Adverse events in people taking macrolide antibiotics versus placebo for any indication

Abstract

Macrolide antibiotics (macrolides) are among the most commonly prescribed antibiotics worldwide and are used for a wide range of infections. However, macrolides also expose people to the risk of adverse events. The current understanding of adverse events is mostly derived from observational studies, which are subject to bias because it is hard to distinguish events caused by antibiotics from events caused by the diseases being treated. Because adverse events are treatment‐specific, rather than disease‐specific, it is possible to increase the number of adverse events available for analysis by combining randomised controlled trials (RCTs) of the same treatment across different diseases. To quantify the incidences of reported adverse events in people taking macrolide antibiotics compared to placebo for any indication. We searched the Cochrane Central Register of Controlled Trials (CENTRAL), which includes the Cochrane Acute Respiratory Infections Group Specialised Register (2018, Issue 4); MEDLINE (Ovid, from 1946 to 8 May 2018); Embase (from 2010 to 8 May 2018); CINAHL (from 1981 to 8 May 2018); LILACS (from 1982 to 8 May 2018); and Web of Science (from 1955 to 8 May 2018). We searched clinical trial registries for current and completed trials (9 May 2018) and checked the reference lists of included studies and of previous Cochrane Reviews on macrolides. We included RCTs that compared a macrolide antibiotic to placebo for any indication. We included trials using any of the four most commonly used macrolide antibiotics: azithromycin, clarithromycin, erythromycin, or roxithromycin. Macrolides could be administered by any route. Concomitant medications were permitted provided they were equally available to both treatment and comparison groups. Two review authors independently extracted and collected data. We assessed the risk of bias of all included studies and the quality of evidence for each outcome of interest. We analysed specific adverse events, deaths, and subsequent carriage of macrolide‐resistant bacteria separately. The study participant was the unit of analysis for each adverse event. Any specific adverse events that occurred in 5% or more of any group were reported. We undertook a meta‐analysis when three or more included studies reported a specific adverse event. We included 183 studies with a total of 252,886 participants (range 40 to 190,238). The indications for macrolide antibiotics varied greatly, with most studies using macrolides for the treatment or prevention of either acute respiratory tract infections, cardiovascular diseases, chronic respiratory diseases, gastrointestinal conditions, or urogynaecological problems. Most trials were conducted in secondary care settings. Azithromycin and erythromycin were more commonly studied than clarithromycin and roxithromycin. Most studies (89%) reported some adverse events or at least stated that no adverse events were observed. Gastrointestinal adverse events were the most commonly reported type of adverse event. Compared to placebo, macrolides caused more diarrhoea (odds ratio (OR) 1.70, 95% confidence interval (CI) 1.34 to 2.16; low‐quality evidence); more abdominal pain (OR 1.66, 95% CI 1.22 to 2.26; low‐quality evidence); and more nausea (OR 1.61, 95% CI 1.37 to 1.90; moderate‐quality evidence). Vomiting (OR 1.27, 95% CI 1.04 to 1.56; moderate‐quality evidence) and gastrointestinal disorders not otherwise specified (NOS) (OR 2.16, 95% CI 1.56 to 3.00; moderate‐quality evidence) were also reported more often in participants taking macrolides compared to placebo. The number of additional people (absolute difference in risk) who experienced adverse events from macrolides was: gastrointestinal disorders NOS 85/1000; diarrhoea 72/1000; abdominal pain 62/1000; nausea 47/1000; and vomiting 23/1000. The number needed to treat for an additional harmful outcome (NNTH) ranged from 12 (95% CI 8 to 23) for gastrointestinal disorders NOS to 17 (9 to 47) for abdominal pain; 19 (12 to 33) for diarrhoea; 19 (13 to 30) for nausea; and 45 (22 to 295) for vomiting. There was no clear consistent difference in gastrointestinal adverse events between different types of macrolides or route of administration. Taste disturbances were reported more often by participants taking macrolide antibiotics, although there were wide confidence intervals and moderate heterogeneity (OR 4.95, 95% CI 1.64 to 14.93; I² = 46%; low‐quality evidence). Compared with participants taking placebo, those taking macrolides experienced hearing loss more often, however only four studies reported this outcome (OR 1.30, 95% CI 1.00 to 1.70; I² = 0%; low‐quality evidence). We did not find any evidence that macrolides caused more cardiac disorders (OR 0.87, 95% CI 0.54 to 1.40; very low‐quality evidence); hepatobiliary disorders (OR 1.04, 95% CI 0.27 to 4.09; very low‐quality evidence); or changes in liver enzymes (OR 1.56, 95% CI 0.73 to 3.37; very low‐quality evidence) compared to placebo. We did not find any evidence that appetite loss, dizziness, headache, respiratory symptoms, blood infections, skin and soft tissue infections, itching, or rashes were reported more often by participants treated with macrolides compared to placebo. Macrolides caused less cough (OR 0.57, 95% CI 0.40 to 0.80; moderate‐quality evidence) and fewer respiratory tract infections (OR 0.70, 95% CI 0.62 to 0.80; moderate‐quality evidence) compared to placebo, probably because these are not adverse events, but rather characteristics of the indications for the antibiotics. Less fever (OR 0.73, 95% 0.54 to 1.00; moderate‐quality evidence) was also reported by participants taking macrolides compared to placebo, although these findings were non‐significant. There was no increase in mortality in participants taking macrolides compared with placebo (OR 0.96, 95% 0.87 to 1.06; I² = 11%; low‐quality evidence). Only 24 studies (13%) provided useful data on macrolide‐resistant bacteria. Macrolide‐resistant bacteria were more commonly identified among participants immediately after exposure to the antibiotic. However, differences in resistance thereafter were inconsistent. Pharmaceutical companies supplied the trial medication or funding, or both, for 91 trials. The macrolides as a group clearly increased rates of gastrointestinal adverse events. Most trials made at least some statement about adverse events, such as "none were observed". However, few trials clearly listed adverse events as outcomes, reported on the methods used for eliciting adverse events, or even detailed the numbers of people who experienced adverse events in both the intervention and placebo group. This was especially true for the adverse event of bacterial resistance. Review question We wanted to find out if people treated with a macrolide antibiotic experienced more adverse events than those treated with placebo. Background Macrolide antibiotics are a group of antibiotics that are commonly used to treat both acute and chronic infections. The four most frequently used macrolides are: azithromycin, clarithromycin, erythromycin, and roxithromycin. People taking macrolide antibiotics are at risk of experiencing adverse events such as nausea, diarrhoea, or rash. Search date We searched the literature up to May 2018. Study characteristics We included 183 studies with a total of 252,886 participants. Most studies were conducted in the hospital setting. Azithromycin and erythromycin were more commonly studied than clarithromycin and roxithromycin. Most studies (89%) reported some adverse events, or at least stated that no adverse events were observed. Study funding sources Drug companies supplied trial medications or funding, or both, in 91 studies. Funding sources were unclear in 59 studies. Key results People treated with a macrolide antibiotic experienced gastrointestinal adverse events such as nausea, vomiting, abdominal pain, and diarrhoea more often than those treated with placebo. Taste disturbances were reported more often by people taking macrolides than those taking a placebo. However, as very few studies reported on these adverse events, these results should be interpreted with caution. Hearing loss was reported more often by people taking macrolide antibiotics, however only four studies reported this outcome. Macrolides caused less cough and fewer respiratory tract infections than placebo. We did not find any evidence that macrolides caused more cardiac disorders, liver disorders, blood infections, skin and soft tissue infections, changes in liver enzymes, appetite loss, dizziness, headache, respiratory symptoms, itching, or rashes than placebo. We did not find more deaths in people treated with macrolides than in those treated with placebo. Very limited information was available to assess if people treated with a macrolide antibiotic were at greater risk of developing resistant bacteria than those treated with placebo. However, bacteria that did not respond to macrolide antibiotics were more commonly identified immediately after treatment in people taking a macrolide than in those taking a placebo, but differences in resistance thereafter were inconsistent. Quality of the evidence The quality of the evidence ranged from very low (cardiac disorders, change in liver enzymes, liver disorders) to low (abdominal pain, death, diarrhoea, dizziness, hearing loss, skin and soft tissue infections, taste disturbance, wheeze) to moderate (appetite loss, blood infection, cough, fever, headache, itching, nausea, rash, respiratory symptoms, respiratory tract infections, vomiting).