In vitro antibacterial activity of piperacillin against gram negative bacteria and its therapeutic efficacy in children with severe bacterial infection

Abstract

Piperacillin is a new broad spectrum semi-synthetic derivative of aminobenzyl penicillin. The purposes of this study was to evaluate the in vitro antimicrobial activity of piperacillin against 460 gram negative bacteria recently isolated from three hospitals in Bangkok (Ramathibodi, Chulalongkorn, and Rajvithi) and Pseudomonas pseudomallii from Udolrajthani hospital. The efficacy of piperacillin in the treatment of severe infection in children, its pharmacokinetics in normal subjects and its serum level in some patients were also studied. The in vitro susceptibility testing of gram negative bacteria isolated by disc diffusion method revealed that piperacillin was highly active against most of the Enterobacteriaceae (80.93%) excepted E. coli (28%) and Enterobacter spp. (43%). Its inhibitory effect against Pseudomonas aeruginosa and Pseudomonas pseudomallii was very high with 80% and 100% of susceptibility, respectively. The antibiotic resistance of isolated strains from three hospitals showed the same pattern. There was the cross resistance between piperacillin and ticarcillin (8 = 0.69) in resistance strain of Pseudomonas aeruginosa. The determination of minimum inhibitory concentration (MICs) and minimum bactericidal concentration (MBCs) of tested strains by broth dilution technique revealed that piperacillin at MIC 8 ug/ml inhibited more than 80% of most of the Enterobacteriaceae excepted E. coli (48%) and Enterobacter spp. (42%). This MIC (8 ug/ml), also inhibited 61% and 100% of Pseudomonas aeruginosa and Pseudomonas pseudomallii. The inoculums effect of CFU/ml and CFU/ml was found in Pseudomonas aeruginosa and CFU/ml in Pseudomonas pseudomallii. Susceptibility pattern of clinical isolated Pseudomonas aeruginosa from 3 hospital centers in Bangkok were the same (by statistic method) independent with the pattern of antimivrobial was found in these hospitals. In clinical efficacy evaluation, 7 patients with serious bacterial infections were treated with piperacillin alone and 8 patients received combination of piperacillin and other drugs (aminoglycosides, other penicillins and cephalosporins). Age of patient varied from one month to 13 years, out of 14 children had underlying compromised factor (acute lymphoblastic leukemia 2, chronic myelocytic leukemia 1, aplastic anemia 1, CNS. diseases 4, bronchopulmonary dysplasia 2, obstructive uropathy 1). Piperacillin 200-300 mg/kg/day was given intravenously every 4-6 hours. There were 18 sites of infections in 7 system, pulmonary 7, urinary tract 5, skin and soft tissue 2, blood 1, CNS 1, mastoid and middle ear 1, and gastrointestinal 1. All of them failed to respond to other antimicrobial agents prior to piperacillin. Seventy three percents (73%) of these infections improved or cured. Piperacillin eradicated 3 out of 11 strains of Pseudomonas aeruginosa and marked reduced the number of organism in 5 cases. It eradicated Pseudomonas pseudomallii from the soft tissue infection and eradicated Proteus mirabilis from a patient with mastoiditis. Microbiological response was good in 71%. Drug fever was observed in 5 children after 8 days of therapy (35%). All of the fever disappeared within 24 hours after the discontinuation of piperacillin. The pharmacokinetics of piperacillin were studied in 7 normal subjects. Mean concentration of 342.31 37.97 and 599.38 68.08 ug/ml were measured at the end of single intravenously bolus doses of 2 g and 4 g (average 40 and 80 mg/kg/day). The antibiotics had a mean terminal half life of 50 and 51 min after intravenous administrations. The apparent volume of distribution at steady state was 11 and 13 litres/1.73 . Mean urinary recovery in 24 h was 80 and 87%. Mean serum drug level in 3 patients were 85.51 ug/ml at 10 min after the dose of 200 mg/kg/day (average 45 mg/kg/dose) In conclusion, the favorable results of antibacterial activity and clinical efficacy of piperacillin supported by its pharmacokinetics properties ion normal subjects proved to be good reasons for selecting this drug in the treatment of severe bacterial infection in paedriatic patients at doses of 200-300 mg/kg/day, every 4-6 hours. Combination of piperacillin and aminoglycoside is preferred in the case of serious bacterial infection of unknown etiology.