Erythromycin

General adverse effects and adverse reactions

Erythromycin is relatively well tolerated, with the exception of gastrointestinal adverse effects. Cholestasis resulting from the use of all forms of erythromycin is virtually the only serious effect. However, local irritation (affecting the gastrointestinal system, the muscles, or the veins, depending on the route of administration) is common. Erythromycin can increase serum theophylline concentrations and occasionally causes theophylline toxicity. Hypersensitivity reactions are rare, unless cholestasis is to be regarded as allergic. They probably have clinical effects in under 0.5% of treated patients, and consist mainly of maculopapular rashes, pruritus, urticaria, and angioedema; anaphylaxis and acute respiratory distress have also been reported. Fixed drug eruptions, urticaria, and Stevens–Johnson syndrome have also been reported.

Comparative studies

In a direct comparison of clarithromycin with erythromycin stearate, the rate of adverse events was 19% in 96 patients taking clarithromycin and 35% in 112 patients taking erythromycin [ ]. Most of the adverse events associated with clarithromycin affect the gastrointestinal tract (7%).

In a prospective, single-blind, randomized study of a 7-day course of clarithromycin (7.5 mg/kg bd) and a 14-day course of erythromycin (13.3 mg/kg tds) in 153 children with pertussis, the incidence of treatment-emergent drug-related adverse events was significantly higher with erythromycin than with clarithromycin (62% versus 45%) [ ]. Three subjects given erythromycin withdrew prematurely because of adverse events: one because of a rash; one with vomiting and diarrhea; and one with vomiting, abdominal pain, and rash.

In a double-blind, randomized, multicenter trial in 302 children, a 10-day course of erythromycin estolate (40 mg/kg/day in two doses) was as safe and effective as amoxicillin (50 mg/kg/day in two doses) in acute otitis media. Treatment-related adverse events occurred in 5.3% of patients given erythromycin and in 7.3% of patients given amoxicillin [ ].

Cardiovascular

Erythromycin has antidysrhythmic properties similar to those of Class IA antidysrhythmic drugs, and causes an increase in atrial and ventricular refractory periods. This is only likely to be a problem in patients with heart disease or in those who are receiving drugs that delay ventricular repolarization [ ]. High-doses intravenously have caused ventricular fibrillation and torsade de pointes [ ]. Each episode of dysrhythmia, QT interval prolongation, and myocardial dysfunction occurred 1–1.5 hours after erythromycin infusion and resolved after withdrawal.

In an FDA database analysis, 346 cases of cardiac dysrhythmias associated with erythromycin were identified. There was a preponderance of women, as there was among those with life-threatening ventricular dysrhythmias and deaths after intravenous erythromycin lactobionate. A sex difference in cardiac repolarization response to erythromycin is a potential contributing factor, since in an in vitro experiment on rabbit hearts, erythromycin caused significantly greater QT prolongation in female than in male hearts [ ].

In the Tennessee Medicaid cohort, during 1 249 943 person-years of follow-up there were 1476 cases of sudden death from cardiac causes; the multivariate adjusted rate of sudden death from cardiac causes among patients currently using erythromycin was twice as high [ ]. There was no significant increase in the risk of sudden death among former users of erythromycin. The adjusted rate of sudden death from cardiac causes was five times as high among those who concurrently used CYP3A inhibitors and erythromycin as among those who had used neither CYP3A inhibitors nor any of the study antibiotic medications.

In 35 women and 28 men erythromycin caused QT interval prolongation after the first few doses of erythromycin [ ]. Similarly, in a prospective, comparative study in 19 patients with uncomplicated community-acquired pneumonia, a single dose of intravenous erythromycin 500 mg increased the heart rate and prolonged the QT interval. These effects were seen after 15 minutes of infusion and disappeared 5 minutes after the infusion had been stopped [ ].

Owing to prolongation of the QT interval, a newborn with congenital AV block developed ventricular extra beats and non-sustained ventricular tachycardia after intravenous erythromycin; the QT interval normalized after withdrawal [ ].

• Intravenous erythromycin (1 g 6-hourly by intravenous infusion over 30 minutes) resulted in QT interval prolongation, ventricular fibrillation, and torsade de pointes in a 32-year-old woman [ ].

Torsade de pointes occurred in 16 of 23 patients who received intravenous erythromycin 3-4 g/day and 3 of 23 who received oral erythromycin 1.5–2 g/day [ ]. There were marked differences in exposure between the two regimens, with typical peak erythromycin concentrations of 30 μg/ml after intravenous administration versus 2–4 μg/ml after oral administration. Non-clinical models have shown a concentration-related effect of erythromycin on action potential duration over a wide range of concentrations.

Intravenous administration of erythromycin into peripheral veins relatively commonly causes thrombophlebitis, although the lactobionate form of erythromycin may be less irritating to veins than other parenteral forms [ , ]. In a prospective study of 550 patients with 1386 peripheral venous catheters, the incidence of phlebitis was 19% with antibiotics and 8.8% without; erythromycin was associated with an increased risk [ ].

Respiratory

Adverse effects involving the respiratory system were reported in 2% of patients taking erythromycin stearate [ ].

A beneficial effect of erythromycin on sputum volume has been reported in a patient with severe airways obstruction due to bronchorrhea [ ].

Nervous system

In patients without neuromuscular disease erythromycin caused subclinical loss of motor unit contractions, which improved with intravenous edrophonium or neostigmine [ ].

Sensory systems

Loss of auditory acuity and tinnitus can occur during treatment with erythromycin, even oral treatment at standard doses [ ].

Ototoxicity, resulting in hearing loss, and usually reversible, has been reported in patients treated with erythromycin lactobionate 4 g/day or more or large oral doses of erythromycin estolate [ ]. Ototoxic reactions have also been seen after the use of esters of erythromycin, such as the ethylsuccinate, stearate, and propionate [ ]. High parenteral doses of erythromycin have resulted in transient perceptive deafness [ ]. Since renal and hepatic disease was a prominent feature in these patients, ototoxicity was thought to result from high blood concentrations [ ]. Recovery occurred within a few days after withdrawal. The phenomenon differs from the permanent type of ototoxicity caused by aminoglycosides. Erythromycin should not be given together with other potentially ototoxic drugs and hearing acuity should be monitored during erythromycin therapy, especially in the elderly. Acute psychotic reactions have been related to ototoxicity and high-dose erythromycin therapy [ ].

Psychiatric

Erythromycin has been associated with complications such as confusion, paranoia, visual hallucinations, fear, lack of control, and nightmares. These suspected psychiatric adverse effects were seen within 12–48 hours of starting therapy with conventional doses. Such complications may even be under-reported [ ].

A 64-year old man developed hallucinations and tremors 24 hours after he started to take oral erythromycin 1 g bd and methylprednisolone 16 mg bd [ ].

Mouth

Black hairy tongue has been associated with long-term oral erythromycin [ ].

Gastrointestinal

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

The prokinetic effect of erythromycin has been investigated in healthy volunteers, in whom a dose of 3 mg/kg seemed to have the largest prokinetic effect [ ].

Pylorospasm and hypertrophic pyloric stenosis is associated with early postnatal erythromycin exposure and has been observed in neonates after 1–2 days of oral erythromycin therapy [ ]. The prominent gastrokinetic properties of erythromycin have been postulated as the mechanism [ ].

• Pyloric stenosis has also been reported in a boy born at 23 weeks gestation, weight 690 g, after treatment of the child with three doses of oral erythromycin 10 mg/kg/day [ ].

The use of erythromycin in postexposure prophylaxis for pertussis in 200 infants was followed by an increased number of cases of infantile hypertrophic pyloric stenosis, and all seven cases had taken erythromycin prophylactically [ ]. A case review and cohort study supported these preliminary findings [ ]. In a retrospective study in 314 029 children, very early exposure to erythromycin (at 3–13 days of life) was associated with a nearly eight-fold increased risk of pyloric stenosis [ ]. There was no increased risk in infants exposed to erythromycin after 13 days of life or in infants exposed to antibiotics other than erythromycin.

Intravenous erythromycin should be restricted to as few patients as possible. It can cause severe abdominal cramps, probably by a direct action on smooth muscle [ ].

In a review of studies of the use of erythromycin for gastrointestinal dysmotility in preterm infants, none of the randomized controlled trials reported any adverse effects, in particular hypertrophic pyloric stenosis [ , ]. However, hypertrophic pyloric stenosis has been described in monovular extremely preterm twins after the use of erythromycin [ ].

Liver

Erythromycin can cause two different types of liver damage [ , ]. Administration of erythromycin as base or salt can be followed in up to 10% of cases by apparently benign increases in serum transaminases, which may or may not recur on rechallenge. In children, raised transaminases were noted at dosages of 40 mg/kg/day but not 20 mg/kg/day.

Cholestatic hepatitis, which is associated primarily with erythromycin estolate, can be caused by all forms of erythromycin, including the base, estolate, ethylsuccinate, propionate, and stearate [ , ]. Although it was originally speculated that a hypersensitivity reaction to the estolate ester rather than to the erythromycin itself was responsible for this adverse reaction [ ], erythromycin does inhibit bile flow [ ]. Most probably the differences in hepatotoxicity between the various erythromycin derivatives are of a quantitative rather than a qualitative nature [ , ], perhaps because of better intestinal absorption of the estolate. Potentially severe but rare cholestatic liver injury occurs in perhaps up to 2–4% of treated patients. Erythromycin-induced cholestasis is rare in children under the age of 12 years, but has occurred in infants at 6 weeks of age, in whom it can mimic acute cholecystitis, biliary atresia, or neonatal hepatitis [ ].

• A young woman developed severe cholestasis and jaundice after taking erythromycin stearate [ ]. A second severe episode of jaundice and malaise occurred after treatment with erythromycin succinate 2 years later pointing to erythromycin itself as the culprit.

• After two doses of erythromycin ethylsuccinate, following unsuccessful treatment with penicillin for a respiratory illness, a 10-year-old previously healthy girl developed liver damage [ ]. Liver biopsy showed moderate panlobular parenchymatous degeneration with cholestasis due to numerous intracellular and intraductal bile plugs. She recovered completely 6–8 weeks after withdrawal of erythromycin.

The syndrome generally starts 10–14 days after the start of therapy, but earlier after re-exposure, sometimes within 12–24 hours [ ]. At all ages it often begins with abdominal pain, nausea, vomiting, pyrexia, pruritus, and jaundice; fever, rash, leukocytosis, raised serum transaminases, and eosinophilia can also occur. However, it can be ushered in with severe acute upper abdominal pain or right subcostal tenderness, simulating an acute abdomen, or it can resemble obstructive jaundice. Serum bilirubin, alkaline phosphatase, and transaminases are raised. Histological examination typically shows intrahepatic cholestasis and periportal inflammatory infiltration, with lymphocytes, neutrophils, and disproportionate numbers of eosinophils [ ]. These histological findings could be interpreted as reflecting a hypersensitivity reaction, but this hypothesis has been rejected [ ]. if erythromycin is promptly withdrawn, the clinical signs often improve rapidly, although prolonged jaundice has been reported.

In a Spanish study, erythromycin-induced hepatotoxicity has been estimated to occur in 3.6 per 100 000 users [ ].

Urinary tract

Acute renal insufficiency has been observed in a patient with Henoch–Schönlein syndrome [ ]. Another case presented as interstitial nephritis with acute renal insufficiency [ ].

Skin

Topical erythromycin in benzoylperoxide, marketed for acne treatment, must be compounded by a pharmacist and requires subsequent refrigeration, warranting the development of alternative formulations. In a double-blind, parallel-group, multicenter study in 327 patients, a single-use erythromycin in benzoylperoxide combination package was compared with the vehicle alone and the original, reconstituted formulation packaged in a jar. Dry skin was the most frequently reported skin-related adverse event; it occurred in 3.2% of patients who used the preformulated erythromycin in benzoylperoxide and 5.0% of those who used the reconstituted erythromycin in benzoylperoxide [ ].

A fixed drug eruption due to erythromycin has been observed [ ]. In another case skin tests with erythromycin were positive for the immediate and or delayed types of hypersensitivity [ ].

• A 27-year-old woman developed urticaria 30 minutes after taking a single dose of erythromycin [ ]. An identical episode had occurred three years before. Erythromycin-specific IgE was detected in her serum by radioimmunoassay.

• Stevens–Johnson syndrome developed in a 64-year-old man who took erythromycin stearate for non-specific upper respiratory tract symptoms [ ]. After four doses of 250 mg, he developed a fever and typical lesions in the mouth and conjunctivae and on the lips. He was treated with prednisolone and recovered rapidly.

Immunologic

An immediate IgE-dependent hypersensitivity reaction has been reported in patients taking erythromycin; the mechanism is unknown and skin tests are negative in most cases [ ].

Teratogenicity

In a retrospective study there was no evidence of an increased risk of pyloric stenosis among infants born to mothers exposed to erythromycin during pregnancy [ ].