The safety of amoxicillin and clavulanic acid use during the first trimester of pregnancy.

AIMS: The goal of the current study was to assess the risk for major congenital malformations following first-trimester exposure to amoxicillin, or amoxicillin and clavulanic acid (ACA). METHODS: A population-based retrospective cohort study was conducted, by linking 4 computerized databases: maternal and infant hospitalization records, drug dispensing database of Clalit Health Services in Israel and data concerning pregnancy terminations. Multivariate negative-binomial regression was used to assess the risk for major malformations following first-trimester exposure, adjusted for mother's age, ethnicity (Bedouin vs Jewish), parity, diabetes mellitus, lack of perinatal care, and the year of birth. RESULTS: The study included 101 615 pregnancies, of which 6919 (6.8%) were exposed to amoxicillin: 1045 (1.0%) to amoxicillin only and 6041 (5.9%) to ACA. No significant association was found, in the univariate and multivariate analyses, between first-trimester exposure to amoxicillin or ACA and major malformations in general (crude relative risk, 1.05 95% confidence interval 0.95-1.16; adjusted relative risk 1.09, 95% confidence interval 0.98-1.20), or for major malformations according to organ systems. No dose-response relationship was found between exposure in terms of the defined daily dose and major malformations. CONCLUSION: Exposure to amoxicillin and ACA during the first trimester of pregnancy was not associated with an increased risk of major congenital malformations.

Neuroprotective effects of clavulanic acid following permanent bilateral common carotid artery occlusion in rats.

We investigated whether clavulanic acid could improve learning and memory, in rats underwent bilateral occlusion of common carotid artery (2VO). Seventy male Wistar rats were subjected to 2VO, with a 1-week interval between right and left artery occlusions. After 2VO, animals received clavulanic acid (10, 20, 40 mg/kg, intraperitoneally), from day 8 to 20. Spatial memory was assessed in the Morris water maze, 1 week after the induction of 2VO (day 15). The mRNA expression levels of bcl-2, bcl2-associated x protein (bax), caspase-3, inducible nitric oxide synthase (iNOS), and amyloid beta precursor protein (APP) were measured in the neocortex and hippocampus. Clavulanic acid significantly decreased the escape latency and swimming time in the training trial days. As well, it increased time and distance percentage in the target quadrant, while it decreased such factors in the opposite quadrant in the final trial day, compared to 2VO + normal saline animals. Real time-PCR data showed a significant higher mRNA expression of bax, caspase 3, and iNOS in the hippocampus and neocortex of 2VO animal compared to nonoccluded rats. APP increased in the neocortex but not hippocampus. Compared with 2VO animals, clavulanic acid significantly down-regulated the expression of iNOS, caspase 3, and APP, accompanied by diminishing the bax/bcl2 ratio. Our results reveal a potential therapeutic use of clavulanic acid for cognitive dysfunction associated with cerebral hypoperfusion in vascular dementia and Alzheimer disease.

Reduced-Concentration Clavulanate for Young Children with Acute Otitis Media.

Amoxicillin-clavulanate (A/C) is currently the most effective oral antimicrobial in treating children with acute otitis media (AOM), but the standard dosage of 90 mg amoxicillin/6.4 mg clavulanate/kg of body weight/day commonly causes diarrhea. We examined whether an A/C formulation containing lower concentrations of clavulanate would result in less diarrhea while maintaining plasma levels of amoxicillin and clavulanate adequate to eradicate middle-ear pathogens and to achieve clinical success. We conducted an open-label study in children with AOM who were 6 to 23 months of age. In phase 1, we treated 40 children with a reduced-clavulanate A/C formulation providing 90 mg amoxicillin/3.2 mg clavulanate/kg/day for 10 days. In phase 2, we treated 72 children with the same formulation at a dosage of 80 mg amoxicillin/2.85 mg clavulanate/kg/day for 10 days. We compared the rates of protocol-defined diarrhea (PDD), diaper dermatitis, and AOM clinical response in these children with rates we had reported in children who received the standard A/C regimen, and we obtained plasma levels of amoxicillin and clavulanate at various time points. Outcomes in phase 1 children and in children who had received the standard regimen did not differ significantly. Rates of PDD in children receiving phase 2 and standard regimens were 17% and 26%, respectively (P = 0.10). The corresponding rates of diaper dermatitis were 21% and 33% (P = 0.04) and of AOM treatment failure were 12% and 16% (P = 0.44). Symptomatic responses did not differ significantly between regimens; both gave clavulanate levels sufficient to inhibit ß-lactamase activity. In young children with AOM, clavulanate dosages lower than those currently used may be associated with fewer side effects without reducing clinical efficacy. (This study has been registered at ClinicalTrials.gov under registration no. NCT02630992.).

Routine antibiotic prophylaxis after normal vaginal birth for reducing maternal infectious morbidity.

BACKGROUND: Infectious morbidities contribute to considerable maternal and perinatal morbidity and mortality, including women at no apparent increased risk of infection. To reduce the incidence of infections, antibiotics are often administered to women after uncomplicated childbirth, particularly in settings where women are at higher risk of puerperal infectious morbidities. OBJECTIVES: To assess whether routine administration of prophylactic antibiotics to women after normal (uncomplicated) vaginal birth, compared with placebo or no antibiotic prophylaxis, reduces postpartum maternal infectious morbidities and improves outcomes. SEARCH METHODS: We searched the Cochrane Pregnancy and Childbirth Group's Trials Register (31 August 2017), LILACS, ClinicalTrials.gov, the WHO International Clinical Trials Registry Platform (ICTRP) (22 August 2017) and reference lists of retrieved studies. SELECTION CRITERIA: We planned to include randomised or quasi-randomised trials evaluating the use of prophylactic antibiotics versus placebo or no antibiotic prophylaxis. Trials using a cluster-randomised design would have been eligible for inclusion, but we found none.In future updates of this review, we will include studies published in abstract form only, provided sufficient information is available to assess risks of bias. We will consider excluded abstracts for inclusion once the full publication is available, or the authors provide more information.Trials using a cross-over design are not eligible for inclusion in this review. DATA COLLECTION AND ANALYSIS: Two review authors conducted independent assessment of trials for inclusion and risks of bias. They independently extracted data and checked them for accuracy, resolving differences in assessments by discussion. They evaluated methodological quality using standard Cochrane criteria and the GRADE approach.We present the summaries as risk ratios (RRs) and mean difference (MDs) using fixed- or random-effect models. For one primary outcome we found considerable heterogeneity and interaction. We explored further using subgroup analysis to investigate the effects of the randomisation unit. All review authors discussed and interpreted the results. MAIN RESULTS: One randomised controlled trial (RCT) and two quasi-RCTs contributed data on 1779 women who had uncomplicated vaginal births, comparing different antibiotic regimens with placebo or no treatment. The included trials took place in the 1960s (one trial) and 1990s (two trials). The trials were conducted in France, the USA and Brazil. Antibiotics administered included: oral sulphamethoxypyridazine or chloramphenicol for three to five days, and intravenous amoxicillin and clavulanic acid in a single dose one hour after birth. We rated most of the domains for risk of bias as high risk, with the exception of reporting bias and other potential bias.The quality of evidence ranged from low to very low, based on the GRADE quality assessment, given very serious design limitations of the included studies, few events and wide confidence intervals (CIs) of effect estimates.We found a decrease in the risk of endometritis (RR 0.28, 95% CI 0.09 to 0.83, two trials, 1364 women,very low quality). However, one trial reported zero events for this outcome and we rate the evidence as very low quality. There was little or no difference between groups for the risk of urinary tract infection (RR 0.25, 95% CI 0.05 to 1.19, two trials, 1706 women,low quality), wound infection after episiotomy (reported as wound dehiscence in the included trials) (RR 0.78, 95% CI 0.31 to 1.96, two trials, 1364 women, very low quality) and length of maternal hospital stay in days (MD -0.15, 95% CI -0.31 to 0.01, one trial, 1291 women, very low quality). Cost of care in US dollar equivalent was 2½ times higher in the control group compared to the group receiving antibiotics prophylaxis (USD 3600: USD 9000, one trial, 1291 women). There were few or no differences between treated and control groups for adverse effects of antibiotics (skin rash) reported in one woman in each of the two trials (RR 3.03, 95% CI 0.32 to 28.95, two trials, 1706 women, very low quality). The incidence of severe maternal infectious morbidity, antimicrobial resistance or women's satisfaction with care were not addressed by any of the included studies. AUTHORS' CONCLUSIONS: Routine administration of antibiotics may reduce the risk of endometritis after uncomplicated vaginal birth. The small number and nature of the trials limit the interpretation of the evidence for application in practice, particularly in settings where women may be at higher risk of developing endometritis. The use of antibiotics did not reduce the incidence of urinary tract infections, wound infection or the length of maternal hospital stay. Antibiotics are not a substitute for infection prevention and control measures around the time of childbirth and the postpartum period. The decision to routinely administer prophylactic antibiotics after normal vaginal births needs to be balanced by patient features, childbirth setting and provider experience, including considerations of the contribution of indiscriminate use of antibiotics to raising antimicrobial resistance. Well-designed and high-powered randomised controlled trials would help to evaluate the added value of routine antibiotic administration as a measure to prevent maternal infections after normal vaginal delivery.

Antiallodynic Activity of Ceftriaxone and Clavulanic Acid in Acute Administration is Associated with Serum TNF-α Modulation and Activation of Dopaminergic and Opioidergic Systems.

Preclinical Research The aim of this study was to determine the antiallodynic effect of acute administration of the ß-lactam antimicrobials, ceftriaxone (CFX) and clavulanic acid (CLAV), for the control of established pain on a model of neuropathic pain (NP). We also investigated the involvement of dopaminergic and opioidergic pathways as well as alterations in serum concentrations of TNF-α in the antiallodynic actions of these drugs. CFX, CLAV, or gabapentin (GAP), a reference drug, were administered i.p. twelve days after constriction of the sciatic nerve in rats. Mechanic and cold allodynia were evaluated for 3 h and alterations in serum concentration of TNF-α determined. Both CFX and CLAV had antiallodynic effects in response to mechanical and cold stimulation, similar to GAP. The antiallodynic effects of CFX and CLAV were blocked by haloperidol (HAL), a D2 receptor antagonist, and by naloxone (NLX), an opioid receptor antagonist. Additionally, serum TNF-α levels were attenuated following CFX and CLAV administration. These results suggest that acute administration of CFX and CLAV may represent a promising approach for treating the acute allodynia of NP, and that the mechanisms involved in these effects involve activation of dopaminergic and opioidergic pathways as well as modulation of TNF-α production. Drug Dev Res 78 : 105-115, 2017. © 2017 Wiley Periodicals, Inc.

Impact of oral antibiotics on health-related quality of life after mandibular third molar surgery: An observational study.

AIM: To compare the impact of antibiotics on health-related quality of life (QoL) outcomes following third molar surgery. MATERIALS AND METHODS: The study population consisted of 135 subjects that required surgical extraction of mandibular third molar under local anesthesia and met the inclusion criteria. The subjects were randomized into three study groups of 45 subjects each: Group A - extended amoxicillin/clavulanic acid (GlaxoSmithKline Beecham England), 1 gram pre-operatively and then 625 mg BD for 5 days Group B - prophylactic amoxicillin/clavulanic acid (GlaxoSmithKline Beecham England) 1 gram pre-operatively only, and Group C - prophylactic levofloxacin 1 gram pre-operatively only. Patients were assessed pre- and post-operatively on days 1, 3, 5, 7, and 14 using the United Kingdom oral health-related QoL (OHRQoL) questionnaire. RESULTS: This study showed that surgical removal of impacted teeth exerted a negative influence on patient's QoL across various physical, social, and psychological aspects of life. Comparing the three groups, Group A showed a slightly better QoL score; although, there was no statistically significant difference among them. Studies have shown better clinical recovery following administration of antibiotics after third molar surgery. CONCLUSION: There was a significant deterioration in OHRQoL in the immediate postoperative period, particularly postoperative days 1 and 3 following third molar surgery. QoL was also observed to be slightly better in Group A than Groups B and C, although this was not statistically significant.

Effectiveness and safety of meropenem/clavulanate-containing regimens in the treatment of MDR- and XDR-TB.

No large study has ever evaluated the efficacy, safety and tolerability of meropenem/clavulanate to treat multidrug- and extensively drug-resistant tuberculosis (MDR- and XDR-TB). The aim of this observational study was to evaluate the therapeutic contribution, effectiveness, safety and tolerability profile of meropenem/clavulanate added to a background regimen when treating MDR- and XDR-TB cases.Patients treated with a meropenem/clavulanate-containing regimen (n=96) showed a greater drug resistance profile than those exposed to a meropenem/clavulanate-sparing regimen (n=168): in the former group XDR-TB was more frequent (49% versus 6.0%, p<0.0001) and the median (interquartile range (IQR)) number of antibiotic resistances was higher (8 (6-9)versus 5 (4-6)). Patients were treated with a meropenem/clavulanate-containing regimen for a median (IQR) of 85 (49-156) days.No statistically significant differences were observed in the overall MDR-TB cohort and in the subgroups with and without the XDR-TB patients; in particular, sputum smear and culture conversion rates were similar in XDR-TB patients exposed to meropenem/clavulanate-containing regimens (88.0% versus 100.0%, p=1.00 and 88.0% versus 100.0%, p=1.00, respectively). Only six cases reported adverse events attributable to meropenem/clavulanate (four of them then restarting treatment).The nondifferent outcomes and bacteriological conversion rate observed in cases who were more severe than controls might imply that meropenem/clavulanate could be active in treating MDR- and XDR-TB cases.

Comparison of effectiveness and safety of imipenem/clavulanate- versus meropenem/clavulanate-containing regimens in the treatment of MDR- and XDR-TB.

No large study to date has ever evaluated the effectiveness, safety and tolerability of imipenem/clavulanate versus meropenem/clavulanate to treat multidrug- and extensively drug-resistant tuberculosis (MDR- and XDR-TB). The aim of this observational study was to compare the therapeutic contribution of imipenem/clavulanate versus meropenem/clavulanate added to background regimens to treat MDR- and XDR-TB cases.84 patients treated with imipenem/clavulanate-containing regimens showed a similar median number of antibiotic resistances (8 versus 8) but more fluoroquinolone resistance (79.0% versus 48.9%, p<0.0001) and higher XDR-TB prevalence (67.9% versus 49.0%, p=0.01) in comparison with 96 patients exposed to meropenem/clavulanate-containing regimens. Patients were treated with imipenem/clavulanate- and meropenem/clavulanate-containing regimens for a median (interquartile range) of 187 (60-428) versus 85 (49-156) days, respectively.Statistically significant differences were observed on sputum smear and culture conversion rates (79.7% versus 94.8%, p=0.02 and 71.9% versus 94.8%, p<0.0001, respectively) and on success rates (59.7% versus 77.5%, p=0.03). Adverse events to imipenem/clavulanate and meropenem/clavulanate were reported in 5.4% and 6.5% of cases only.Our study suggests that meropenem/clavulanate is more effective than imipenem/clavulanate in treating MDR/XDR-TB patients.

Clavulanic acid enhances glutamate transporter subtype I (GLT-1) expression and decreases reinforcing efficacy of cocaine in mice.

The ß-lactam antibiotic ceftriaxone (CTX) reduces cocaine reinforcement and relapse in preclinical assays through a mechanism involving activation of glutamate transporter subtype 1 (GLT-1). However, its poor brain penetrability and intravenous administration route may limit its therapeutic utility for indications related to CNS diseases. An alternative is clavulanic acid (CA), a structural analog of CTX that retains the ß-lactam core required for GLT-1 activity but displays enhanced brain penetrability and oral activity relative to CTX. Here, we tested the hypothesis that CA (1, 10 mg/kg ip) would enhance GLT-1 expression and decrease cocaine self-administration (SA) in mice, but at lower doses than CTX. Experiments revealed that GLT-1 transporter expression in the nucleus accumbens of mice treated with repeated CA (1, 10 mg/kg) was enhanced relative to saline-treated mice. Repeated CA treatment (1 mg/kg) reduced the reinforcing efficacy of cocaine (0.56 mg/kg/inf) in mice maintained on a progressive-ratio (PR) schedule of reinforcement but did not affect acquisition of cocaine SA under fixed-ratio responding or acquisition or retention of learning. These findings suggest that the ß-lactamase inhibitor CA can activate the cellular glutamate reuptake system in the brain reward circuit and reduce cocaine's reinforcing efficacy at 100-fold lower doses than CTX.

Severe delayed skin reactions related to drugs in the paediatric age group: A review of the subject by way of three cases (Stevens-Johnson syndrome, toxic epidermal necrolysis and DRESS).

Severe delayed drug-induced skin reactions in children are not common but potentially serious. This article describes aspects concerning the etiology, pathogenesis and clinical manifestations of these processes; it presents three paediatric cases, namely STS (Steven Johnson Syndrome), TEN (toxic epidermal necrolysis), probably related to amoxicillin/clavulanate and ibuprofen and DRESS (a drug reaction with eosinophilia and systemic symptoms) secondary to phenytoin; and in relation to them, the diagnosis and the treatment of these processes are discussed and reviewed. The AGEP (acute generalised exanthematous pustulosis) is also reviewed. The aetiological diagnosis of severe non-immediate reactions is difficult, and the value of current allergological testing is not well defined in these cases. Diagnosis is based on clinical history, the empirical risk of drugs to trigger SJS/TEN or DRESS, and the in vivo and in vitro testing of the suspect drug. Skin biopsy confirms that the clinical diagnosis and delayed hypersensitivity tests, especially the patch test and the lymphoblastic transformation test (LTT), may be important to confirm the aetiological diagnosis, in our cases emphasising the latter. These diseases can be life threatening (especially DRESS and TEN) and/or have a high rate of major complications or sequelae (SJS/TEN). The three cases described progressed well without sequelae. All were treated with corticosteroids, which is the most currently accepted treatment although the effect has not been clearly demonstrated.

Implementation of Hospital's Antibiotic Policy Decreases Antimicrobial Use in the General Pediatric Ward.

Hospitalized children are often treated with antibiotics. However, 30-75% of antibiotic treatment in pediatric hospitals is administrated incorrectly or unreasonably. Implementation of Hospital's Antibiotic Policy (HAP) should improve antibiotic consumption patterns in pediatric wards. The objective of this study was to determine the effectiveness of HAP by assessing antibiotic consumption in the General Pediatric Ward of an academic hospital in the city of Warsaw, Poland before and after this policy was introduced in the years 2012 and 2013, respectively. Antibiotic use was calculated in daily-defined doses (DDDs) per 100 patient-days and DDDs per 100 admissions. Antibiotics were ranked by the volume of DDDs and the number of antibiotics which accounted for 90% and 100% of the total volume: DU90% and DU100% (where DU stands for drug use). The total antibiotic consumption and significantly decreased after the implementation of HAP; DDDs were 2,177.5 before and 1,335.4 after implementation of HAP. The number of DDDs/100 patient-days was also lower; 36.3 vs. 24.9 before and after HAP, respectively. After implementation of HAP a decreased use of ceftriaxone and cefuroxime was observed. The most commonly used antibiotic was amoxicillin with clavulanic acid. The DU100% rates remained the same (8 antibiotics) and DU90% increased (from 3 in 2012 to 5 in 2013). We conclude that implementation of HAP resulted a decreased consumption of antibiotics in the General Pediatric Ward, despite the hardly changed number of children treated with antibiotics.

Development and validation of stability-indicating HPLC method for simultaneous determination of meropenem and potassium clavulanate.

A stability-indicating LC assay method was developed and validated for a simultaneous determination of meropenem and potassium clavulanate in the presence of degradation products formed during acid-base hydrolysis, oxidation and thermolysis. The isocratic RP-HPLC method was developed with a LiChrospher RP-18 (250 mm x 4.6 mm, 5 microm) column and gradient elution of 12 mmol/L ammonium acetate and acetonitrile. The flow rate of the mobile phase was 1.0 mL/min, the detection wavelength 220 nm and the temperature 303 K. The method was validated with regard to linearity, accuracy, precision, selectivity and robustness, and was applied successfully for the determination of meropenem and potassium clavulanate separately as well as jointly in pharmaceutical formulations.

[The etiology of urinary tract infections and antimicrobial susceptibility: study based on children hospitalized in 2012]. / Etiologia zakazen ukladu moczowego i profil lekowrazliwosci drobnoustrojów: badania przeprowadzone u dzieci hospitalizowanych w 2012 roku.

AIM: Assessment of the etiology of urinary tract infections and pathogen drug sensitivity in hospitalized children. MATERIALS AND METHODS: We analyzed 156 medical records of patients admitted to the Clinical Department of Pediatrics, Bielanski Hospital in Warsaw in 2012, with a suspected UTI. Positive urine culture results were found in 113 (72.4%) children (68; 60.2% of girls and 45; 39.8% of boys), aged from 2 months to 17.9 years (the average age was 2 years and 3 months). RESULTS: E. coli was the most frequent isolated pathogen - 92.0% of patients (104/113). The greatest sensitivity of pathogens showed to cephalosporins of the second and third generation (80.5-90.3%). The sensitivity to amoxicillin with clavulanic acid was 71.7% and 41.6% for ampicillin. The length of hospital stay and treatment ranged from 2 to 16 days (average 8.6 days). In 60.2% (68/113) of patients were treated with second cephalosporin, in 17.7% (20/113) with third generation cephalosporins. Only 11.5% of them (13/113) received amoxicillin with clavulanic acid. Before the treatment, 69.9% (79/113) of children had a fever from 38 up to 41,7ºC, and the fever persisted for the average of 2.5 days (1-8 days). We found significantly higher levels of CRP in children aged between 2-4 in comparison to other age groups (p= 0.0290). In 44.2% (50/113) of children the cystourethrography was performed and in 22% (11/50) cases we recognized a unilateral or bilateral vesicoureteral-ureter of a I to IV degree, on one or both sides. CONCLUSION: The most common etiological agent of UTIs in children remains E. coli. The sensitivity of urinary pathogens to the commonly used antibiotics is still high, however, finds a large percentage of strains resistant to ampicillin and to amoxicillin with clavulanic acid. The antibiotic recommended for empiric therapy of UTIs in children should be cephalosporins, if there is such a possibility, the treatment should be based on drug sensitivity tests of the organisms grown. Because of the relatively long hospitalization of children with UTIs and the possibility of hospital complications, sequential treatment should also be considered sequential.

In vitro and in vivo efficacy of ß-lactams against replicating and slowly growing/nonreplicating Mycobacterium tuberculosis.

Beta-lactams, in combination with beta-lactamase inhibitors, are reported to have activity against Mycobacterium tuberculosis bacteria growing in broth, as well as inside the human macrophage. We tested representative beta-lactams belonging to 3 different classes for activity against replicating M. tuberculosis in broth and nonreplicating M. tuberculosis under hypoxia, as well as against streptomycin-starved M. tuberculosis strain 18b (ss18b) in the presence or absence of clavulanate. Most of the combinations showed bactericidal activity against replicating M. tuberculosis, with up to 200-fold improvement in potency in the presence of clavulanate. None of the combinations, including those containing meropenem, imipenem, and faropenem, killed M. tuberculosis under hypoxia. However, faropenem- and meropenem-containing combinations killed strain ss18b moderately. We tested the bactericidal activities of meropenem-clavulanate and amoxicillin-clavulanate combinations in the acute and chronic aerosol infection models of tuberculosis in BALB/c mice. Based on pharmacokinetic/pharmacodynamic indexes reported for beta-lactams against other bacterial pathogens, a cumulative percentage of a 24-h period that the drug concentration exceeds the MIC under steady-state pharmacokinetic conditions (%TMIC) of 20 to 40% was achieved in mice using a suitable dosing regimen. Both combinations showed marginal reduction in lung CFU compared to the late controls in the acute model, whereas both were inactive in the chronic model.

Efficacy and safety of meropenem-clavulanate added to linezolid-containing regimens in the treatment of MDR-/XDR-TB.

Clinical experience on meropenem-clavulanate to treat tuberculosis (TB) is anecdotal (according to case reports on 10 patients). The aim of our case-control study was to evaluate the contribution of meropenem-clavulanate when added to linezolid-containing regimens in terms of efficacy and safety/tolerability in treating multidrug-resistant (MDR) and extensively drug-resistant (XDR) TB cases after 3 months of second-line treatment. 37 cases with MDR-/XDR-TB were prescribed meropenem-clavulanate (3 g daily dose) in addition to a linezolid-containing regimen (dosage range 300-1200 mg·day(-1)), designed according to international guidelines, which was prescribed to 61 controls. The clinical severity of cases was worse than that of controls (drug susceptibility profile, proportion of sputum-smear positive and of re-treatment cases). The group of cases yielded a higher proportion of sputum-smear converters (28 (87.5%) out of 32 versus nine (56.3%) out of 16; p=0.02) and culture converters (31 (83.8%) out of 37 versus 15 (62.5%) out of 24; p=0.06). Excluding XDR-TB patients (11 (11.2%) out of 98), cases scored a significantly higher proportion of culture converters than controls (p=0.03). One case had to withdraw from meropenem-clavulanate due to increased transaminase levels. The results of our study provide: 1) preliminary evidence on effectiveness and safety/tolerability of meropenem-clavulanate; 2) reference to design further trials; and 3) a guide to clinicians for its rationale use within salvage/compassionate regimens.

Once or twice daily versus three times daily amoxicillin with or without clavulanate for the treatment of acute otitis media.

BACKGROUND: Acute otitis media (AOM) is a common problem in children, for which amoxicillin, with or without clavulanate, is frequently prescribed as a treatment of choice. The conventional recommendation is either three or four daily doses. However, nowadays it is frequently prescribed as once or twice daily doses. If once or twice daily amoxicillin, with or without clavulanate, is as effective for acute otitis media as three or four times a day, it may be more convenient to give the medication once or twice a day to children and hence improve compliance. OBJECTIVES: To compare the effectiveness of one or two daily doses with three or four daily doses of amoxicillin, with or without clavulanate, for the treatment of AOM in children; and to compare complication rates and adverse reactions. SEARCH METHODS: We searched CENTRAL 2013, Issue 2, MEDLINE (January 1950 to March week 1, 2013), EMBASE (1974 to March 2013) and the Science Citation Index (2001 to March 2013). SELECTION CRITERIA: We included randomised controlled trials (RCTs) of children aged 12 years or younger with AOM, diagnosed by acute ear pain (otalgia) and inflamed ear drum (confirmed by positive tympanocentesis or tympanogram of type B or C). DATA COLLECTION AND ANALYSIS: Two review authors independently extracted data on treatment outcomes from individual trials and assessed trial quality based on selection bias, performance bias and detection bias, attrition bias, reporting bias and other biases. We defined the quality grading as low risk of bias, high risk of bias or unclear risk of bias. We summarised the results as risk ratio (RR) with 95% confidence intervals (CI). MAIN RESULTS: We included five studies with 1601 children in the review. Pooled analysis demonstrated that the following outcomes were comparable between the two groups: clinical cure at the end of therapy (RR 1.03, 95% CI 0.99 to 1.07); during therapy (RR 1.06, 95% CI 0.85 to 1.33) and at follow-up (RR 1.02, 95% CI 0.95 to 1.09); recurrent AOM (RR 1.21, 95% CI 0.52 to 2.81); compliance rate (RR 1.04, 95% CI 0.98 to 1.10) and overall adverse events (RR 0.92, 95% CI 0.52 to 1.63). When we performed subgroup analysis separately for trials with amoxicillin only and amoxicillin/clavulanate only, it showed that all important outcomes were comparable between once or twice daily groups and the three times daily group. The risk of bias amongst the five included studies was as follows: for random sequence generation we graded two studies as low and three unclear risk of bias; for allocation concealment all studies were at unclear risk of bias; for blinding (performance and detection bias) we graded four as high and one as unclear risk of bias; for incomplete outcome data (attrition bias) we graded two low, two high and one as unclear risk of bias; for reporting bias four were at low and one at high risk; and for 'other' bias four were at low and one at unclear risk of bias. AUTHORS' CONCLUSIONS: This review showed that the results of using once or twice daily doses of amoxicillin, with or without clavulanate, were comparable with three doses for the treatment of AOM.

High-dose amoxicillin with clavulanate for the treatment of acute otitis media in children.

OBJECTIVE: This study uses the acute otitis media clinical practice guideline proposed in 2004 as a reference to evaluate whether antibiotics doses that are in line with the recommendations lead to better prognosis. The study also attempts to clarify possible factors that influence the outcome. STUDY DESIGN: Retrospective cohort study. SUBJECTS AND METHODS: A total of 400 children with acute otitis media were enrolled. The dosage of amoxicillin was considered to be appropriate when in accord with clinical practice guidelines, that is, 80-90 mg/kg/day. The outcome was defined according to the description of tympanic membrane on medical records. Multivariate logistic regression was used to analyze the relationship between antibiotic dosage and prognosis after adjusting for baseline factors. RESULTS: The majority of prescriptions were under dosage (89.1%) but it was not noticeably associated with outcome (P = 0.41). The correlation between under dosage and poor prognosis was significant in children below 20 kg with bilateral acute otitis media (odds ratio 1.63; 95% CI 1.02-2.59, P = 0.04). CONCLUSION: Treating acute otitis media in children, high-dose amoxicillin with clavulanate as recommended in the clinical practice guideline was superior to conventional doses only in children under 20 kg with bilateral diseases.

Comparison of adherence between twice- and thrice-daily regimens of oral amoxicillin/clavulanic acid.

BACKGROUND AND OBJECTIVE: Few studies have analysed adherence with antibiotic treatment in patients with respiratory tract infections. The aim of this study was to compare the compliance of patients taking a pharmacokinetically enhanced formulation of amoxicillin/clavulanic acid twice daily with that of patients taking the standard formulation thrice daily. METHODS: Patients with suspected bacterial lower respiratory tract infections, pharyngitis and dental infections were included. Adherence was assessed by electronic monitoring, which recorded every opening of the patient's bottle of pills. The outcome variables were compliance with taking the medication, taking the correct dose and with timing of the dose. RESULTS: A total of 240 patients were enrolled (167 in the thrice-daily group and 73 in the twice-daily group). The percentage of doses taken was greater with the twice-daily regimen (84.5 ± 22.8%) than with the thrice-daily regimen (72.7 ± 20.1%; P < 0.001). Forty patients in the twice-daily group opened the container every 12 ± 6 h during at least 80% of the course (54.8%), while only 19.6% of the patients assigned to the thrice-daily formulation did so every 8 ± 4 h (P < 0.001). The percentage of patients who opened the container a satisfactory number of times per day was significantly higher among those taking the twice-daily regimen on days three, four, five, six and seven. Moreover, the thrice-daily group more frequently forgot to take the afternoon dose. CONCLUSIONS: The rate of compliance with amoxicillin/clavulanic acid therapy was very low. However, compliance with the new formulation that is taken twice-daily was significantly better.