Search

Objectives: Amoxycillin/clavulanic acid is the most common antimicrobial cause of drug-induced liver injury in adults. It is a less common cause of severe drug-related hepatotoxicity in children despite its frequent use. We studied the incidence, characteristics and predictive factors for amoxycillin/clavulanic acid hepatoxicity in children., Design: Retrospective cohort study of children who received oral or intravenous amoxycillin/clavulanic acid at a quaternary children's hospital over a 5-year period. Children were included if they had liver function tests (LFTs) determined at baseline, during and within 3 months after the treatment course. Causality was assessed using the Naranjo criteria for adverse drug reactions and Roussel Uclaf Causality Assessment Method., Results: Of 3271 children prescribed amoxycillin/clavulanic acid, 374 were included. Forty-nine (13%) had LFT abnormalities related to amoxycillin/clavulanic acid. Fourteen (3.6%) fulfilled Common Terminology Criteria for Adverse Events (CTCAE) grade 2 criteria with clinically significant hepatotoxicity. Age <2 years, sepsis, post-gastrointestinal surgical indications, prolonged treatment course of >7 days and higher cumulative amoxycillin (>10 g) and clavulanic acid dose (>1 g) were predictive of hepatotoxicity. The median time to resolution of LFT abnormalities was 4 weeks (range 3-7)., Conclusions: The incidence of amoxycillin/clavulanic acid related LFT abnormalities (CTCAE Grade 2 or above) in children was 3.6%. A prolonged treatment course >7 days, high cumulative amoxycillin (10 g) and clavulanic acid (>1 g) doses, those aged <2 years, and patients with sepsis or post-gastrointestinal surgery were predictive of a higher likelihood of abnormal LFTs. LFT monitoring should be considered in children receiving ≥7 days of treatment, particularly in those with other predisposing factors., (© The Author(s) 2024. Published by Oxford University Press on behalf of British Society for Antimicrobial Chemotherapy. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Background: A series of cases of piperacillin-tazobactam (P/T)-associated neutropenia has been observed recently in children in our center. Because neutropenia was seldom observed in children treated with ticarcillin-clavulanic acid (T/C), we conducted a study to determine if there is an increased risk of neutropenia in children exposed to P/T in comparison with T/C., Methods: Medical records of subjects aged <18 years who received at least 1 dose of P/T or T/C between 1 January 2008 and 30 June 2011 were reviewed., Results: Two hundred ninety-nine episodes of treatment (65 P/T, 234 T/C) met inclusion criteria. Among those episodes, 213 had data allowing complete white blood cell count analysis and were included in the final analysis. Thirteen cases of neutropenia were observed during the study period. The average time to onset was 17.6 days and all patients were aged <13 years. Seven cases (10.8%) occurred in the P/T group and 6 (2.6%) in the T/C group (unadjusted odds ratio, 4.59; 95% confidence interval, 1.48-14.17). Although a statistically significant correlation was observed between age, treatment duration, and total dose and the development of neutropenia (r = -0.121, P = .037; r = 0.267, P < .001; r = 0.260, P < .001, respectively), this was not the case for sex, indications, neutrophil count at initiation, and concomitant drug treatments., Conclusions: Although our results need to be confirmed, they suggest that children receiving long courses of therapy (>2 weeks) with P/T may be at increased risk of neutropenia, compared with T/C., (© The Author 2014. Published by Oxford University Press on behalf of the Infectious Diseases Society of America. All rights reserved. For Permissions, please e-mail: journals.permissions@oup.com.)

Background: The Intermountain Cystic Fibrosis Pediatric Center utilizes ticarcillin-clavulanate 400mg/kg/day divided every 6h, (maximum 24 g/day). This dosing strategy is higher than the Cystic Fibrosis Foundation (CFF) recommendations and the Food and Drug Administration (FDA) approved package labeling. The purpose is to determine the safety of this dosing regimen., Methods: A retrospective study of pediatric cystic fibrosis (CF) patients admitted from January 1, 2005 to December 31, 2009 who received the dosing regimen for at least 7 days. Baseline and follow-up laboratory parameters were recorded. Statistical analysis was performed., Results: 127 patients met inclusion criteria. The mean (+ or - SD) ticarcillin dose was 3.5 g (+ or - 2.16) every 6 h; while the mean (+ or - SD) total ticarcillin dose was 13.5 g (+ or - 6.5) per day. No significant differences occurred in liver function tests, white blood count, and platelet count from baseline. Serum creatinine showed a statistically significant decrease from baseline., Conclusions: Higher than FDA approved doses of ticarcillin-clavulanate may be safely used in the treatment of exacerbations in pediatric cystic fibrosis patients., (Copyright 2010 European Cystic Fibrosis Society. Published by Elsevier B.V. All rights reserved.)

Beta-lactam antibiotics are the drugs most frequently involved in drug hypersensitivity reactions that are mediated by specific immunologic mechanisms. In addition to benzylpenicillin, several chemical structures belonging to 5 major subgroups can induce reactions. The most relevant structure is that of the amoxicillin molecule. Reactions belong to the 4 major mechanisms described by Coombs and Gell, whereby type IV reactions have recently been further subclassified. The most frequent reactions are type I, which are IgE mediated, and type IV, which are nonimmediate and T-cell dependent. IgE-specific antibodies may recognize the benzylpenicilloyl structure or another part of the molecule, such as the side chain, as antigenic determinants. Depending on specific recognition, subjects can be either cross-reactors or selective responders. A variety of entities exist in T-cell reactions, ranging from mild exanthema to life-threatening, severe reactions, such as Stevens-Johnson syndrome or toxic epidermal necrolysis. Diagnostic tests for IgE-mediated reactions can be done in vivo by testing skin with different penicillin determinants or in vitro by quantitating specific IgE antibodies. For nonimmediate reactions, there are also in vitro and in vivo tests, with variable degrees of sensitivity and specificity. The natural history of IgE-mediated reactions indicates that the count of specific IgE antibodies decreases over time and that results of diagnostic tests can become negative., (Copyright (c) 2010 Elsevier Inc. All rights reserved.)

Continuous infusion (CI) ticarcillin-clavulanate is a potential therapeutic improvement over conventional intermittent dosing because the major pharmacodynamic (PD) predictor of efficacy of beta-lactams is the time that free drug levels exceed the MIC. This study incorporated a 6-year retrospective arm evaluating efficacy and safety of CI ticarcillin-clavulanate in the home treatment of serious infections and a prospective arm additionally evaluating pharmacokinetics (PK) and PD. In the prospective arm, steady-state serum ticarcillin and clavulanate levels and MIC testing of significant pathogens were performed. One hundred and twelve patients (median age, 56 years) were treated with a CI dose of 9.3-12.4g/day and mean CI duration of 18.0 days. Infections treated included osteomyelitis (50 patients), septic arthritis (6), cellulitis (17), pulmonary infections (12), febrile neutropenia (7), vascular infections (7), intra-abdominal infections (2), and Gram-negative endocarditis (2); 91/112 (81%) of patients were cured, 14 (13%) had partial response and 7 (6%) failed therapy. Nine patients had PICC line complications and five patients had drug adverse events. Eighteen patients had prospective PK/PD assessment although only four patients had sufficient data for a full PK/PD evaluation (both serum steady-state drug levels and ticarcillin and clavulanate MICs from a bacteriological isolate), as this was difficult to obtain in home-based patients, particularly as serum clavulanate levels were found to deteriorate rapidly on storage. Three of four patients with matched PK/PD assessment had free drug levels exceeding the MIC of the pathogen. Home CI of ticarcillin-clavulanate is a safe, effective, convenient and practical therapy and is a therapeutic advance over traditional intermittent dosing when used in the home setting.

Antibiotics represent a powerful weapon against infections. As dentists we are faced almost on a daily basis with the need to prescribe antibiotics. At the same time, we can often see that the antibiotics use tends to get out of control or that they are used indiscriminately with no real need. The aim of this case study is to investigate the effectiveness of amoxicillin and clavulanic acid combination in various dental ailments but also to demonstrate possible difference in the severity of symptoms after the use of amoxicillin and antibiotic combination of amoxicillin and clavulanic acid after surgical and oral interventions. The investigation involved 102 patients who were divided into two groups (the first group consisting of 59 and the second one of 43 patients). Following surgical treatment the first group of patients was prescribed antibiotic combination of amoxicillin and clavulanic acid in the dosage of 625 mg, 3 times per day. The second group of 43 patients was prescribed amoxicillin in the dosage of 500 mg, 4 times per day. The recommended therapy for antibiotic combination of amoxicillin and clavulanic acid was 5 to 10 days after the operation and 8 to 10 days for amoxicillin. In other words, both groups of patients started to use antibiotics after the surgical or oral intervention such as operative removal of impacted wisdom teeth, apicoectomy or complicated extractions, and also after the treatment of odontogenic abscesses etc. The same parameters were measured prior to the surgical intervention in cases when patients demonstrated the symptoms before the operational treatment while in all other cases the parameters were measured 48 hours and seven days following the operation. The measured parameters were: pain, swelling, body temperature, dysfunction such as dysphagus trismus, chewing disorder and possible allergic or gastrointestinal reactions. All parameters observed were precisely set in order to harmonize the investigation criteria and facilitate statistical data processing. With respect to pain before the operation there was no substantial statistical difference, p>0.05 (t=0.56; t=0.69). With respect to the onset of pain and the use of antibiotics after 48 hours there is a significant difference in favor of antibiotic combination of amoxicillin and clavulanic acid (X= 14.83, p= 0.002; p <0.01). Thus, pain is less acute if antibiotic combination of amoxicillin and clavulanic acid is administered. With respect to swelling and administration of antibiotics 48 hours after the operation there is no significant difference between the use of the two antibiotic therapies (X= 4.89; p=0.18; p>0.05). The investigation conducted seven days after the operation with regard to pain and the use of either antibiotic therapies demonstrated significant statistical difference (X=9.35, p<0.01) in favor of antibiotic combination of amoxicillin and clavulanic acid. In other words, patients who used amoxicillin and clavulanic acid felt significantly less intense pain. With respect to swelling, significant statistical difference between the two groups of patients was established in favor of antibiotic combination of amoxicillin and clavulanic acid, i.e. p<0.05 (X=6.45, p=0.03). The combination of amoxicillin and clavulanic has proven to be significantly more effective in comparison with the use of amoxicillin after oral-surgical interventions, and therefore antibiotic combination of amoxicillin and clavulanic acid is recommended for use in further practice.

This study tested whether levofloxacin, at a new high dose of 750 mg, was effective for the treatment of complicated skin and skin-structure infections (SSSIs). Patients with complicated SSSIs (n=399) were randomly assigned in a ratio of 1:1 to 2 treatment arms: levofloxacin (750 mg given once per day intravenously [iv], orally, or iv/orally) or ticarcillin-clavulanate (TC; 3.1 g given iv every 4-6 hours) followed, at the investigator's discretion, by amoxicillin-clavulanate (AC; 875 mg given orally every 12 hours). In the clinically evaluable population, therapeutic equivalence was demonstrated between the levofloxacin and TC/AC regimens (success rates of 84.1% and 80.3%, respectively). In the microbiologically evaluable population, the overall rate of eradication was 83.7% in the levofloxacin treatment group and 71.4% in the TC/AC treatment group (95% confidence interval, -24.3 to -0.2). Both levofloxacin and TC/AC were well tolerated. These data demonstrate that levofloxacin (750 mg once per day) is safe and at least as effective as TC/AC for complicated SSSIs.

Acute interstitial nephritis (AIN) is often induced by drug therapy and accounts for 1%-3% of adult cases of renal failure. A 13-year-old white female with cystic fibrosis developed two episodes of biopsy proven AIN following antibiotic use over a 5-year period. The first episode resolved with pulse steroid therapy and the second resolved without intervention. Steroid therapy may play a role in aborting subsequent AIN attacks.

Efficacy of ticarcillin/clavulanate was studied in the treatment of 11 patients with severe community- and hospital-acquired pneumonia in an open controlled trial. The drug was administered in a dose of 3.1 g every 4 or 6 hours depending on the infection severity. When pneumonia was due to Pseudomonas aeruginosa, amikacin was additionally used. The positive clinical effect of ticarcillin/clavulanate was stated in 73 per cent of the patients. The pathogen eradication was stated in all the patients. However, in 2 cases superinfection due to P.aeruginosa developed. Mild adverse effects were observed in 2 cases. It is concluded that ticarcillin/clavulanate is highly efficient in the treatment of patients with severe or complicated pneumonia. In cases with ventilator-associated pneumonia it is advisable to use ticarcillin/clavulanate in combination with an aminoglycoside.

Efficacy of timentin was studied in the treatment of 19 patients with peritonitis of various etiology and clinical and laboratory signs of systemic inflammatory reaction characteristic of abdominal sepsis. The clinical and bacteriological effects were recorded in 84.2 and 87.5 per cent of the cases respectively. The drug was administered intravenously dropwise for 30 minutes in a dose of 3.1 g every 4 hours. The treatment course was 4-11 days. The treatment failed in 3 patients. One of them had general peritonitis of gynecological etiology. In the other no significant regression of abdominal sepsis was observed, Pseudomonas aeruginosa strains were isolated from the abdominal cavity, the antibiotic was changed, still incurable polyorganic insufficiency developed and the patient died. The third patient had perforation of the large intestine due to tumor. No adverse reactions to the use of timentin in any of the cases was observed.

Antibiotic-associated haemorrhagic colitis is an uncommon cause of bloody diarrhoea in patients taking penicillin or penicillin-related antibiotics. Symptoms of abdominal pain and bloody diarrhoea occur within 1 week of antibiotic use and resolve without specific therapy within days of discontinuing the offending antibiotic. There is an apparent increased incidence of the disease in patients of Oriental ethnicity. The pathogenesis is unknown. We present two cases of haemorrhagic colitis in patients taking penicillin-related antibiotics who presented within 4 months of each other. One of the patients was being treated for Helicobacter pylori infection. The published literature is reviewed with particular emphasis on the histology and pathogenesis of the condition.

A high incidence (39%) of positive direct antiglobulin tests (DATs) has been reported in patients taking Unasyn [ampicillin sodium plus sulbactam sodium (a beta-lactamase inhibitor)]. Three of four patients, with positive DATs, receiving Unasyn or Timentin [ticarcillin disodium plus clavulanate potassium (also a beta-lactamase inhibitor)] developed a haemolytic anaemia (HA) associated with a positive DAT, which resolved when drug therapy was stopped. The patients' sera did not react with red blood cells (RBCs) in the presence of Unasyn or Timentin, but when drug-treated RBCs were tested, patients' sera and normal sera reacted equally by indirect antiglobulin test. Following incubation in normal sera, RBCs treated with Unasyn, Timentin, Augmentin (amoxicillin + clavulanate), sulbactam and clavulanate reacted with anti-human globulin and anti-human albumin (an index of non-specific adsorption); RBCs treated with ampicillin and amoxicillin were nonreactive. The beta-lactamase inhibitors sulbactam and clavulanate seem to cause nonimmunologic adsorption of protein onto RBCs in vitro. This may explain the high incidence of positive DATs detected in patients taking Unasyn, which contains sulbactam. It was not possible to prove that there was a direct association between the nonspecific uptake of protein onto drug-treated RBCs in vitro with the positive DATs or the HA.

Cefdinir is an extended-spectrum oral cephalosporin that is active against pathogens commonly seen in acute community-acquired bacterial sinusitis (ACABS), including Streptococcus pneumoniae, Haemophilus influenzae, and Moraxella catarrhalis. Two randomized, investigator-blind, multicenter trials (one in the United States and one in Europe) compared two dosage regimens of cefdinir (600 mg once a day for 10 days and 300 mg twice a day for 10 days) to amoxicillin-clavulanate (A-C) (500 mg three times a day for 10 days) for adult and adolescent patients with ACABS. Twelve hundred twenty-nine patients entered the U.S. study, 698 with antral puncture; 569 patients entered the European study, all with antral puncture. Clinical response (cure or improvement) was determined 7 to 14 days and 3 to 5 weeks posttherapy. Microbiologic eradication rates were determined 10 to 30 days posttherapy in a subset of patients who underwent pre- and posttherapy sinus aspirate culture. Rates of adverse events and treatment discontinuations due to adverse events were examined. Cefdinir, given once or twice daily, was as effective clinically (approximately 90% cure rate) as amoxicillin-clavulanate given three times daily in the treatment of ACABS. Microbiologic eradication rates were also similar in the three groups. The major side effect was mild diarrhea, occurring in approximately 20% of each group. Cefdinir caused fewer adverse events requiring treatment discontinuation.

The efficacy and tolerability of once- or twice-daily ceftibuten (400 mg daily) were compared with three-times daily amoxicillin/clavulanate (AMX/CA, 500 mg/125 mg) in the treatment of acute exacerbations of chronic bronchitis (AECB) in an open, parallel-group 10- to 14-day study in 443 patients. Patients were assessed at baseline and on days 5, 10-14 and after 4-6 weeks of treatment, and the clinical response defined as cured, improved, stabilized or failed. Clinical efficacy between the 3 groups was equivalent (p = 0.002) with 90% of patients in each group responding to treatment (cured or improved) and the incidence of complete cures (with no clinical signs of relapse) was also equivalent. In conclusion, this study showed that ceftibuten is clinically equivalent to a standard regimen of amoxicillin/clavulanate in the treatment of AECB, including those patients infected with Streptococcus pneumonia. Ceftibuten was better tolerated than AMX/CA and was associated with significantly fewer gastrointestinal side effects. Furthermore, once-daily was a well tolerated and effective as twice-daily ceftibuten.

Objective: To determine the propensity of beta-lactam antimicrobials to ameliorate or potentiate aminoglycoside-induced renal enzymuria., Design: Two open, randomized, double-blind, parallel-group studies were conducted in young, healthy, male volunteer subjects. Using a common protocol, 24-hour urine collections were analyzed for the renal tubular enzymes alanine aminopeptidase (AAP) and N-acetyl-beta-D-glucosaminidase (NAG), as well as for creatinine. Antimicrobial combinations studied included gentamicin plus placebo and gentamicin plus ticarcillin/clavulanate (protocol 1); and gentamicin plus placebo, gentamicin plus piperacillin, and gentamicin plus ceftazidime (protocol 2). The antimicrobial regimens were administered for 7 days. Eight subjects completed each treatment group., Results: There were no significant differences between treatment groups with regard to urine creatinine excretion or serum gentamicin concentrations in either protocol. Enzymuria (AAP [p = 0.039] and NAG [p = 0.337]) was decreased in the gentamicin plus ticarcillin/clavulanate treatment compared with that in the gentamicin plus placebo treatment. Increased enzymuria, as indicated by increased urine concentrations of AAP and NAG, was observed in the gentamicin plus ceftazidime treatment (p < 0.05) compared with the other two treatments., Conclusions: Based on relative enzymuria, ticarcillin/clavulanate may be renal protective. Piperacillin neither potentiated nor ameliorated aminoglycoside-induced enzymuria. Since acute elevations in AAP and NAG reflect insults to the kidney, these studies suggest that ceftazidime may enhance aminoglycoside-induced renal injury. Piperacillin had no effect on enzymuria and would appear not to enhance or protect against aminoglycoside-induced renal injury.

Children with acute otitis media (AOM), aged 2-12 years, were randomised to 10 days treatment with amoxycillin/clavulanate (A/C) 70/10 mg/kg/day given b.i.d. (231 patients) or to A/C 60/15 mg/kg/day given t.i.d. (232 patients). Clinical success rates at end of therapy (10-17 days) were 91.8% for the b.i.d. group and 90.5% for the t.i.d. group and at follow-up (28-42 days) were 80.1% for the b.i.d. group and 77.6% for the t.i.d. group, indicating that the b.i.d. regimen was as effective as the t.i.d. regimen. There was no statistically significant difference in incidence of adverse experiences between the two groups. The overall incidence of protocol defined diarrhoea assessed from diary booklets was low, with a lower incidence in the b.i.d. group (6.7%) than in the t.i.d. group (10.3%). Significantly more patients in the b.i.d. group (83.1%) than in the t.i.d. group (72.8%) had at least 80% compliance over a 7-10 day treatment period. A/C given twice or three-times daily was highly effective in the treatment of AOM in children. The two regimens showed equivalent clinical efficacy, both were well tolerated, and there was evidence of improved compliance with the b.i.d. regimen.

Objective: To compare the safety and efficacy, in treating acute otitis media (AOM) in children, of a new formulation of amoxicillin/clavulanate potassium (Augmentin) oral suspension providing 45/6.4 mg/kg/day and administered twice daily (bid) for 5 and 10 days, respectively, with the safety and efficacy of the original formulation providing 40/10 mg/kg/day and administered three times daily (tid) for 10 days., Study Design: Eight hundred sixty-eight children ages 2 months to 12 years with AOM were randomly assigned to one of the three treatment groups. Stringent criteria were used for the diagnosis of AOM and for determinations of "cure" and "improvement." Subjects were reexamined on Days 12 to 14 and 32 to 38., Results: Among subjects whose treatment and follow-up conformed fully to protocol, the proportion of treatment successes (clinically cured or improved) on Days 12 to 14 was 78.8% (149 of 189) in the tid 10-day group, 86.5% (154 of 178) in the bid 10-day group and 71.1% (140 of 197) in the bid 5-day group. Corresponding values on Days 32 to 38 were 64.2% (95 of 148) in the tid 10-day group, 63.1% (94 of 149) in the bid 10-day group and 57.8% (93 of 161) in the bid 5-day group. None of the differences between the tid 10-day regimen and either of the 2 bid regimens were statistically significant, but the bid 10-day regimen was significantly more effective than the bid 5-day regimen in younger subjects. In the study population as a whole, results were similar to those in per protocol subjects. Overall the incidence of protocol-defined diarrhea was 26.7% (74 of 277) in the tid 10-day group, compared with 9.6% (27 of 280) in the bid 10-day group (P < 0.0001) and 8.7% (25 of 286) in the bid 5-day group (P < 0.0001)., Conclusions: In comparison with the original formulation of Augmentin administered tid for 10 days in the treatment of AOM in children, the new formulation administered bid for 10 days provides at least equivalent efficacy and causes substantially less diarrhea. Administration for 5 days appears not to provide equivalent efficacy, but the difference appears limited to younger children and the margin of difference is small.

Toxic hepatitis is an infrequent secondary effect of amoxycillin-clavulanic acid with fewer than 30 well documented cases in the literature. Presentation is usually that of acute cholestasis several weeks after the initiation of treatment with this antibiotic. A new case of hepatic toxicity by amoxycillin-clavulanic acid is reported in a 47-years-old male who had taken this drug for a diarrhea syndrome. A brief review of the literature is made with special emphasis on the anatomopathologic aspects.

In this double-blind study, 557 patients with lower respiratory tract infection were randomly assigned to receive amoxicillin/clavulanate orally either every 12 hours (875/125 mg) or every 8 hours (500/125 mg) for 7-15 days. For the 455 patients evaluable for clinical efficacy at the end of therapy, clinical success was similar in the two groups: 93% and 94% in the 12-hour and 8-hour groups, respectively (P = .42). Bacteriologic success at the end of therapy was also comparable: 97% and 91% in the 12-hour and 8-hour groups, respectively (P = .86). The occurrence of adverse events related to treatment was similar for the two groups, but fewer patients in the 12-hour group reported moderate or severe diarrhea. Amoxicillin/clavulanate (875/125 mg) given every 12 hours is as effective and safe as every-8-hours administration of the combination (500/125 mg) for the treatment of lower respiratory tract infection.

An investigator-blinded, randomized, multicenter study was conducted to compare the efficacy and safety of cefdinir and amoxicillin/clavulanate (amoxicillin/CA) in the treatment of pediatric patients with acute suppurative otitis media. Patients 6 months to 12 years of age were randomized in a 1:1:1 ratio to receive cefdinir 14 mg/kg once-daily, cefdinir 7 mg/kg b.i.d., or amoxicillin/CA 13.3 mg/kg t.i.d. Test-of-cure was determined 11 to 16 days post therapy. Of the 752 patients who entered the study, 665 (88%) completed treatment and 595 (79%) were evaluable. Response rates in the three treatment groups were similar. Overall rates of adverse events were statistically lower in the cefdinir once-daily group than in the amoxicillin/CA group. Diarrhea was the most common adverse event in all treatment groups. Cefdinir given either once-daily or twice-daily is a safe and effective treatment for pediatric patients with acute suppurative otitis media.

Clinical and pathological findings of five cases of acute hepatitis due to amoxicillin-clavulanic acid intake are reported. Liver biopsies revealed cholestasis in all cases, associated with varied degrees of interlobular bile duct injury in four patients. There was no ductopenia. These alterations may mimic lesions observed in intra- and/or extrahepatic biliary tract obstruction. Drug-induced intrahepatic bile duct injuries are not uncommon and can lead to diagnosis difficulties.

Azithromycin, a broad-spectrum azalide, and co-amoxiclav were compared in a randomized, multicentre, open-label trial in 759 patients treated for acute tracheobronchitis (n = 620) or acute infectious exacerbations of chronic bronchitis (n = 139). Patients were randomized (2:1) to a 3-day regimen of two azithromycin 250 mg capsules once daily or a 5-10-day regimen of co-amoxiclav, one 625 mg tablet three times daily. Azithromycin produced a significantly higher cure rate (70.6% versus 61.1%) than co-amoxiclav (P = 0.011) and there were fewer failures (7.8% versus 13.6%) and relapses in the azithromycin-treated group, giving a higher overall response rate for azithromycin (89.7% versus 80.2%, P = 0.0003). With azithromycin, compliance was better than with co-amoxiclav and there was a significantly shorter time to improvement or cure. A higher incidence of adverse events, mostly gastrointestinal, was reported by patients taking co-amoxiclav (21.3% versus 14%, P = 0.0097), causing more patients in this group to discontinue therapy (7% versus 1.2%, P = 0.00004).

Amoxycillin/clavulanic acid liver injury is very rare. We describe an exceptional case of intrahepatic cholestasis without hepatitis induced by amoxycillin/clavulanic acid. Recognition of this benign cholestatic syndrome as a side-effect may obviate unnecessary complementary and costly procedures.

Aims: To review spontaneous reports of drug-associated adverse hepatic reactions., Methods: Reports of drug-associated adverse hepatic reactions received by the New Zealand Centre for Adverse Reactions Monitoring over the 21 year period January 1974 to December 1994 were reviewed. Subdivision into three 7 year periods was undertaken to compare patterns., Results: Of a total of 22,455 adverse medicine reaction (AMR) reports there were 943 reports of liver injury (4.2%). Two hundred and five drugs were associated with hepatic reactions. The top 20 drugs accounted for 57% of all liver reactions. Fifty-seven percent were reported in females. Hepatotoxicity was most commonly reported among patients 50-80 years old. Liver reactions were associated with a 3.3% mortality, but were responsible for 7.4% of all fatal occurrences. There was a steady increase in the number of reports over the 21 years. Although the largest number of reports of liver injury were received between 1988 and 1994, mortality was lowest during this period. There were substantial differences in the medicines associated with hepatic reactions during each of the three periods, although erythromycin was the commonest cause throughout. Erythromycin was associated with two deaths. Halothane and perhexilene were the most frequent cause of death and were two of the most important causes of liver injury during the first and second periods. Diclofenac, Augmentin and flucloxacillin were important causes of hepatotoxicity during period 3 but were not associated with a fatal outcome., Conclusion: Hepatic reactions accounted for 4.2% of all adverse medicine reactions and 7.4% of all fatal occurrences. The top 20 drugs were responsible for 57% of all liver reactions. Despite a steady increase in the number of reports during the 21 years, mortality was lowest during the last 7 years. Differences in the medicines causing liver injury during the three periods influenced the number of fatalities. Erythromycin was the most commonly reported cause of hepatic reactions but was usually associated with a favourable outcome. There were no reported deaths with diclofenac, Augmentin or flucloxacillin.

Seventy-five pregnant women (mean gestational age 32.26 weeks, range 20-36 weeks) with premature rupture of the membranes (PROM) were admitted in our department during 1989 and the first 6 months of 1990. Amoxicillin and clavulanic acid was initially administered at a dose of 1.2 g i.v. every 8 hours for 3-4 days and was followed by oral administration of 625 mg every 8 hours until labor. Sixty-one patients (mean gestational age 32.6 +/- 2.3 weeks, range 26-36 weeks) achieved an uncomplicated course of their pregnancies with a mean time of 11.4 +/- 5.7 days (range 3-27 days), from rupture to delivery. Fourteen women (mean gestational age 30.8 +/- 5 weeks, range 20-36 weeks) developed chorioamnionitis 3.5 +/- 0.9 days (range 1.4-5.6 days) after the rupture with several degrees of leukocyte infiltration of the membranes, placenta and the umbilical cord. Five women (mean gestational age 23.8 +/- 2.3 weeks, range 20-26 weeks) had complications resulting in fetal/infant death, three of them because of fetal sepsis (Escherichia coli, Pseudomonas aeroginosa, Staphylococcus aureus). The newborns were followed up 6 months from delivery and had no signs of drug influence. Few side effects were observed with the chief complaints involving the gastrointestinal tract (4%). No one discontinued the drug. It seems therefore, that the prophylactic administration of amoxicillin and cluvalanic acid in women with PROM is associated with a significant prolongation of pregnancy and with a reduction in the incidence of fetal/maternal infections.

Background: Amoxicillin-clavulanic acid combination-associated hepatitis and jaundice was first identified in 1988. Numerous case reports and case series have been published since then, but there is no precise estimate of this risk., Methods: A retrospective cohort study in the United Kingdom to estimate the risk of acute liver injury associated with the combination of amoxicillin and clavulanic acid and compare it with the one of amoxicillin alone. Data were derived from a cohort of 93,433 users of the combination drug amoxicillin-clavulanic acid and 360,333 users of amoxicillin alone who were aged between 10 and 79 years and who were followed up from 1991 through 1992. After reviewing the information on subjects with suspected liver injury that was recorded on computer files, the clinical records of 177 patients from the attending general practitioners were requested., Results: They were 35 cases of idiopathic acute liver injury. None was fatal. There were 14 cases of acute liver injury among users of amoxicillin alone. The type of liver injury was hepatocellular in half the cases. There were 21 cases of acute liver injury among users of amoxicillin and clavulanic acid together. The type of liver injury was cholestatic in three quarters of the cases. The incidence rates and 95% confidence intervals (CIs) of developing acute liver injury associated with the combination of amoxicillin and clavulanic acid and amoxicillin alone were 1.7 (1.1-2.7) and 0.3 (.02-0.5) per 10 000 prescriptions, respectively. The rate ratios and 95% CIs of acute liver injury for amoxicillin and clavulanic acid together compared with amoxicillin alone were 6.3 (3.2-12.7) for all patients and 8.4 (3.6-20.8) for patients presenting with jaundice. Among users of amoxicillin and clavulanic acid together, the risk of developing acute liver injury was more than 3 times greater after a course of 2 or more consecutive prescriptions than after a single course of therapy. The risk also increased with age among users of amoxicillin and clavulanic acid together. The combination of advancing age and repeated prescriptions resulted in a risk of developing acute liver injury greater than 1 per 1000 users of amoxicillin and clavulanic acid together.

A 3-day regimen of azithromycin (500 mg once daily) and a 10-day regimen of co-amoxiclav (625 mg three times daily) were compared in a double-blind study of 67 patients with acute infectious exacerbations of chronic bronchitis (AIECBs, n = 54), acute bronchitis (n = 7), or pneumonia (n = 6). In patients treated with azithromycin, satisfactory clinical responses (cure or improvement) were seen in 24/28 (86%) patients with AIECBs, 2/4 (50%) with acute bronchitis and 2/2 (100%) with pneumonia. Responses were satisfactory in 24/26 (92%), 4/4 (100%) and 4/4 (100%) patients, respectively, receiving co-amoxiclav. Streptococcus pneumoniae and Haemophilus influenzae were the commonest pathogens isolated at baseline. At the end of treatment, baseline pathogens were eradicated in 9/10 microbiologically-assessable patients treated with azithromycin and in 10/10 treated with co-amoxiclav. Adverse events related or possibly related to treatment occurred in five patients in each treatment group; the majority of these events affected the gastrointestinal system. One patient in each treatment group discontinued therapy because of adverse events. The study, therefore, demonstrates that 500 mg azithromycin administered once daily for 3 days is as efficacious and well tolerated as co-amoxiclav given three times daily for 10 days in the domiciliary treatment of adults with acute lower respiratory tract infections.

Clinical and bacteriological efficacy and tolerability of azithromycin (500 mg once daily for 3 days) and those of a 10-day regimen of co-amoxiclav (37 mg three times daily) were evaluated in a large-scale, double-blind comparative study of 369 patients (> or = 18 years old) with acute lower respiratory tract infections. After treatment, 165/173 (95%) azithromycin- and 166/173 (96%) co-amoxiclav-treated patients had responded satisfactorily (cure or improvement). Baseline pathogens (mainly Streptococcus pneumoniae and Haemophilus influenzae) were eradicated in 82/82 (100%) azithromycin- and 73/74 (99%) co-amoxiclav-treated patients who were bacteriologically assessable. Adverse events, which were predominantly of mild to moderate severity and mostly affected the gastrointestinal system, were recorded in 13/186 (7%) azithromycin- and 19/183 (10%) co-amoxiclav-treated patients. Only two (1%) azithromycin-treated patients discontinued treatment due to adverse events compared with eight (4%) who received co-amoxiclav. The results show that azithromycin at a dose of 500 mg once daily for 3 days is an effective and safe alternative to a 10-day, three-times-daily course of co-amoxiclav in the treatment of lower respiratory tract infections in adults.

Objective: Evaluate antibiotic-associated diarrhea and toxigenic Clostridium difficile in stool specimens obtained from children before and after 10 days of amoxicillin/clavulanate for otitis media., Design: Children, 12 to 47 months of age, treated with amoxicillin/clavulanate for otitis media in an outpatient setting were enrolled. Stool specimens were obtained at enrollment, when diarrhea occurred and at the end of therapy. All stool specimens were tested for C. difficile toxins A and B by enzyme immunoassay., Results: Seventy-six children who had stool specimens collected at enrollment and after therapy were included in the analysis. None had C. difficile toxin in stool specimens at enrollment. Six (27%) of 22 children with diarrhea, and 4 (7%) of 54 children without diarrhea had C. difficile toxin present at completion of therapy (P = 0.03)., Conclusion: Toxigenic C. difficile was identified in 13% of children at the conclusion of amoxicillin/clavulanate therapy with a significantly higher frequency in children with diarrhea.

Cefuroxime axetil has been evaluated previously in the treatment of lower respiratory tract infections, but not specifically in the treatment of community-acquired pneumonia. In a multicentre, investigator-blinded clinical trial, 162 patients with community-acquired pneumonia were randomly assigned to receive orally either cefuroxime axetil 500 mg bid (n = 84) or amoxycillin/clavulanate 500 mg/125 mg tid (n = 78) for 10 days. Organisms were isolated from the pretreatment sputum specimens of 97 of 162 (60%) patients, the commonest isolates being Streptococcus pneumoniae (38%) and Haemophilus influenzae (18%). A satisfactory clinical outcome (cure or improvement) was achieved in 100% (55 of 55) and 96% (49 of 51) of the clinically evaluable patients treated with cefuroxime axetil or amoxycillin/clavulanate, respectively (P = 0.23). With respect to eradication of bacterial pathogens, a satisfactory outcome (cure, presumed cure or cure with colonization) was obtained in 94% (32 of 34) and 93% (37 of 40) of bacteriologically evaluable patients treated with cefuroxime axetil or amoxycillin/clavulanate, respectively (P = 1.00). Both treatment regimens used in this study were well tolerated. The most common drug-related adverse experiences were gastrointestinal events, reported by 8% and 4%, respectively, of the patients in the amoxycillin/clavulanate and cefuroxime axetil groups, a difference which was not statistically significant (P = 0.32). These results indicate that cefuroxime axetil twice a day is as effective as amoxycillin/clavulanate three times a day in the treatment of outpatients with mild to moderate community-acquired pneumonia.

Background: In recent years there has been considerable interest in reducing the duration of antibiotic treatment regimens in patients with common bacterial infections. We conducted two independent, investigator-blinded, multicenter, randomized clinical trials, one of which included microbiologic evaluation of middle ear fluid obtained by tympanocentesis, comparing the efficacy and safety of 5 or 10 days of treatment with cefuroxime axetil suspension (CAE) with that of 10 days of treatment with amoxicillin/clavulanate suspension (AMX/CL) in children with acute otitis media., Methods: A total of 719 pediatric patients from the ages of 3 months to 12 years were enrolled in the 2 studies. Patients received CAE for either 5 or 10 days at 30 mg/kg/day in 2 divided doses (n = 242 and 235, respectively) or AMX/CL for 10 days at 40 mg/kg/day in 3 divided doses (n = 242). Patients in the CAE (5 days) group received placebo on Days 6 through 10. In the study that included tympanocentesis, bacteriologic assessments were based on middle ear fluid cultures obtained pretreatment and, when possible, after treatment in patients with an unsatisfactory clinical outcome., Results: Organisms were isolated from the pretreatment middle ear fluid specimens of 177 of 244 (73%) patients undergoing tympanocentesis, with the primary pathogens being Streptococcus pneumoniae, Haemophilus influenzae and Moraxella catarrhalis (37, 35 and 12% of isolates, respectively). Pathogens were eradicated or presumed to be eradicated in 92% (24 of 26), 84% (32 of 38) and 95% (36 of 38) of bacteriologically evaluable patients treated with CAE for 5 or 10 days or with AMX/CL, respectively. A satisfactory clinical outcome (cure or improvement) occurred in 69% (101 of 147), 70% (121 of 173) and 74% (131 of 177) of clinically evaluable patients treated with CAE (5 days), CAE (10 days) or AMX/CL, respectively. Treatment with AMX/CL was associated with a significantly higher incidence of drug-related adverse events than was treatment with CAE for either 5 or 10 days (P < 0.001), primarily reflecting a higher incidence of drug-related gastrointestinal adverse events (34% vs. 17 and 12%, respectively; P < 0.001), particularly diarrhea., Conclusions: Treatment with CAE given twice daily for 5 days is equivalent to treatment for 10 days either with the same regimen of CAE or with AMX/CL given three times daily in pediatric patients with acute otitis media.

The association amoxicillin-clavulanic acid is a widely used medication. Only about 15 cases of cholestatic hepatitis were reported in Belgium between 1990 and 1993; about 100 cases have been reported to the pharmaceutical company. This effect is severe but reversible. The injury is probably idiosyncratic or immunologically based. Age, sex and treatment duration are as many agents of risk. The diagnosis is undertaken on basis of clinical examination, chronological study, biological evolution and histology.

The treatment of community-acquired pneumonia is empirical in most cases and must cover a wide range of potential pathogens, such as Streptococcus pneumoniae, including penicillin-resistant strains, Haemophilus influenzae and intracellular microorganisms. The objective of this double-blind, randomized, parallel group study was to compare the efficacy and safety of sparfloxacin (400 mg loading dose, followed by 200 mg o.d.) with that of oral amoxycillin-clavulanic acid (500/125 mg t.i.d.) or oral erythromycin (1 g b.i.d.), during 7-14 days in 808 patients with confirmed community-acquired pneumonia. The overall success rates for sparfloxacin (87%), amoxycillin-clavulanic acid (80%) and erythromycin (85%) were similar in evaluable patients, and the equivalence hypothesis used for the statistical analysis showed at least an equivalent efficacy for the three antibiotics tested. The analysis of microbiologically documented infections (40% of the patients) showed that overall success rates were similar for S. pneumoniae and H. influenzae infections. Treatment withdrawal was necessary in 3.5, 2.5 and 7.7% of the patients treated with sparfloxacin, amoxycillin-clavulanic acid and erythromycin, respectively. This study indicates that sparfloxacin was at least as effective as amoxycillin-clavulanic acid or erythromycin in the treatment of mild-to-moderate community-acquired pneumonia and that the adverse effects were similar in the three groups.

Five hundred thirty-seven patients were enrolled in two independent, investigator-blinded, multicenter, randomized clinical trials comparing the clinical and bacteriologic efficacies and the safety of 5- or 10-day treatment with cefuroxime axetil with those of 10-day treatment with amoxicillin-clavulanate in the treatment of secondary bacterial infections of acute bronchitis. Patients received either 5 or 10 days of treatment (n = 177 in each group) with cefuroxime axetil at 250 mg twice daily or 10 days of treatment (n = 183) with amoxicillin-clavulanate at 500 mg three times daily. Patients in the cefuroxime axetil (5 days) group received placebo on days 6 to 10. Bacteriologic assessments were based on sputum specimen cultures obtained preceding and, when possible, following treatment. Organisms were isolated from the pretreatment sputum specimens of 242 of 537 (45%) patients, with the primary pathogens being Haemophilus influenzae, Haemophilus parainfluenzae, Moraxella catarrhalis, Streptococcus pneumoniae, and Staphylococcus aureus (28, 25, 13, 9, and 8% of isolates, respectively). Pathogens were eradicated or presumed to be eradicated in 87% (52 of 60), 91% (53 of 58), and 86% (60 of 70) of bacteriologically evaluable patients treated with cefuroxime axetil (5 days), cefuroxime axetil (10 days), and amoxicillin-clavulanate, respectively. A satisfactory clinical outcome (cure or improvement) was achieved in 82% (107 of 130), 86% (117 of 136), and 83% (130 of 157) of the clinically evaluable patients treated with cefuroxime axetil (5 days), cefuroxime axetil (10 days), and amoxicillin-clavulanate, respectively. Treatment with amoxicillin-clavulanate was associated with a significantly higher incidence of drug-related adverse events than was treatment with cefuroxime axetil for either 5 or 10 days (P = 0.001), primarily reflecting a higher incidence of drug-related gastrointestinal adverse events (37 versus 19 and 15%, respectively; P < 0.001), particularly diarrhea and nausea. These results indicate that treatment with cefuroxime axetil at 250 mg twice daily for 5 days is as effective as treatment for 10 days with either the same dose of cefuroxime axetil or amoxicillin-clavulanate at 500 mg three times daily in patients with acute bronchitis. In addition, treatment with cefuroxime axetil for either 5 or 10 days is associated with significantly fewer gastrointestinal adverse events, particularly diarrhea and nausea, than is 10-day treatment with amoxicillin-clavulanate.

In a prospective clinical trial the pre- and postoperative presence of S. aureus was examined in 130 patients undergoing nasal septal surgery. The patients were randomized into three groups. The first group received no perioperative antibiotics, the second group was given oral amoxicillin plus clavulanic acid, while the third group was treated with oral sulfamethoxazol and trimethoprim. A significant decrease in the incidence of S. aureus was observed in post-operative cultures, but the difference was not attributable to the antibiotic use. Overall, 18.9% of the S. aureus carriers harbored toxic shock syndrome toxin-1 positive strains. However, the decrease in the presence of S. aureus and the risk for toxic shock syndrome was not influenced by the antibiotics administered. These findings show that the routine use of oral prophylactic antibiotics for patients undergoing nasal surgery seems not indicated.

History and Findings: A 61-year-old woman fell ill with recurrent nausea, loss of appetite and tiredness. Five days later she noted increasing jaundice of skin and sclerae, pale stools and dark urine, and she developed itching over the whole body. Among biochemical tests alkaline phosphatase (537 U/l) and bilirubin (32.0 mg/dl) were markedly increased, while both GOT (102 U/l) and GPT (39 U/l) were only slightly elevated. Ultrasonography was normal and extrahepatic cholestasis appeared unlikely on endoscopic retrograde cholangiopancreatography. Cholestasis due to virus hepatitis was also excluded. It was only on repeated and direct questioning that the patient reported having taken three tablets daily of Augmentin (amoxicillin and clavulanic acid) for 12 days 5 weeks before the onset of symptoms., Treatment and Course: After symptomatic treatment with Colestyramine (4 g three times daily), ursodeoxycholic acid (250 mg twice daily) and the antihistaminic Clemastine (1 g two times daily) the severe pruritus decreased quickly and alkaline phosphatase concentration became normal. At follow-up examination 4 and 8 weeks later the laboratory tests were normal., Conclusions: This report of Augmentin-induced cholestasis is not unique. It shows that previous drug intake must be carefully investigated in any case of cholestasis of unknown cause.

Two independent, investigator-blinded, multicenter, randomized clinical trials compared the clinical and bacteriologic efficacy and safety of two oral antibiotics, cefuroxime axetil and amoxicillin/clavulanate, in the treatment of patients with secondary bacterial infections of acute bronchitis (hereafter denoted acute bronchitis). Three hundred sixty patients with signs and symptoms of acute bronchitis were enrolled at 22 centers and were randomly assigned to receive 10 days of treatment with either cefuroxime axetil 250 mg twice daily (BID) (n= 177) or amoxicillin/clavulanate 500 mg three times daily (TID) (n = 183). Patients were assessed for both clinical and bacteriologic responses once during treatment (at 3 to 5 days) and twice after treatment (at 1 to 3 days and at 13 to 15 days). Bacteriologic assessments were based on sputum specimen cultures obtained before treatment and, when possible, after treatment. Organisms were isolated from the pretreatment sputum specimens of 162 (45%) of 360 patients, with the primary pathogens being Haemophilus influenzae, Haemophilus parainfluenzae, Streptococcus pneumoniae, Moraxella catarrhalis, and Staphylococcus aureus (28%, 25%, 11%, 9%, and 8% of isolates, respectively). Thirty-four percent of the H influenzae isolates and 94% of the M catarrhalis isolates that were tested for beta-lactamase production were positive. A satisfactory clinical outcome (cure or improvement) was achieved in 86% (117 of 136) and 83% (130 of 157) of the clinically assessable patients treated with cefuroxime axetil or amoxicillin/clavulanate, respectively (P = 0.45). With respect to the eradication of bacterial pathogens, a satisfactory outcome (cure, presumed care, or cure with colonization) was obtained in 91% (53 of 58) and 86% (60 of 70) of bacteriologically assessable patients treated with cefuroxime axetil or amoxicillin/clavulanate, respectively (P = 0.32). Treatment with amoxicillin/clavulanate was associated with a significantly higher incidence of drug-related adverse events than was treatment with cefuroxime axetil (39% vs 23%; P = 0.001), primarily reflecting a higher incidence of drug-related gastrointestinal adverse events (37% vs 15%; P < 0.001), particularly diarrhea and nausea. Four patients in the cefuroxime axetil group and eight patients in the amoxicillin/clavulanate group withdrew from the study because of drug-related adverse events. These results indicate that cefuroxime axetil 250 mg BID is as effective as amoxicillin/clavulanate 500 mg TID in the treatment of patients with acute bronchitis but produces fewer gastrointestinal adverse events, particularly diarrhea and nausea.