Incidence of amoxycillin-clavulanic acid associated hepatotoxicity in an Australian children's hospital.

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.

Higher risk of neutropenia associated with piperacillin-tazobactam compared with ticarcillin-clavulanate in children.

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 complex clinical picture of beta-lactam hypersensitivity: penicillins, cephalosporins, monobactams, carbapenems, and clavams.

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.

High dose intermittent ticarcillin-clavulanate administration in pediatric cystic fibrosis patients.

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.

Continuous infusion of ticarcillin-clavulanate for home treatment of serious infections: clinical efficacy, safety, pharmacokinetics and pharmacodynamics.

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.

Combined application of amoxicillin and clavulanic acid after oral surgical interventions.

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.

Once-daily, high-dose levofloxacin versus ticarcillin-clavulanate alone or followed by amoxicillin-clavulanate for complicated skin and skin-structure infections: a randomized, open-label trial.

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.

Antibiotic-induced recurring interstitial nephritis.

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.

[A trial of using timentin (ticarcillin/clavulanate) in treating abdominal surgical infection]. / Opyt primeneniia timentina (tikartsillin/klavulanata) v lechenii abdominal'noi khirurgicheskoi infektsii.

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.

[The clinical efficacy of ticarcillin/clavulanate in severe pneumonia]. / Klinicheskaia éffektivnost' tikartsillin/klavulanata pri tiazheloi pnevmonii.

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.

Antibiotic-associated haemorrhagic colitis.

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.

Positive direct antiglobulin tests and haemolytic anaemia following therapy with beta-lactamase inhibitor containing drugs may be associated with nonimmunologic adsorption of protein onto red blood cells.

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.

Comparative effectiveness and safety of cefdinir and amoxicillin-clavulanate in treatment of acute community-acquired bacterial sinusitis. Cefdinir Sinusitis Study Group.

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.

Comparison of ceftibuten versus amoxicillin/clavulanate in the treatment of acute exacerbations of chronic bronchitis.

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.

Assessment of the enzymuria resulting from gentamicin alone and combinations of gentamicin with various beta-lactam antibiotics.

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.

Efficacy of twice-daily dosing of amoxycillin/clavulanate in acute otitis media in children.

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.