Amoxicillin joint pain

41 165 NA 165 2000 1 7 Dental Adult Prophylaxis for dental implant No ? 42 254 NA 255 2000 1 7 Dental Adult Prophylaxis for dental implant No ?

43 NA 10 11 750 30 NR Dental Adult Periodontal infection No ?

44 96 NA 96 2000 1 NR Dental

Adult

46 NA 10 11 1500 10 24 Dental Adult Periodontal disease No No No Yes 1 Obstetric or gynecologic treatment or prophylaxis Almeida et al. 47 50 NA 56 2250 1 NR Referral Adult Prophylaxis for premature rupture of membranes No ? 48 NA 76 73 1500 7 or 14 — ‡ Referral Adult Prophylaxis for preterm delivery of twins No ?

49 NA 22 22 1500 3–20 20 Referral Adult Foot ulcers in diabetic neuropathy No ?

50 22 NA 78 25/kg 180 NR Primary Child Malabsorption and growth No ? 51 952 NA 959 80–90/kg 5 14 Primary Child Severe acute malnutrition No Yes Yes Yes 6 Total no.

of studies 28 18 45 NA NA NA 20 referral, 15 primary, 9 dental, 1 primary or referral 26 adult, 17 child, 2 child and adult 20 preventive or prophylaxis 8 Yes 6 Yes, 6 No, 33 uncertain NA 25 Yes, 20 No NA Median or mean Median 14 Mean 2.7 § Total no.

acid = amoxicillin–clavulanic acid; ENT = ear, nose, throat; NA = not applicable; NR = harms data not reported; UTI = urinary tract infection; ? Funnel plots for the harms from diarrhea and rash were symmetric (Appendix 2, www.cmaj.ca/lookup/suppl/doi:10.1503/cmaj.140848/-/DC1). We found a low risk of bias in the reporting of antibiotic harms, although the principal focus of each trial was efficacy (Appendix 3, www.cmaj.ca/lookup/suppl/doi:10.1503/cmaj.140848/-/DC1). However, the reporting of such harms was poor: only 25 (56%) of the 45 studies reported harms in sufficient detail to allow meta-analysis of their data. The rate of studies reporting harms did not improve over time ( Figure 2 ).

Even studies that reported usable harms data rarely gave detailed information about how they were collected, and studies were sometimes unclear about whether all harms were reported (or, for example, whether they reported only those harms that led to withdrawal of patients from the trial).

Nine trials were registered, but registering harms among the secondary outcomes did not guarantee that harms would be reported ( Table 1 ), and registries did not provide

any

The result was not significant for the subgroup of studies involving amoxicillin alone.

In addition to explicit candidiasis, one trial reported rates of diaper rash of about 50% among infants treated with amoxicillin–clavulanic acid.

10 This rash was likely related to candidiasis as well.

Analysis with inclusion of these data yielded the same OR value (data not shown).

Rashes, nausea and vomiting were not reported significantly more frequently with antibiotic than with placebo ( Figure 3B ). No trials reported itching, and only 1 trial reported abnormal results on liver function tests (which occurred in 2 placebo-treated patients and 1 amoxicillin-treated patient). Meta-analyses of reported harms with amoxicillin and amoxicillin–clavulanic acid: nausea, vomiting and rash.

There were large variations in dose and duration of treatment among studies, and we explored this heterogeneity by subgroup analysis.

Analyzing studies that used common doses of amoxicillin and those that used high doses, analyzing children and adults separately, and analyzing studies with common duration of therapy (roughly 1–2 wk) and those with long courses of therapy yielded the same summary effect sizes for diarrhea (see Appendix 4, www.cmaj.ca/lookup/suppl/doi:10.1503/cmaj.140848/-/DC1).

There were too few studies reporting other outcomes to undertake subgroup analyses. In this meta-analysis of randomized trials, we found statistically significant results for just 2 harms: diarrhea from amoxicillin–clavulanic acid and candidiasis from amoxicillin with or without clavulanic acid.

Reported harms were fewer than we expected from clinical anecdotal experience and observationally derived data, which have primarily reported common harms as rashes (at rates of 5%–8% of those treated and even higher, up to 20%, among those with mononucleosis treated with amoxicillin) and gastrointestinal disturbance. 52 , 53 At least 1 case–control study found a relative risk of 7 for thrush after therapy with amoxicillin or amoxicillin–clavulanic acid. Our reported rates of diarrhea (about 10% of courses of treatment) were similar to those in observational reports for amoxicillin–clavulanic acid 53 and similar to the rates from observational studies of amoxicillin (2%). 52 Standard texts 52 , 53 report rash as common with these antibiotics, but we did not find a significant increase. However, the wide 95% CI for the OR means that meta-analysis did not rule out rash as a common harm.

The most important limitation of this systematic review derives from the fact that every trial had a primary outcome relating to efficacy rather than harm. Many of the studies failed to report any harms, which led us to suspect that their authors simply did not collect such information or, if they did, failed to publish it.

This problem was compounded by the lack of published protocols and registry information for most trials, which prevented analysis of planned measures, thus creating potential for selective reporting. In some of the studies that did report them, harms were probably recorded passively (that is, recording these outcomes only if volunteered by patients, rather than routinely asking all patients about them), which means underestimation of their rates was likely.

55 The low number of events also means that we had insufficient power to detect all but the most common harms. Each of these effects would lead to underestimation of harms. One method of improving the power of a study like ours would be to undertake a network meta-analysis, including not only studies of antibiotic versus placebo, but also antibiotic versus other antibiotics (of which there are many), thereby exploiting differences among different antibiotics in their incidence of harms. Nevertheless, these are currently

the

Well-conducted, relatively large trials of amoxicillin and amoxicillin–clavulanic acid continue to be conducted, and better estimates may therefore be possible in the future, particularly with respect to the relationship between harms and dose, length of treatment and population. However, the availability of usable harms data from future studies will depend on adequate reporting by trial authors.

We found that usable harms data were lacking in many of the studies included in our analysis, despite the existence of a CONSORT extension statement designed to encourage better reporting of harms.

56 , 57 In our sample of trials, there was no discernible improvement in the reporting of harms for trials published in the decade since this extension statement was published, compared with trials published before.