Resistance surveillance in Italy: four-year results from the MYSTIC program.

The MYSTIC program is an international, multicenter surveillance study that compares the activity of meropenem, in centers that are prescribers, with that of imipenem, ceftazidime, piperacillin/tazobactam, ciprofloxacin and gentamicin. These Italian data are from 3 centers (neutropenia, cystic fibrosis and intensive care units). A total of 2,072 (238 Gram-positive and 1,834 Gram-negative) aerobic microorganisms were collected during the study. Pseudomonas aeruginosa (33.4%) was the most isolated species followed by Escherichia coli (14.4%). All except one Enterobacteriaceae strain isolated were fully susceptible to meropenem. Moreover, the activity of meropenem against Enterobacteriaceae was about eight-fold greater than that of imipenem and four- to eight-fold more active than that of ceftazidime. Meropenem was highly active against non-fermentative Gram-negative microorganisms, exceeding the activity of most of the other antimicrobial agents tested. Moreover, meropenem showed increasing activity during the 4 years of study (starting from 86.2% in 1997 to 94.0% in 2000). In conclusion, our results indicate that meropenem has excellent potency and spectrum of activity despite being prescribed for the treatment of seriously ill patients, and appears to be a reliable option for the initial empirical treatment of serious nosocomial infections.

Meropenem stability to beta-lactamase hydrolysis and comparative in vitro activity against several beta-lactamase-producing Gram-negative strains.

The interaction between meropenem and class A, B, C and D beta-lactamases was studied by a spectrophotometric method. Class A, C and D beta-lactamases were unable to confer in vitro resistance to carbapenems. Surprisingly, several class B metallo-beta-lactamases expressed in Escherichia coli failed to confer resistance when a conventional inoculum (105 cfu/mL) was used.

Carbapenems in the treatment of severe community-acquired pneumonia in hospitalized elderly patients: a comparative study against standard therapy.

In this open, prospective, study were enrolled 204 hospitalized elderly patients with severe (88 males, 116 females, age range 70-94). Patients were randomized to receive one of the following antibiotic treatment regimens: meropenem 500 mg i.v. t.i.d. (52); imipenem/cilastatin 500 mg i.v. t.i.d. (51), clarithromycin 500 mg + ceftriaxone 1 g i.v. b.i.d. (52), clarithromycin 500 mg + amikacin 250 mg i.v. b.i.d. (49). In 99 cases causative germs were isolated (24 meropenem, 26 imipenem, 23 clarithromycin + ceftriaxone, 26 ceftriaxone + amikacin). A satisfactory clinical, bacteriological response was achieved respectively in 86.5% 77% in meropenem; 86.3% 71% in imipenem/cilastatin; 69% 61% in ceftriaxone + clarithromycin and in 85.7% 77% in clarithromycin + amikacin. The mean total cost for each patient was $1,560; $1,620; $1,760 and $1,792 in meropenem, imipenem/cilastatin, clarithromycin + ceftriaxone and clarithromycin + amikacin respectively. This study shows that treatment with either meropenem or imipenem is as efficacious as conventional therapy in the treatment of community acquired pneumonia (CAP), and that meropenem is the most cost-effective.

Concentrations of single-dose meropenem (1 g iv) in bronchoalveolar lavage and epithelial lining fluid.

The concentrations of meropenem were measured in plasma, bronchoalveolar lavage (BAL) and epithelial lining fluid (ELF) 0.5-8 h after the administration of a single 1 g iv dose of meropenem. Thirty-five patients undergoing bronchoscopy were studied. Mean concentrations in plasma, BAL and ELF, respectively, measured by high performance liquid chromatography, were as follows: 0.5 h: 25. 96, 0.14, 5.04 mg/L; 1 h: 14.98, 0.09, 7.07 mg/L; 2 h: 12.01, 0.06, 3.86 mg/L; 4 h: 2.51, 0.04, 2.20 mg/L; 6 h: 0.57, 0, 0.59 mg/L; 8 h: 0.29, 0, 0 mg/L. Throughout the 2 h following infusion, concentrations in ELF exceeded the MIC90 for all nosocomial and community-acquired respiratory pathogens, including Pseudomonas aeruginosa (3.05 mg/L), Haemophilus influenzae (0.16 mg/L) and penicillin-resistant Streptococcus pneumoniae (0.86 mg/L). These results support the clinical efficacy of meropenem in the treatment of a wide range of pulmonary infections.

Interaction of cefotetan and the metallo-beta-lactamases produced in Aeromonas spp. and in vitro activity.

Aeromonas spp. are increasingly being recognized as human pathogens. The presence of metallo-beta-lactamases in these organisms represents a potential problem in antimicrobial therapy. Mechanism-based inactivators of beta-lactamases are used to overcome the resistance of clinical pathogens to beta-lactam antibiotics, but no clinical useful inhibitors of the metallo-beta-lactamases are presently known. Studying the interaction between cefotetan and Aeromonas spp. producing metallo-beta-lactamase activity, we observed that cefotetan behaved as a transient inactivator for both the crude extracts of Aeromonas strains and the purified enzymes from Aeromonas hydrophila AE036 and Aeromonas schubertii MNSA20. The direct hydrolysis of cefotetan showed that it was a poor substrate for both purified enzymes. In view of the minimum inhibitory concentrations, cefotetan shows to be a useful antimicrobial agent against Aeromonas spp.

Multicenter randomized trial comparing meropenem (1.5 g daily) and imipenem/cilastatin (2 g daily) in the hospital treatment of community-acquired pneumonia.

An open, multicenter study with 144 patients, aged between 18 and 94 years, was performed to compare the efficacy and safety of meropenem with imipenem/cilastatin in the hospital treatment of community-acquired pneumonia. Patients were randomized to receive either intravenous meropenem (500 mg every 8 h) or intravenous imipenem/cilastatin (1,000 mg every 12 h). The primary end point was considered to be clinical efficacy and the secondary end points were bacteriological response and safety assessment. At the end of therapy, cure or improvement in signs and symptoms as a satisfactory clinical response was observed in 57 of 64 (89.1%) meropenem-treated patients and in 60 of 66 (90.9%) imipenem/cilastatin patients. The mean duration of treatment was 10 days for meropenem and 9.7 days for imipenem/cilastatin. In patients who were followed up for weeks 2-4, the response was satisfactory (100%) for both treatments. A satisfactory bacteriological response, defined as either presumed or confirmed eradication of all pathogens, was found in eight patients who had received meropenem and in 14 patients who had received imipenem/cilastatin. Response was considered satisfactory in 100% of the meropenem group and in 92.9% of the imipenem/cilastatin group and at follow-up, it was 100% for both treatments. Drug-related adverse events were reported in three (4.2%) meropenem-treated patients and in eight (11.0%) imipenem/cilastatin-treated patients. None of these events was classified as serious. The results of this study show that the clinical and bacteriological efficacy and tolerability of meropenem (500 mg every 8 h) are similar to that of imipenem/cilastatin (1,000 mg every 12 h) in the hospital treatment of community-acquired pneumonia.

Mechanisms of beta-lactam resistance amongst Pseudomonas aeruginosa isolated in an Italian survey.

The mechanisms of resistance to beta-lactam antibiotics in 325 isolates of Pseudomonas aeruginosa were examined. These isolates were selected because of their resistance to meropenem and imipenem (breakpoint, >4 mg/L), carbenicillin (>128 mg/L), ceftazidime (>8 mg/L), piperacillin and ticarcillin/clavulanate (>64 mg/L). The most frequent mechanism of resistance was beta-lactamase-independent, so called 'intrinsic resistance', which was found in 183 isolates and was probably due to impermeability and/or efflux mechanisms. beta-Lactamase-mediated resistance was demonstrated in 111 strains (11.1%). Derepression of Ambler Class C chromosomal beta-lactamase was detected in 64 isolates, most of which were resistant to ceftazidime and piperacillin but susceptible to meropenem, whereas secondary plasmid-encoded beta-lactamases were found in 34 isolates, all of them resistant to carboxypenicillins and ureidopenicillins and susceptible to carbapenems. Twelve strains showed more than one plasmid-encoded beta-lactamase plus derepression of chromosomal Class C enzyme. Resistance to carbapenems was independent of resistance to other beta-lactam antibiotics, indicating a different mechanism of resistance, probably due to the loss of the D2 porin. In total, 32 strains were resistant to carbapenems: 24 only to imipenem and eight to both imipenem and meropenem.

Effect and pharmacokinetics of netilmicin given as bolus intramuscular administration: an open comparative trial versus amikacin and fosfomycin in elderly patients affected by urinary tract infections.

A randomized comparative open clinical trial was performed on 96 hospitalized patients of both sexes, most of whom (84.4%) over 60 years of age, affected by simple and complicated urinary tract infections. Patients were divided in three unequal sized groups and treated with a single administration of netilmicin (5 mg/kg intramuscularly), of amikacin (15 mg/kg i.m.) or of fosfomycin (3 g per os). Patients were evaluated clinically and microbiologically before the beginning of the therapy, 1, 7, 15, 30 days thereafter and at monthly intervals, up to the 18th month, after the drug administration. The pharmacokinetic study was performed in six elderly patients of both sexes, apparently in good general health, except for their urinary tract infections. Symptoms of urinary tract infection disappeared in 50 out of 53 (94.3%) patients treated with netilmicin 14.48 +/- 9.6 hours after the drug administration, in 22 out of 23 (95.6%) of those treated with amikacin after 31.9 +/- 14.3 hours and in 16 (84.2%) out of 19 of symptomatic patients treated with fosfomycin after 37.5 +/- 10.6 hours. The disappearance of symptoms in netilmicin-treated patients is significantly (p less than 0.01) faster than in the other two groups. Twenty-four hours after the administration, netilmicin and amikacin produced sterilization of the cultures in more than 95% of cases, fosfomycin in 90%. Of those patients in which sterilization of cultures was achieved about 70%, in the netilmicin group, and 50% in the other two treatment groups had sterile urine cultures after one month. At the end of the study, 18 months later, more than 60% of the patients treated with netilmicin, the infection had not recurred in comparison with 39.1% and 50% in the amikacin and fosfomycin groups respectively. If only the patients with uncomplicated infections were considered, 88.9% and 83.3% had sterile cultures after 1 and 18 months respectively in the netilmicin group. The corresponding figures in other two groups were: 66.7% for both time intervals in the case of amikacin and 60% both for 1 and 18 months in the case of fosfomycin. The pharmacokinetic results indicate that netilmicin is rapidly absorbed and distributed from the injection site, possesses a beta half-life of about two hours and is mainly excreted by the kidneys. The single dose administration produces very high urinary concentrations of the drug in the first 24 hours and concentrations above 4 micrograms/ml, the 90% minimum inhibitory concentration cut-off point for netilmicin sensitive strains, for four days(ABSTRACT TRUNCATED AT 400 WORDS)

[Netilmicin in a single daily dose for treatment of systemic infections]. / Netilmicina in dose singola giornaliera nel trattamento di infezioni sistemiche.

The Authors report the results obtained in 35 patients of either sex suffering from various systemic infections and treated with netilmicin. Netilmicin has been intramuscularly administered in once daily dose of 4.5 mg/kg (mean daily dose 294.3 mg) for a mean duration of 17.8 days. The clinical resolution of the infections has been achieved in 97.1% (34 patients) of the study population; only one patient showed failure. Thirty-three of the 35 baseline causative pathogens have been eradicated. The local and systemic tolerability was good. The serum pharmacokinetics showed bactericidal levels of netilmicin and no serum accumulation.

[Antibiotic prophylaxis with netilmicin in patients undergoing cystoscopic study]. / Antibiotico-profilassi con netilmicina in pazienti sottoposti ad indagine cistoscopica.

Thirty adults of either sex, in several cases affected by severe urinary pathology, underwent check cystoscopy. An intramuscular injection of netilmicin 200 mg was administered one hour before the diagnostic procedure as antibiotic prophylaxis. Treated patients were controlled up to three months after cystoscopy, in order to verify the presence of urinary infections. Data obtained proved the efficacy of netilmicin in preventing postcystoscopy urinary infections in 87% of the cases. Safety was very good in all patients.

[Netilmicin in single daily doses for the bacterial bronchopulmonary complications in patients with advanced bronchogenic carcinoma]. / La netilmicina in monodose giornaliera nelle complicanze batteriche broncopolmonari in pazienti con carcinoma broncogeno avanzato.

In 40 patients with bacterial bronchopulmonary complications during polychemotherapy for advanced bronchogenic carcinoma, once-daily netilmicin (4.5 mg/kg every 24 h) brought about complete resolution of the infective process in 90% of the cases and eradication of the responsible pathogen in 82%. This result must be considered good in view of the patients' precarious condition due to their advanced neoplastic disease.

[Netilmicin in the treatment of infections of the lower urinary tract]. / La netilmicina nel trattamento delle infezioni delle basse vie urinarie.

The authors treated 30 patients (11 females and 19 males) with cystitis or cystopyelitis. Patients were randomly assigned to one of the following treatments: a) netilmicin 200 mg daily, b) netilmicin 200 mg + ampicillin 1 g daily. Clinical and bacteriologic results were positive in all cases with resolution of clinical signs of infection and negative cultures at the end of treatment. Netilmicin alone yielded the same results as its combination with ampicillin. The safety, monitored also with netilmicin serum levels, was always good.

[Endobronchial administration of netilmicin in patients with bronchopulmonary infections seen in the neurosurgical intensive care unit]. / Somministrazione endobronchiale di netilmicina in pazienti con infezioni broncopolmonari ricoverati in unità di terapia intensiva neurochirurgica.

The Authors report the results obtained in the treatment of bronchopulmonary infections in patients hospitalized in the Neurosurgical Intensive Care Unit. Netilmicin was administered by systemic and endobronchial routes. The cleaning of the bronchial tree was always performed. Twenty-six patients (16 males and 10 females) were enrolled and assigned to one of the following groups. Group A: 16 patients with confirmed pneumonia; Group B: 10 patients without bronchopulmonary infections, as controls for serum pharmacokinetic study. In the majority of the cases pneumonia was caused by Staphylococcus aureus and Pseudomonas aeruginosa. The results obtained were positive: pneumonia resolution was observed in 10 patients (67%), improvement in 4 (27%) and failure in one case (6%). A pharmacokinetic study has confirmed bacteriologically active serum levels of netilmicin and also the availability of netilmicin within the bronchial secretions. Endobronchial plus systemic netilmicin administration was active and well tolerated in these critical patients.