Macrolide antibiotics

Actions and uses in non-infective conditions

Erythromycin is a motilin receptor agonist [ ]. Azithromycin also produced a significant increase in postprandial antral motility [ ]. Clarithromycin is also prokinetic, as shown in 16 patients with functional dyspepsia and Helicobacter pylori gastritis [ ]. For this reason, the macrolides have been used to treat gastroparesis [ ].

Azithromycin may be useful in reducing ciclosporin-induced gingival hyperplasia in renal transplant recipients [ ].

A beneficial effect of low doses of clarithromycin on sputum rheology has been reported in patients with chronic pulmonary diseases, such as chronic bronchitis [ ].

In a murine model of virus-induced lung injury, erythromycin significantly improved survival rate [ ]. This may be explained by inhibition of inflammatory-cell responses and suppression of nitric oxide overproduction in the lungs of the virus-infected mice.

In 202 patients with unstable angina pectoris, roxithromycin prevented death and re-infarction for at least 6 months after initial treatment [ ]. However, these findings could not be confirmed in another study in 302 patients with coronary heart disease and a seropositive reaction to Chlamydia pneumoniae who were treated with azithromycin. While global tests of markers of inflammation improved, there were no differences in antibody titers and clinical events [ ].

General adverse effects and adverse reactions

Macrolides are in general well tolerated and are used over wide dosage ranges. The rates of adverse reactions are dose-related, as exemplified by the rate of adverse reactions to clarithromycin, which was higher with 2000 or 4000 mg in two doses per day than with 500 or 1000 mg/day. Severe toxicity is very rarely observed with macrolides. Most adverse reactions are rated as either mild or moderate, regardless of the macrolide used. Among 245 patients who were hospitalized because of toxic epidermal necrolysis or Stevens–Johnson syndrome, six patients had had exposure to macrolides within the week before the onset of the illness; however, the results suggest that macrolides do not pose an excess risk of this toxic complication [ ]. Anaphylactic reactions to macrolides are exceedingly uncommon, but anaphylaxis and acute respiratory distress have been reported [ , ]. Skin tests with erythromycin were positive for the immediate and/or delayed types of hypersensitivity [ ]. Tumor-inducing effects have not been reported.

Tables 1 and 2 summarize the frequencies of adverse reactions and premature withdrawal of the most widely used macrolides.

Pharmacoeconomics

Adverse reactions to antimicrobial drugs have an enormous pharmacoeconomic impact. Antibacterial drug reactions account for about 25% of adverse drug reactions. The adverse reactions profile of an antimicrobial agent can contribute significantly to its overall direct costs (monitoring costs, prolonged hospitalization due to complications or treatment failures) and indirect costs (quality of life, loss of productivity, time spent by families and patients receiving medical care). In one study an adverse event in a hospitalized patient was associated on average with an excess of 1.9 days in the length of stay, extra costs of $US2262 (1990–3 values), and an almost two-fold increase in the risk of death. In the outpatient setting, adverse drug reactions result in 2–6% of hospitalizations, and most of them were thought to be avoidable if appropriate interventions had been taken. In a review, economic aspects of antibacterial therapy with macrolides have been summarized and critically evaluated [ ].

Cardiovascular

Of the currently available antimicrobial classes, the macrolides appear to be associated with the greatest degree of QT interval prolongation and risk of torsade de pointes [ ]. Macrolides with at least one published report of torsade de pointes include azithromycin, clarithromycin, erythromycin, roxithromycin, spiramycin, and troleandomycin. However, cardiovascular reactions are rare if macrolide antibiotics are used in the absence of susceptibility factors, which include drug interactions, increasing age, female sex, concomitant diseases, and co-morbidity [ ].

Respiratory

In an animal model, acute lung injury was inhibited by pretreatment with clarithromycin or roxithromycin, which significantly ameliorated bleomycin-induced increases in the total cell and neutrophil counts in bronchoalveolar lavage fluids and wet lung weight [ ]. Pretreatment with clarithromycin or roxithromycin also suppressed inflammatory cell infiltration and interstitial lung edema. Pretreatment with azithromycin was much less effective.

Nervous system

Table 1 lists the rates of adverse events affecting the nervous system attributed to erythromycin and newer macrolides.

Sensory systems

Psychological, psychiatric

Although there is no evidence that neuropsychiatric complications of macrolides develop more readily in uremic patients, several factors may predispose toward these adverse effects, such as reduced drug clearance, altered plasma protein binding, different penetration of drug across the blood–brain barrier, and an increased propensity for drug interactions.

Two women, aged 49 and 50 years, developed altered mental status a few days after starting to take clarithromycin for eradication of Helicobacter pylori [ ]. There was incoherent speech with perseveration, inability to sustain attention, impaired ability to comprehend, coprolalia, euphoria, restlessness, visual hallucinations, anxiety, and inappropriate affect. Similarly, in three cases, a 46-year-old man, a 39-year-old woman, and a 4-year-old boy, treatment with clarithromycin was followed by nervous system and psychiatric symptoms that included euphoria, insomnia, aggressive behavior, hyperactivity, and emotional lability [ ].

Hematologic

Clarithromycin and roxithromycin slightly inhibited the down-regulation of L-selectin expression on neutrophils induced by interleukin-8 stimulation [ ]. Furthermore, clarithromycin strongly inhibited the interleukin-8-induced up-regulation of the expression of Mac-1, an adhesion molecule, on neutrophils.

Hematological changes with macrolides are very rare. Isolated instances of neutropenia are occasionally reported [ ].

Gastrointestinal

Gastrointestinal adverse reactions are the most common untoward effects of the macrolides ( Table 1 ). Nausea and vomiting associated with abdominal pain and occasionally diarrhea can be minor and transitory or, in a small percentage of patients, become severe enough to result in premature withdrawal. The rate of these adverse reactions varies among the different antibiotics. In general, newer macrolides, such as azithromycin, clarithromycin, or roxithromycin, are better tolerated and cause fewer adverse reactions than erythromycin.

Erythromycin is a motilin receptor agonist [ ]. This mechanism may be at least partly responsible for gastrointestinal adverse reactions to macrolides.

Based on observations in dogs and rabbits, clarithromycin is a significantly less potent agonist than azithromycin and erythromycin for stimulating smooth muscle contraction [ ]. A lower rate of gastrointestinal adverse events would therefore be expected with clarithromycin than with azithromycin ( Table 1 ). Since most of these data were compiled from several studies, and since most have not been obtained by direct comparison of the various macrolides in single studies, the rates should be interpreted with caution. They most probably provide only an approximate indication of the rate of adverse events. Small differences in rates between individual macrolides will in most cases not be clinically useful indicators of the true risk for the occurrence of adverse events.

In contrast to the macrolides mentioned above, macrolides with a 16-membered lactone ring (acetylspiramycin, josamycin, leucomycin, midecamycin, rokitamycin, spiramycin, tylocin) have little if any motor-stimulating effects [ , ].

Drug-induced esophagitis is rare, accounting for about 1% of all cases of esophagitis. An incidence of 3.9 in 100 000 has been reported. After the first description, there have been more than 250 observations, with more than 50 different drugs. Among those, the principal antibiotics included tetracyclines (doxycycline, metacycline, minocycline, oxytetracycline, and tetracycline), penicillins (amoxicillin, cloxacillin, penicillin V, and pivmecillinam), clindamycin, co-trimoxazole, erythromycin, lincomycin, spiramycin, and tinidazole. Doxycycline alone was involved in one-third of all cases. Susceptibility factors included prolonged esophageal passage, due to motility disorders, stenosis, cardiomegaly, the formulation, supine position during drug ingestion, and failure to use liquid to wash down the tablet. Direct toxic effects of the drug (pH, accumulation in epithelial cells, non-uniform dispersion) also seem to contribute to the development of drug-induced esophagitis [ ].

Liver

Erythromycin can cause two different types of liver damage [ , ], benign increases in serum aminotransferases, which may or may not recur on rechallenge, and cholestatic hepatitis. Reports of intrahepatic cholestasis with azithromycin [ ], clarithromycin [ , ], and josamycin [ ] suggest that the newer macrolides are not free of this adverse effect, although the relative risks compared with erythromycin are unclear. Similar involvement of the liver has been seen with the ester of triacetyloleandomycin, but not with the unesterified antibiotic.

Macrolides such as josamycin, midecamycin, and spiramycin, which do not form stable complexes with cytochrome P450, rarely if ever cause cholestatic hepatitis.

Urinary tract

• A 77-year-old man taking regular captopril, furosemide, salbutamol inhaler, vitamin C, and nasal beclomethasone dipropionate took clarithromycin 250 mg bd for sinusitis and bronchitis and 5 days later developed abdominal pain and intermittent fever [ ]. Laboratory findings included raised serum creatinine and blood urea nitrogen, aspartate aminotransferase, amylase, lactate dehydrogenase, and creatine kinase (not of the MB isoenzyme). The cause of the non-oliguric renal insufficiency was diagnosed by renal biopsy as interstitial nephritis with eosinophilic infiltrates. During the course of illness he also developed thrombocytopenia.

Skin

Rashes and fixed drug eruptions can occur during treatment with various macrolides but are rare (under 1%) [ ].

Immunologic

Immunomodulatory effects of macrolides have been repeatedly reported; for example suppression of the release of chemotactic mediators may be important for the clinical effect of roxithromycin in patients with chronic lower respiratory tract infections [ ]. Both clarithromycin and azithromycin altered cytokine production in human monocytes in vitro [ ].

The suppressive activity of macrolide antibiotics on pro-inflammatory cytokine production has also been shown in human peripheral blood monocytes, in which roxithromycin inhibited the in vitro production of interleukin-1 beta and tumor necrosis factor alfa [ ]. It also suppressed cytokine production after a prolonged pretreatment period in mice. In another mouse model both roxithromycin and clarithromycin inhibited angiogenesis and enhanced the antitumor activity of some cytotoxic agents, suggesting a beneficial effect when combined with such drugs against solid tumors [ , ]. Furthermore, growth suppression of human fibroblasts by roxithromycin has been demonstrated both in vitro and in vivo [ ].

Together, these anti-inflammatory effects result in improved pulmonary functions and fewer airway infections [ ], and for this reason the macrolides are sometimes used after lung transplantation.

Azithromycin has been associated with Churg–Strauss syndrome in a patient with atopy [ ].

• A 46-year-old man with asthma was treated with oral roxithromycin 300 mg/day for 5 days for purulent rhinitis and 2 weeks later developed arthritis, mononeuritis multiplex, eosinophilia (64%), eosinophilic infiltrations in the bone marrow, raised IgE concentrations, and transient pulmonary infiltrates. Churg–Strauss syndrome was diagnosed.

A similar course of disease had occurred 1 year before, after the administration of azithromycin [ ].

Leukocytoclastic vasculitis associated with clarithromycin has been reported in an 83-year-old woman who was treated for pneumonia. All her symptoms resolved after withdrawal and a short course of glucocorticoids [ ].

• Henoch–Schönlein purpura developed in an 84-year-old Indian woman 10 days after she started to take clarithromycin (250 mg bd) for pneumonia [ ]. She was otherwise healthy and taking no regular medications. Histology confirmed a leukocytoclastic vasculitis of superficial vessels, with extravasation of erythrocytes, and direct immunofluorescence showed immunoglobulin A in superficial dermal vessels. Treatment with prednisone (1 mg/kg/day) was required. Most of the symptoms and signs resolved within a few days, but renal function remained impaired.

The authors identified two previous case reports of clarithromycin-induced leukocytoclastic vasculitis.

• A 39-year-old man developed acute angioedema and urticaria 6 hours after taking erythromycin base 500 mg in enteric-coated pellets for acute sinusitis [ ]. He remembered having taken erythromycin once before without any problem. He had no known allergies and was taking no regular medications, but he had had chemotherapy for non-Hodgkin’s lymphoma several years earlier.

The authors identified five previous reports of erythromycin-associated urticarial reactions. However, it was not possible to exclude a reaction to the ingredients of the coated pellets.