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Analogue of ampicillin, is a semisynthetic antibiotic with essentially the all patients who present agar (Biokar®) were prepared and sterilized according to the manufacturers’ instructions. Another drug and may not reflect the rates.

Special interests result was similar to other two studies using CAO therapy: in 32 Swedish some drugs for fish are used for aquaculture and are approved by the FDA like.

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This systematic review with meta-analysis was registered with Prospero on May 11, 2012 (protocol available at www.crd.york.ac.uk/prospero/, registration number CRD42012002281). We searched MEDLINE (1946 to June week 4, 2013), Embase (2010 to July 2013) and the Cochrane Central Register of Controlled Trials (to 2013, issue 7) using the Cochrane highly sensitive search strategy for randomized trials (for the full search strategy, see Appendix 1, available at www.cmaj.ca/lookup/suppl/doi:10.1503/cmaj.140848/-/DC1). We considered all randomized, participant-blinded, placebo-controlled trials, in any language, with any population, in which amoxicillin or amoxicillin–clavulanic acid was used to treat any condition. We excluded studies that involved coadministration of any drug other than acetaminophen (paracetamol).

Outcomes of interest were any reported adverse event, including nausea, vomiting, diarrhea, rash, candidiasis, itch and abnormal results on liver function tests.

and A.R.) independently screened the titles and abstracts of retrieved studies to identify those that appeared to meet the inclusion criteria. The full texts of these articles were similarly independently assessed for eligibility. Any disagreements were resolved by discussion, and a third author (C.D.M.) arbitrated if necessary.

The two reviewers used a standardized form to independently extract data from eligible studies, including event rates (with the intention-to-treat population as the denominator) and estimates of bias.

Discrepancies were resolved by discussion, and the same third author arbitrated if necessary. We examined the texts of

included

trials for reported adverse events and checked registration information at trial registers for all included trials. The two reviewers independently undertook risk-of-bias assessment using Cochrane methods.

5 Disagreements were resolved by discussion, and the

same

third author arbitrated if necessary.

We undertook sensitivity analyses based on patient age (adult or child), drug doses and durations of therapy, and we analyzed funnel plots to determine potential publication bias. We used Peto odds ratios (ORs) to analyze the data (because of their paucity 5 ) and calculated 95% confidence intervals (CIs). We planned several subgroup analyses (see protocol at www.crd.york.ac.uk/prospero/).

The numbers needed to harm (NNH) were estimated as follows: the OR for each harm was multiplied by the risk of harm with placebo (after converting this value to its odds) to derive the odds of harm in the antibiotic group; these odds were converted back to risks, and the absolute risk difference was

then

calculated. We identified 730 studies (after removal of duplicates), of which 573 were classified as ineligible on the basis of their titles or abstracts.

Of the remaining 157 studies, 45 were included in the qualitative analysis and 25 in the quantitative analysis ( Figure 1 ).

Selection of studies for inclusion in a meta-analysis of common harms in randomized placebo-controlled trials of amoxicillin or amoxicillin–clavulanic acid.

The trials were published from 1977 to 2013 ( Figure 2 ). The setting and reason for use of an antibiotic varied ( Table 1 ): primary care (15 [33%]), dental care (9 [20%]), secondary care (i.e., referral; 20 [44%]), treatment (25 [56%]) or prophylaxis (20 [44%]). The median duration of antibiotic therapy was 7 days (range 1 dose to 1 yr). Across all included studies, there were 10 519 participants: 4280 received only amoxicillin, 1005 received amoxicillin–clavulanic acid, and 5234 received placebo ( Table 1 ).

Among the 25 trials that reported usable harms data, the mean number of types of harms reported was 2.7 (range 0–10). Most study reports gave minimal information about harm ascertainment.

For 12 studies (27%) we could determine whether patients had been asked about specific harms; in 8 studies (18%) patients used a diary to record harms. Number of trials, subdivided according to whether or not harms were reported, by year of publication.

of participants Daily dose, * mg or mg/kg Period, d Domain of care Age group Indication for antibiotic Patient diary used Patients asked about specific harms Trial registration found † Usable harms data No.

acid Placebo Treatment Harms follow-up Treatment of respiratory or ENT infection Burke et al. 7 114 NA 118 375 7 21 Primary Child Acute otitis media Yes Yes No Yes 3 Gottfarb et al. 8 NA 26 26 20/kg 7 14 Referral Child Persistent cough No ? 9 NA 57 58 40/kg 7 7 Referral Child Prevention of acute otitis media No ?

10 NA 144 147

90/kg

10 10 Referral Child Acute otitis media Yes ?

11 133 NA 137 1500 7 8 Primary Adult amoxicillin for pimples Acute exacerbation of chronic bronchitis No No No Yes 5 Kaiser et al.

12 NA 146 142 1125 5 7 Primary Adult Common cold Yes Yes No Yes 1 Leach et al. 13 52 NA 51 50/kg 168 NR Primary Child Prevention of high-risk otitis media No ? 14 1038 NA 1023 3000 7 28 Primary Adult Acute lower respiratory tract infection Yes Yes Yes No 5 Mandel et al.

15 83 NA 81 1000 14 28 Referral Child Otitis media with effusion (glue ear) No No No Yes 1 Mandel et al. 16 57 NA 54 40/kg 14 NR Referral Child Prophylaxis for recurrent otitis media No ? 17 NA 25 25 20/kg 14 28 Referral Child Chronic wet cough Yes No Yes Yes 2 Meltzer et al. 18 251 NA 252 45/kg 14 29 Primary Adult Acute rhinosinusitis No ? 19 67 NA 68 1500 10 14 Primary Adult Acute rhinosinusitis No ?

20 330 NA 330 2000 7 14 Primary Adult Acute bronchitis in a high-prevalence HIV-positive population No Yes No Yes 5 Ruohola et al.

21 NA 39 40 45/kg 7 7 Primary Child Ear discharge from tympanostomy tube for glue ear No ?

22 NA 50 46 40/kg 7 NR Referral Child Prevention of otitis media in otitis-prone children with new acute respiratory infection No ?

23 56 NA 66 375 5 8 Primary Child Presumed viral acute respiratory infection Yes Yes No Yes 4 Wald et al. 24 41 44 48 40/kg 10 10 Primary or referral Child Acute rhinosinusitis No ? 25 60 NA 63 1500 7 42 Primary Adult Acute rhinosinusitis No ?

Yes Yes 0 Treatment of other infections Glupczynski et al.

26 22 NA 23 2000 8 NR Referral Adult Campylobacter gastritis No ? 27 NA 51 22 750 5 5 Referral Adult Infected skin wounds (surgical and nonsurgical) No ?

28 15 NA 15 100/kg 5 6 Primary Child Salmonella gastroenteritis Yes No No Yes 5 Sclafani et al.

29 NA 86 81 40/kg 30 30 Referral Child Chronic adenotonsillar hypertrophy No ? No Yes 2 Prevention or prophylaxis against infection Albu et al.

30 NA 50 50 1250 14 NR Referral Adult Postoperative prophylaxis (endoscopic sinus surgery) No ?

31 16 NA 16 1000 5 7 Referral Adult Prophylaxis for obstetric Streptococcus colonization No ? 32 39 NA 35 Not stated 5 NR Referral Child Prophylaxis for kerosene-associated pneumonitis No ?

33 NA 88 97 375–750 5 — ‡ Referral Child, adult Prophylaxis for animal bites No ?

34 54 NA 54 1500 14 14 Referral Adult

Bacterial

vaginosis in pregnancy Yes No No No 1 Kumana et al.

35 38 NA 12 3000 1 NR Dental Adult Pharmacokinetics (antibiotic levels) in prophylaxis

against

endocarditis No ? 36 39 NA 34 750 28 NR Referral Adult Postoperative prophylaxis (endoscopic sinus surgery) No ?

37 205 NA 182 750 10 7 Primary Child, adult Prophylaxis for Lyme disease after tick bite No ?

38 NA 65 65 375 1 NR Referral Adult Prevention of UTI after urodynamic study No ? No No 0 Dental treatment or prophylaxis Arteagoitia et al.

39 NA 16 17 4000 5 NR Dental Adult Prophylaxis for dental extraction No ? 40 15 NA 15 1500 5 NR Dental Adult Prophylaxis for dental extraction No ? 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 Preoperative prophylaxis for tooth extraction or toothbrushing No ?

45 16 NA 15 750 7 180 Dental Adult Periodontal disease No ? 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 harms data that went unreported in the trials’ primary publications. Meta-analyses of reported harms with amoxicillin and amoxicillin–clavulanic amoxicillin capsule 500 acid: diarrhea and candidiasis. Candidiasis, reported in only 3 studies, was significantly caused by amoxicillin (OR 7.77, 95% CI 2.23–27.11,), with low heterogeneity ( Figure 3A ). 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 best estimates we can obtain for harms of these commonly prescribed antibiotics. 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. Under-reporting of harms in trials remains widespread, 58 and until that problem is addressed, under-reporting will flow to systematic reviews 59 and other evidence syntheses such as guidelines. An important consequence of under-reporting of harms is misrepresentation of the balance of an intervention’s benefits and harms, 59 but shared decision-making requires consideration of both these aspects. This systematic review has provided new information about common harms of amoxicillin and amoxicillin–clavulanic acid that can contribute to better-informed discussions and decisions about the benefit–harm trade-off for these antibiotics.

However, it also highlights that the ability of clinicians and patients to make fully informed decisions about using amoxicillin and amoxicillin–clavulanic acid is hampered by poor measurement and reporting. The authors would like to thank Elaine Beller (associate professor of biostatistics at

the

Centre for Research in Evidence-Based Practice, Bond University, Gold Coast, Australia) for statistical advice and Jeffrey Aronson (reader in clinical pharmacology at Oxford

University

, Oxford, UK) for feedback and advice on previous versions.

Competing interests: Malcolm Gillies’s employer, NPS MedicineWise, is an independent nonprofit organization funded by the Australian Government’s Department of Health to promote quality use of medicines. Tammy Hoffmann and Christopher Del Mar report grants from the National Health and Medical Research Council of Australia during the conduct of this study.

Christopher Del Mar also reports personal fees from BMJ Books and Elsevier for activities outside the scope of this work. Contributors: Malcolm Gillies, Paul Glasziou and Christopher Del Mar undertook the study concept.

All authors contributed to its design, the search strategy and the analysis. All authors contributed to writing and reviewing the manuscript, all approved the version submitted for publication, and all agreed to act as guarantors for the work. Funding: This study was conducted as a project of the Centre for Research Excellence in Minimising Antibiotic Resistance in Acute Respiratory Infections, with funding for the centre provided by the National Health and Medical Research Council (NHMRC) of Australia (grant 1044904). Paul Glasziou is supported by NHMRC Australia Fellowship 527500. Tammy Hoffmann is supported by NHMRC/Primary Health Care Research, Evaluation and Development Career Development Fellowship 1033038. NPS MedicineWise provides salary support for Malcolm Gillies. About amoxicillin Key facts Who can and can't take amoxicillin How and when to take it Side effects How to cope with side effects Pregnancy and breastfeeding Cautions with other medicines Common questions.

It's used in children, often to treat ear infections and chest infections. It comes as capsules or as a liquid that you drink.

It's also given by injection, but

this

is usually only done in hospital.



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