Azithromycin - Clinical Tree

General information

The overall adverse reactions rate for azithromycin is 0.7% [ ]. Only diarrhea, nausea, and abdominal pain occurred in over 1% of patients. Other adverse effects that were reported from clinical trials in adults are palpitation, angina, dyspepsia, flatus, vomiting, melena, jaundice, vaginal candidiasis, vaginitis, nephritis, dizziness, headache, vertigo, somnolence, and fatigue. Azithromycin has also been reported to cause angioedema and photosensitivity, intrahepatic cholestasis, hypersensitivity syndrome, toxic pustuloderma, and irreversible deafness after low-dose use. It can cause a maculopapular eruption when given to patients with infectious mononucleosis. It can also cause contact dermatitis.

Drug studies

Observational studies

In 3995 patients who took azithromycin 1.5 g in divided doses over 5 days or who took 1 g as a single dose for urethritis/cervicitis adverse events occurred in 12% [ ]. In patients over 65 years the rate was 9.3%, and in children under 14 years of age it was 5.4%. The most common adverse effects were gastrointestinal (9.6%); central nervous system and peripheral nervous system effects were reported in 1.3%. Overall, 59% of the adverse events were considered mild, 34% moderate, and only 6% severe, involving mainly the gastrointestinal tract. Adverse events resulted in withdrawal in 0.7% of patients, lower than the rate reported with other macrolides. Treatment-related rises in liver enzymes were uncommon (under 2%), as was leukopenia (1.1–1.5%).

Phase II/III clinical trials in the USA have yielded data on 1928 children aged 6 months to 15 years who took azithromycin for infections that included acute otitis media (n = 1150) and streptococcal pharyngitis (n = 754) [ ]. Most took a 5-day course of azithromycin (5–12 mg/kg/day). There were adverse effects in 190 patients (9.9%): diarrhea (3.1%), vomiting (2.5%), abdominal pain (1.9%), loose stools (1%), and rash (2.5%). In three comparisons with co-amoxiclav, the overall incidence of adverse effects was significantly lower with azithromycin (7.7% versus 29%), with withdrawal rates of 0.3% versus 3.6%. However, the incidence of adverse effects was significantly greater with azithromycin than with penicillin V in comparisons in patients with streptococcal pharyngitis (13% versus 6.7%). In conclusion, it appears that the safety and tolerability of azithromycin is similar in children and adults.

In an open study, children with end-stage lung disease or chronic airflow limitation unresponsive to conventional therapy were treated with long-term azithromycin. Seven children (mean age 12 years), all of whom were colonized with Pseudomonas aeruginosa and who took azithromycin for more than 3 months, were studied. There was a significant improvement in FVC and FEV ₁ [ ]. The mechanism whereby azithromycin works is unknown, but it may be other than antibacterial. It has been hypothesized that the effect may be due to upregulation of a P glycoprotein, a member of the family of multidrug resistant proteins, since erythromycin upregulates P glycoprotein expression in a monkey model. Multidrug resistance (MDR) is homologous to CFTR, and previous in vitro experiments have shown that the MDR and CFTR genes can complement each other [ ]. However, direct proof of this hypothesis is lacking at the moment.

Of 42 adult HIV-positive patients with confirmed or presumed acute toxoplasmic encephalitis who received azithromycin 900, 1200, or 1500 mg/day plus pyrimethamine, 28 responded to therapy during the induction period [ ]. Six patients withdrew during the induction period because of reversible toxic effects (three with raised liver enzymes, two with hearing loss, one with neutropenia). Treatment-terminating adverse events occurred most often among the patients who took 1500 mg/day.

In an open, prospective trial gingival hyperplasia due to ciclosporin was successfully treated with azithromycin 250 mg/day for 5 days in 30 of 35 patients, who reported esthetic satisfaction and disappearance of bleeding and pain [ ]. There was no change in ciclosporin concentration or renal function after azithromycin.

Comparative studies

The tolerability of azithromycin oral suspension, 10 mg/kg od for 3 days, has been assessed in children in a review of 16 multicenter studies [ ]. Of 2425 patients, 1213 received azithromycin and 1212 received other drugs. The incidence of treatment-related adverse events was significantly lower in those who took azithromycin, while withdrawal rates were similar. There were significantly fewer gastrointestinal events with azithromycin and their duration was significantly shorter.

Co-amoxiclav

In a multicenter, parallel-group, double-blind trial in 420 evaluable patients aged 6 months to 16 years with community-acquired pneumonia, the therapeutic effect of azithromycin (once-daily for 5 days) was similar to that of co-amoxiclav in children under 5 years and to that of erythromycin tds for 10 days. Treatment-related adverse events occurred in 11% of those given azithromycin and 31% in the comparator group [ ].

Azithromycin (500 mg/day for 3 days) has been used to treat acute periapical abscesses [ ]. Of 150 patients treated with azithromycin 18 reported a total of 26 adverse events. Slightly more (24 out of 153) treated with co-amoxiclav reported 34 adverse events, but this difference did not reach statistical significance. Most of the adverse events (44/60) were gastrointestinal, mostly diarrhea or abdominal pain. There were no significant differences between the two groups in the severity of adverse events or in the number of withdrawals because of adverse events.

Fluoroquinolones

In a multicenter, open, randomized comparison of levofloxacin 500 mg/day orally or intravenously and azithromycin 500 mg/day intravenously for up to 2 days plus ceftriaxone 1 g/day intravenously for 2 days in 236 patients, the most common drug-related adverse events in those given azithromycin were diarrhea (4.2%), vein disorders (2.5%), and pruritus (1.7%) [ ].

In a randomized, double-blind comparison, single doses of azithromycin 1000 mg and levofloxacin 500 mg were used for travelers’ diarrhea [ ]. The most common adverse events in those given azithromycin were mild abdominal pain (20%) and fecal urgency (13%). There were also one case each of anxiety and a transient rash.

Other macrolides

The incidence of disseminated MAC infection has increased dramatically with the AIDS epidemic. Treatment regimens for patients with a positive culture for MAC from a sterile site should include two or more drugs, including clarithromycin. Prophylaxis against disseminated MAC should be considered for patients with a CD4 cell count of less than 50 × 10 ⁶ /l [ ]. In a randomized, open trial in 37 patients with HIV-associated disseminated MAC infection, treatment with clarithromycin + ethambutol produced more rapid resolution of bacteremia, and was more effective at sterilization of blood cultures after 16 weeks than azithromycin + ethambutol [ ].

Tetracyclines

Compared with tetracycline, azithromycin had a favorable short-term effect on childhood morbidity in a mass trial for trachoma in rural Gambian villages, and adverse effects were limited [ ].

Treatment of facial comedonic and papulopustular acne with azithromycin (500 mg/day for 4 days in four cycles every 10 days) may be at least as effective as minocycline (100 mg/day for 6 weeks). Both were well tolerated and mild adverse effects were reported in 10% of patients given azithromycin and 12% of those given minocycline [ ].

Placebo-controlled studies

In 169 patients with acute infective rhinitis, azithromycin (500 mg/day for 3 days) resulted in a better cure rate after 11 days than placebo; however, after 25 days the results for both improvement and cure were equal [ ].

In a randomized, double-blind, placebo-controlled multicenter trial in 174 HIV-infected patients with CD4 cell counts of under 100 × 10 ⁶ /l, azithromycin (1200 mg once a week) was safe and effective in preventing disseminated MAC infection, death due to MAC infection, and respiratory tract infections [ ].

In a triple-masked, randomized, placebo-controlled study in 1867 women, prophylaxis with azithromycin 500 mg 1 hour before IUCD insertion did not affect the rate of IUCD removal, the frequency of medical attention after insertion, or the risk of upper genital tract infection at 90 days [ ]. Women were at low risk of sexually transmitted disease according to self-reported medical history. Gastrointestinal adverse effects were infrequent (3% azithromycin; 2% placebo). Fewer women taking azithromycin (0.7%) than those taking placebo (1.3%) were treated with antibiotics for pelvic tenderness; however, this difference was not statistically significant. Since cervical infections increase the risk of pelvic infection in women who use IUCDs, generalization of these results may be difficult [ ].

In a meta-analysis of randomized, controlled trials of 3–5 days of azithromycin or other antibiotics that are typically given in longer courses for upper respiratory tract infections, there were no significant differences in bacteriological outcomes [ ]. Azithromycin was withdrawn because of adverse events in only 37 (0.8%) of 4870 patients.

Three well-designed randomized controlled trials have demonstrated a small but significant improvement in respiratory function with azithromycin compared with placebo [ ]. Mild adverse events (wheeze, diarrhea, and nausea) were significantly increased in one trial. Daily azithromycin (250 mg/day) as prophylaxis against malaria in adults was well-tolerated during 20 weeks in 148 patients, but azithromycin recipients complained more frequently of heartburn, paresthesia, and itching than those taking doxycycline [ ]. There was no evidence of hearing loss or hematologic, hepatic, or renal toxicity.

Organs and systems

Cardiovascular

Azithromycin can prolong the QT interval [ , ], although in a prospective study in 47 healthy subjects, azithromycin (3 g total dose given during 5 days) resulted in only a small, non-significant prolongation of the QT interval [ ].

A 65-year-old man with idiopathic dilated cardiomyopathy developed significant prolongation of the QT interval after taking azithromycin for 2 days for a community-acquired pneumonia. Three days after withdrawal the QT interval returned to normal.

Azithromycin can cause life-threatening bradycardia [ ].

A 9-month-old infant who was inadvertently given azithromycin 50 mg/kg, taken from floor stock, instead of the prescribed ceftriaxone, became unresponsive and pulseless. The initial heart rhythm observed when cardiopulmonary resuscitation was started was a broad-complex bradycardia, with a prolonged rate-corrected QT interval and complete heart block. She was resuscitated with adrenaline and atropine but suffered severe anoxic encephalopathy. Polymorphous ventricular tachycardia has been attributed to azithromycin [ ].
A 51-year-old woman took azithromycin 500 mg for an upper respiratory tract infection shortly after a dose of over-the-counter pseudoephedrine. Two hours later she had two syncopal events due to polymorphous ventricular tachycardia without QT interval prolongation. Azithromycin was withdrawn and the ventricular tachycardia abated after 10 hours. She was symptom-free 1 year later.

Significant prolongation of the QT interval leading to torsade de pointes has been reported within a few hours of a dose of azithromycin [ ].

Torsade de pointes and cardiorespiratory arrest have been reported in a patient with congenital long QT syndrome who took azithromycin [ ]. In a prospective study of 47 previously healthy people, there was a modest statistically insignificant prolongation of the QT _c interval without clinical consequences after the end of a course of azithromycin 3 g/day for 5 days [ ].

Sensory systems

Ears

Azithromycin can cause ototoxicity. In one study, 8 (17%) of 46 HIV-positive patients had probable (n = 6) or possible (n = 2) ototoxicity with azithromycin [ ]. The effects were hearing loss (88%), tinnitus (37%), plugged ears (37%), and vertigo (25%), developing at a mean of 7.6 weeks (1.5–20 weeks) after the start of long-term azithromycin therapy for Mycobacterium avium infection. The symptoms resolved in a mean of 4.9 weeks (2–11 weeks) after withdrawal.

Sensorineural hearing loss has been attributed to azithromycin [ ].

A 35-year old Caucasian man with AIDS and multiple opportunistic infections, including Mycobacterium kansasii and Mycobacterium avium complex (MAC) disease developed moderate to severe primary sensorineural hearing loss after 4–5 months of therapy with oral azithromycin 500 mg/day. Other medications included ethambutol, isoniazid, rifabutin, ciprofloxacin, co-trimoxazole, fluconazole, zidovudine (later switched to stavudine), lamivudine, indinavir, methadone, modified-release oral morphine, pseudoephedrine, diphenhydramine, megestrol acetate, trazodone, sorbitol, salbutamol by metered-dose inhaler and nebulizer, ipratropium, and oral morphine solution as needed. Significant improvement of the hearing impairment was documented 3 weeks after drug withdrawal.

Azithromycin has been associated with mild to moderate, gradual, reversible sensorineural hearing loss in the speech frequencies, as in a patient with otitis media who took low-dose oral azithromycin [ ].

A literature review identified several cases of ototoxicity in HIV-positive patients treated with azithromycin for M. avium complex infection. In four series, 14–41% of such patients had some degree of hearing loss. However, some patients were also taking other potentially ototoxic drugs, which may have contributed to the high frequency of hearing loss reported. Hearing loss improved markedly after withdrawal of azithromycin. Hearing loss may be more common and probably more severe with high-dose azithromycin than with high-dose clarithromycin.

A 47-year-old woman who had a left lung transplantation 3 months earlier and who was taking ticarcillin + clavulanate and aztreonam for sinusitis, was given co-trimoxazole, ticarcillin + clavulanate, azithromycin (500 mg/day intravenously), and ganciclovir for presumed pneumonia [ ]. Other drugs included tacrolimus, mycophenolate, prednisone, lansoprazole, diltiazem, itraconazole, warfarin, alendronate, ipratropium bromide, folic acid, and nystatin. The next day, rimantadine and vancomycin were added, and co-trimoxazole was reduced. A neurological examination to assess symptoms of peripheral neuropathy noted no hearing deficit. On day 3, vancomycin, ticarcillin + clavulanate, and ganciclovir were withdrawn. On the fifth day, mild tinnitus and reduced hearing developed and gradually progressed to complete deafness. After eight doses, azithromycin was withdrawn, and 20 days later her hearing was back to baseline.

Low-dose exposure to azithromycin has been associated with irreversible sensorineural hearing loss in otherwise healthy subjects [ ]. Even a single oral dose of azithromycin altered the conjunctival bacterial flora of children from a trachoma endemic area [ ]. However, the clinical significance is not yet clear.

Taste

Dysgeusia after a course of azithromycin has been described [ ].

Nervous system

A 55-year-old man took azithromycin 500 mg/day for pharyngitis and within 12 hours of the first dose he developed hiccups, which were persistent and very distressing [ ]. They lasted for 3 days and resolved when azithromycin was withdrawn.

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