore inhibit the metabolism of methadone. However, troleandomycin has very little effect on the metabolism of methadone. In one study it inhibited in vitro microsomal methadone metabolism by 20–30% but did not affect in vivo methadone concentrations [134]. In healthy volunteers troleandomycin had a small effect on the metabolism of methadone but did not alter its plasma concentrations, oral clearance, or other kinetic parameters, although in human intestinal microsomes in vitro troleandomycin inhibited the formation of the methadone metabolites EDDP and EMDP by over 70% [135]. Presumably the difference between the in vitro and the in vivo results is because there are in vivo pathways of elimination of methadone other than via CYP3A4.

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Antimicrobial agents

D. Greenwood, W.L. Irving, in Medical Microbiology (Eighteenth Edition), 2012

Macrolides

Macrolide antibiotics have a large macrocyclic lactone ring substituted with some unusual sugars. They act by interfering with the translocation of mRNA on the bacterial ribosome. They are used mainly as antistaphylococcal and antistreptococcal agents, though some have wider applications. They have no useful activity against enteric Gram-negative bacilli. The original macrolide, erythromycin, is unstable in gastric acid and is usually administered orally as the stearate salt or as an esterified pro-drug (pharmacological preparations that improve absorption and deliver the active drug into the circulation). Salts suitable for intravenous administration are also available. Certain other macrolides, notably clarithromycin, offer improved pharmacological properties.

The macrolactone ring of most macrolides is composed of 14 atoms, but others have a 16-membered structure. These include spiramycin, which has some useful activity against the protozoan parasite, Toxoplasma gondii.

Some macrolides feature structural changes in the macrocyclic ring: in azithromycin, a compound distinguished by good tissue penetration and a long terminal half-life, the ring has been expanded by inclusion of a nitrogen atom to form an azalide; in telithromycin, a compound that retains activity against macrolide-resistant Gram-positive cocci, a keto function has been introduced to produce a ketolide.

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A worldwide yearly survey of new data and trends in adverse drug reactions and interactions

I. Aursnes, in Side Effects of Drugs Annual, 2008

Drug interactions with statins

Pharmacokinetic interactions with statins can occur by inhibition or induction of CYP isozymes. Pharmacodynamic interactions can occur through additive effects on muscle. There have been more reports of both types of interactions.

Clarithromycin

Macrolide antibiotics are potent inhibitors of CYP3A4 and amiodarone less potent. Severe myopathy has been attributed to the combination of simvastatin with clarithromycin and amiodarone(15A).

A 56-year-old man taking simvastatin was given clarithromycin and amiodarone for pneumonia and a supraventricular tachycardia. He found it difficult to move and complained of general weakness and muscle pain. The blood creatine kinase activity was over 20 000 IU/l. Simvastatin was withdrawn on day 19 and during days 22–31 he steadily improved.

Clopidogrel

Clopidogrel is a prodrug that is converted to its active form by CYP3A4. The active drug irreversibly blocks one specific platelet adenosine5-diphosphate (ADP) receptor (P2Y12). As certain lipophilic statins (atorvastatin, lovastatin, simvastatin) are substrates of CYP3A4, drug interactions are possible. However, previous studies with atorvastatin have given variable results (SEDA-28, 536; SEDA-29, 548). In a recent study the inhibitory potency of clopidogrel on ADP-induced platelet activation was not attenuated when it was co-administered with atorvastatin (20 mg/day) for 5 weeks in 51 patients with acute coronary syndromes(16A). Atorvastatin had no effect on either clopidogrel-induced inhibition of platelet aggregation initiated by ADP 5 or 10 μmol/l or clopidogrel-induced reduction of the membrane expression of P-selectin and CD40L induced by ADP. The same authors found a similar result in a previous study with a lower dosage of atorvastatin (10 mg/day) (SEDA-29, 548).

Colchicine

Interactions of statins with colchicine have been reported.

A 70-year-old man with hyperlipidemia and gout had been taking fluvastatin 80 mg/day for 2 years(17A). After taking colchicine 1.5 mg/day for acute gouty arthritis for 3 days he developed stomach ache and nausea followed by severe pains and weakness in his arms and legs. After 10 days he developed rhabdomyolysis and non-oliguric myoglobinuric acute renal insufficiency.

A 65-year-old woman who had been taking pravastatin 20 mg/day for 6 years developed acute gout(18A). Her blood urea nitrogen and serum creatinine concentrations were 48 and 1.3 mg/dl respectively. She was given colchicine 1.5 mg/day but 20 days later developed symmetrical proximal muscle weakness in the legs. Examination, laboratory findings, and electromyelography suggested myopathy. The weakness improved 7 days after withdrawal of colchicine and pravastatin and the enzyme activities returned to normal. Colchicine 1 mg/day was restarted 5 days later and the myopathy did not recur.

Colchicine is cleared by a different CYP450 isozyme than fluvastatin and pravastatin are, but another possible mechanism is synergistic myotoxicity, since colchicine causes myopathy by disrupting tubular function with subsequent vacuolization. Patients taking colchicine should be informed about possible muscular and gastrointestinal adverse effects and advised to stop.

Fluconazole

Azoles are potent inhibitors of drug metabolism, and fluconazole has previously been reported to interact with simvastatin. A similar interaction with atorvastatin has now been reported(19A).

A 76-year-old man taking antimicrobial drug treatment including fluconazole switched from pravastatin to atorvastatin 40 mg/day. After 1 week he began to feel tired and became oliguric, and on day 2 the serum myoglobin concentration was 16 120 μg/l. After 8 days in intensive care he died in multiorgan failure.

Gemfibrozil

In a randomized crossover study gemfibrozil increased the AUC of atorvastatin and its metabolites(20c). Low doses of atorvastatin should be used if gemfibrozil is co-administered.

Rifampicin

In a randomized crossover study rifampicin reduced the total AUC of atorvastatin and increased the Cmax of 2-hydroxyatorvastatin acid by 68%(20c). It is advisable to increase the dosage of atorvastatin and preferable to administer it in the evening to guarantee adequate concentrations during the period of rapid cholesterol synthesis that occurs at night when rifampicin or other potent inducers of CYP3A4 are co-administered.

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Antimicrobial Chemotherapy

Tomoari Kuriyama, ... David W. Williams, in Biofilms in Infection Prevention and Control, 2014

Macrolides

The macrolide antibiotics have the common structure of a macrocyclic lactone ring to which are attached one or more deoxy sugars. The macrolide antibiotics are bacteriostatic agents that inhibit bacterial protein synthesis by binding reversibly to 50S ribosomal subunits of sensitive micro-organisms. The prototypic macrolide is erythromycin; other clinically important macrolides include clarithromycin and azithromycin.

The antimicrobial spectra of the macrolide agents are similar to those of penicillin.10,19 These agents are active against Gram-positive cocci, including streptococci and staphylococci and spirochaetes, but are not active against enterococci, penicillin-resistant staphylococci and most Gram-negative bacteria with the notable exception of Neisseria gonorrhoeae. Erythromycin has weak activity against Haemophilus influenzae, but clarithromycin and azithromycin exhibit considerably better activity against this micro-organism. Consequently, macrolides are often used in the treatment of infections caused by Gram-positive bacteria as alternatives for patients who are allergic to penicillin.

The macrolide antibiotics are generally active against strict anaerobes. They are also effective against chlamydia, Legionella pneumophila and mycoplasma, against which many types of antibiotics, including β-lactams, are ineffective.18,19 Macrolides are commonly administrated orally, although erythromycin can be given parenterally. Erythromycin is somewhat unstable in the presence of gastric acid, while clarithromycin and azithromycin are more acid-stable.10,19 Macrolides diffuse readily into most tissues, but do not cross the blood–brain barrier.

The plasma half-life of clarithromycin and azithromycin is 3 times and 8 to 16 times longer than that of erythromycin’s 90 minutes, respectively.19 The macrolides enter and are concentrated within phagocytes.19 Especially in the case of azithromycin, phagocytes may act as important vehicles for delivering the antibiotic to the infection site and sustaining its high concentration in the tissue. Because of this unique property and the extremely long elimination half-life, the clinical effects of this agent, with once-daily dosing for only 1 to 3 days, can be maintained for 7 days or more.22

The macrolides are inactivated in the liver, and the major route of elimination is in the bile. They have low toxicity, and serious untoward effects are rarely encountered. Possible adverse effects include hypersensitivity reactions, hepatitis, elevation of liver enzymes and gastrointestinal disturbance (e.g., diarrhea, nausea, vomiting).1,10,19

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Strategy and Drug Research

E.E. Swayze, ... C.F. Bennett, in Comprehensive Medicinal Chemistry II, 2007

2.26.3.4.2 Macrolides

The macrolide antibiotics are an important class of orally active antibiotics.18 Major members of the class include erythromycin and azithromycin, as well as telithromycin, which was approved in 2004 (Figure 4). The macrolides are most commonly used against Gram-positive organisms, as they are weakly active against most Gram-negative bacilli. The macrolides are generally bacteriostatic agents that bind to the 23S rRNA on the large subunit and block the ‘tunnel’ through which the growing peptide chain exits. Resistance to macrolides arises from a methylase which modifies the ribosomal target and reduces binding, along with enzymes that chemically modify the drug structures and more general uptake/efflux resistance mechanisms. Unlike the aminoglycosides, the macrolides are generally well tolerated and give rise to few serious toxicity issues, and as such are used broadly.

Figure 4. Macrolides that bind to the 50S subunit.

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