Piperacillin Concentrations Research Articles

Adhesion of Proteus species to various cell types.

Pathogenic and saprophytic Proteus strains from the urine of patients with urinary tract infections and healthy adults respectively were evaluated with regard to their ability to adhere in vitro to homologous cells (uroepithelial cells from urinary sediment and cultured WISH cells) and heterologous cells (RK-13 and MDCK cells). The effect on attachment of pretreating bacteria with subinhibitory concentrations of piperacillin and sagamicin was also determined for one sensitive and one resistant strain. Fifty percent of the pathogenic Proteus strains demonstrated good adherence to human urinary epithelial cells, whereas saprophytic strains did not adhere. There was a lower rate of attachment to culture cells. Piperacillin and sagamicin in subinhibitory concentrations caused a decrease in the attachment of the sensitive Proteus strain.

The effect of piperacillin prophylaxis on the colonic microflora In patients undergoing colorectal surgery.

Piperacillin was given parenterally in doses of 4 g every 8 h for two days to 20 patients undergoing colorectal surgery. A series of serum and fecal specimens were taken to analyse piperacillin concentrations. Tissue samples from the gut wall were taken during surgery. The maximum serum concentrations during surgery were reached 15 min after piperacillin administration. On Day 0 the mean half-life was 1.9 h and the mean area under the serum concentration curve was 536.8 mg/l. The piperacillin concentrations in the tissue samples ranged from 4.2 to 103.5 mg/kg. The tissue/serum ratio was 0.45. The piperacillin concentrations in the fecal samples ranged from not detectable to 101.2 mg/kg. Fecal samples were also collected during the investigation period for the cultivation of aerobic and anaerobic bacteria. Of the aerobic bacteria, enterococci, streptococci and enterobacteria decreased in on fourth of the patients during the prophylaxis period. Anaerobic bacteria, e. g. cocci, gram-positive rods, fusobacteria and bacteroides, decreased in two thirds of the patients during the same period. After the piperacillin administration period, the aerobic and anaerobic colon microflora returned to the pre-treatment pattern in most patients. Postoperative infections due to Escherichia coli, Morganella morganii, Bacteroides fragilis, peptococci and peptostreptococci occurred in two patients.

Pharmacokinetics of intravenously administered piperacillin in preadolescent children

We studied the pharmacokinetics of piperacillin in 37 preadolescent children (mean age 52 months, range 1 month to 11 years) after 50 mg/kg IV doses. Pharmacokinetic parameters were determined after the initial dose in 18 instances and after subsequent doses in 32 instances. There were no significant differences between the initial doses and the subsequent doses in the plasma piperacillin concentrations at comparable times, the elimination rate constants, the elimination-phase plasma half-lives, the total body clearances, the apparent volumes of distribution, or the areas under the concentration curves. At the end of a 30-minute infusion of the drug, the plasma concentration was 166.2 +/- 42.2 mg/L (mean +/- SD) and ranged from 91.6 to 268.3 mg/L. The mean half-life was 31.0 +/- 9.4 minutes. The half-life of piperacillin in children 1 to 6 months of age (47.2 minutes) was significantly longer than in older children (28.8 minutes) (P less than 0.05). Likewise, the total body clearance of the drug in the younger age group (71.7 ml/min/m2) was significantly lower than in the older children (130.8 ml/min/m2) (P less than 0.05). The mean renal clearance of the drug was only 63% (range 39% to 85%) of the total body clearance, suggesting a variable but substantial nonrenal route of elimination. The intravenous administration of 50 mg/kg piperacillin every four hours results in adequate plasma concentrations for the treatment of most infections caused by gram-negative and gram-positive organisms.

Biliary excretion of piperacillin.

1. The excretion of piperacillin sodium in bile was studied after intravenous injection of 2 g (n = 5) and 4 g (n = 7). All patients had undergone cholecystectomy and exploration of the common bile duct for cholelithiasis. Bile, serum and urine concentrations were measured by a microbiological technique. 2. Peak concentrations of piperacillin were found in bile at 150 minutes after 4 g and at 210 minutes after 2 g. 3. Both the concentration of piperacillin in bile at the end of a 6 1/2 hour study and the calculated mean bile concentration of piperacillin were above the minimum inhibitory concentration (MIC) of this drug for organisms commonly found in acute biliary tract infections. We believe piperacillin may be useful in the management of such conditions.

Interactions of antimicrobial drugs and combined phagocytic/serum bactericidal activity of defibrinated human blood against Serratia marcescens. III. beta-Lactam antibiotics and fosfomycin.

Neither cefoperazone, cefotaxime, mezlocillin nor piperacillin significantly killed intraphagocytic bacteria of representative assay strains of Serratia marcescens, as determined with 55 vol% of fresh defibrinated human blood treated with 2 mg/ml of phenylbutazone, which permitted phagocytic ingestion of bacteria, but selectively inhibited the microbicidal activity of peripheral blood leukocytes. Extraphagocytic bacteria were killed with group A (phage tail) bacteriocins of S. marcescens. However, minimal bactericidal concentrations of fosfomycin displayed intraphagolysosomal bactericidal activity which approximated that of rifampin. Inhibitory and subinhibitory concentrations of cefoperazone, cefotaxime, fosfomycin, mezlocillin, and piperacillin combined with 55 vol% of defibrinated human blood, respectively, yielded additive effects against all test strains of S. marcescens utilized and Escherichia coli control strain ATCC 25922.

Piperacillin distribution into bile, gallbladder wall, abdominal skeletal muscle, and adipose tissue in surgical patients.

The concentrations of piperacillin in serum, bile, gallbladder wall, abdominal skeletal muscle, and adipose tissue were measured simultaneously at various times after the intravenous administration of a single 5-g dose to each of 14 patients undergoing biliary tract surgery. Piperacillin concentrated in the bile with peak levels exceeding 4,000 micrograms/ml. In a single patient with cystic duct obstruction, trace gallbladder bile piperacillin levels were measured. Gallbladder wall concentrations of piperacillin tended to be higher than corresponding serum concentrations, with a correlation observed between tissue values and the degree of acute gallbladder inflammation and gallbladder bile piperacillin concentrations. Mean peak muscle and adipose tissue piperacillin concentrations of 31 and 27 micrograms/g, respectively, were reached at between 2 and 3 h after the start of infusion. These concentrations exceeded the minimum inhibitory concentration for a majority of susceptible organisms. A single 5-g dose of piperacillin achieved therapeutic levels in gallbladder wall, intraabdominal skeletal muscle, and adipose tissue and concentrated in the bile of patients with patent biliary tracts.

Effect of subinhibitory antibiotic concentrations on the phagocytosis of Staphylococcus aureus.

The effect of subinhibitory antibiotic concentrations on the phagocytosis of Staphylococcus aureus was studied by pretreating 3H-thymidine labelled bacteria with one-third the minimal inhibitory concentration of clindamycin, doxycyclin, cefotiam, vancomycin, piperacillin and penicillin G, respectively. Pretreatment with clindamycin and doxycyclin resulted in enhanced uptake of the bacteria by polymorphonuclear leukocytes compared to the untreated control. The augmented phagocytosis was still observed at 1/32 the MIC of clindamycin and 1/64 the MIC of doxycyclin, and when the serum was diluted to a concentration of 1%. Pretreatment of the bacteria with penicillin, cefotiam, piperacillin and vancomycin had no effect on phagocytosis. Inhibitors of bacterial protein synthesis induce alterations of Staphylococcus aureus leading to increased phagocytosis, whereas antibiotics acting on cell wall synthesis are without effect.

Zur Empfindlichkeit in vitro von Listeria monocytogenes unter besonderer Berücksichtigung neuerer Beta-Laktamantibiotika

Minimal inhibitory (MIC) and minimal lethal concentrations (MLC) of ampicillin, mezlocillin, piperacillin, cephalothin, cefamandole cefoxitin, cefuroxime, cefotaxime, gentamicin, and doxycycline against 44 strain of Listeria monocytogenes from clinical specimens were determined by broth dilution tests. With regard to the MIC90 and MLC90 values (concentrations which inhibited or killed 90 percent of the strains) ampicillin showed the greatest anti-listeric activity with 0,48 and 20,8 microgram/ml. The corresponding results for mezlocillin were 8,0 and 54,4 microgram/ml, for piperacillin 5,2 and 128 microgram/ml, resp. Among the cephalosporins, cephalothin showed the best activity (MIC90, 5,8 microgram/ml, MLC90, 76,8 microgram/ml). The MIC90 values of cefamandole and cefoxitin were 7,8 and 89,6 microgram/ml, resp. and the MLC90 was more than 128 microgram/ml while there was no clinically relevant activity of cefuroxime and cefotaxime (MIC90 more than 128 microgram/ml). The MIC90 and MLC90 results of gentamicin were 12 and 15,2 microgram/ml, resp, and those of doxycycline 8 and 25,6 microgram/ml, resp. There were only slight differences between gentamicin MIC and MLC values. Henceforward the drug of choice for the treatment of generalized listeric infections should be ampicillin eventually in combination with gentamicin.

379 PHARMACOKINETICS OF PIPERACILLIN IN INFANTS AND CHILDREN

Piperacillin (PIP) is a new penicillin derivative with enhanced activity against gram-negative organisms. We evaluated the pharmacokinetics of this compound in 13 children (ages 1.1-12.7 years). 5 children had Pseudomonas infections (3 osteitis, 1 urinary tract infection, 1 peritonitis). 1 child had foot cellulitis and the remaining 8 had fever and neutropenia. Piperacillin was administered by constant 30 min. intravenous infusion; blood was collected at the end of the infusion and 30, 60, 90 and 120 min. thereafter. The concentration of Piperacillin in serum was determined by a newly developed HPLC assay. The data appeared to fit a one compartment model with first order kinetics. Preliminary results from patients with normal renal function revealed a narrow range of serum half-life(T½); 25.7 to 32.2 min. The apparent volume of distribution (Vd) varied from 0.19 to 0.35 L/Kg. Total body clearance (C1B) varied from 155 to 361 ml/min/1.73m2; C1B correlated directly with creatinine clearance (r=.87) In one patient with renal failure (Creat. clear = 6.9 ml/min/1.73m2) the T½ (70.6 min) was prolonged and the C1B (104 ml/min/1.73m2) was slightly decreased. This suggests that PIP is eliminated both by renal excretion and by non-renal mechanisms; determinations of urinary excretion and renal clearance of PIP are in progress. These initial data suggest that a desired peak concentration of 150 μg/ml can be achieved with an average dose of 55 mg/Kg; drug accumulation does not occur with dosing intervals of 4 hours in patients with normal renal function.

Biliary concentrations of piperacillin in patients undergoing cholecystectomy.

Piperacillin is a new semisynthetic, expanded-spectrum penicillin with marked activity against Pseudomonas aeruginosa. The biliary excretion of piperacillin was studied in patients undergoing cholecystectomy. Concentrations of piperacillin in common duct bile at 35 to 90 min postinfusion of 1-g doses ranged from 31 to 920 micrograms/ml, with a mean (+/- standard deviation) of 467 +/- 363 micrograms/ml. Gallbladder piperacillin levels at 30 to 75 min postinfusion ranged from 2.2 to 80 micrograms/ml, with a mean of 27 +/- 31 micrograms/ml. No correlation occurred with peak serum level of antibiotic, creatinine, bilirubin, or alkaline phosphatase. Significant amounts of piperacillin were excreted via the biliary system.

In-vitro inactivation of aminoglycoside antibiotics by piperacillin and carbenicillin.

Clinical microbiology laboratory experiences wherein aminoglycoside serum assay results appeared inconsistent with the amount of the compound given when administered in combination with a semisynthetic penicillin led us to compare the interaction of three currently available aminoglycoside antibiotics with carbenicillin, as a representative semisynthetic penicillin given in large doses, and with piperacillin, a new broad-spectrum semisynthetic penicillin. Amikacin, gentamicin, and tobramycin were incubated in serum in vitro with various concentrations of carbenicillin and piperacillin. In the presence of very high concentrations of the two penicillins, tobramycin was the most rapidly inactivated aminoglycoside, gentamicin was next, and amikacin was only slightly inactivated. With low concentrations of the two penicillins, the rates of aminoglycoside inactivation were negligible. Carbenicillin, in high concentration, inactivated the aminoglycosides more rapidly than piperacillin. In patients experiencing renal failure, the maintenance of moderate serum levels of carbenicillin and piperacillin may be important in attempting to maintain adequate aminoglycoside serum levels.

Piperacillin kinetics

Piperacillin was administered to normal, healthy volunteers by an intravenous infusion over 30 min at dosage regimens of 12 gm daily (4 gm every 8 hr) and 24 gm daily (6 gm every 6 hr) for 5 consecutive days. Mean peak serum level after 12 gm daily was 244 +/- 24 (SE) microgram/ml and after 24 gm daily, 353 +/- 7 microgram/ml. After infusion the serum level declined monoexponentially in most subjects. On the 12-gm daily dosage mean values were 60 min for half-life (t1/2), 16 1 for volume of distribution, 188 ml/min for body clearance, and 139 ml/min for renal clearance. The same values on day 4 were 47 min, 12 1, 181 ml/min, and 125 ml/min; the volume of distribution was lower than on day 1. On the 24-gm daily dosage regimen, t1/2 was 60 min; volume of distribution, 16 1; body clearance, 183 ml/min; and renal clearance, 101 ml/min on day 1 compared to 68 min, 15 1, 148 ml/min, and 71 ml/min on day 4, the last 2 being significantly lower than on day 1. High renal clearance values were observed at low serum concentrations and vice versa, suggesting saturation of the tubular secretion process at high piperacillin concentrations in serum.

Comparative Evaluation of Piperacillin in Vitro

The minimal inhibitory concentrations of piperacillin and seven other betalactam antibiotics were determined against 407 bacterial isolates. Piperacillin was found to be more active than ampicillin against susceptible gram-negative bacilli and more active than either carbenicillin or ticarcillin against Pseudomonas aeruginosa and streptococci. Although piperacillin was active against Klebsiella pneumoniae, this activity was less than that of the cephalosporins. Piperacillin was not active against penicillin-resistant Staphylococcus aureus and Enterobacteriaceae that were resistant to the other test antibiotics.

In vitro studies of piperacilin, a new semisynthetic penicillin.

Piperacillin, a new semisynthetic penicillin, was compared with other semisynthetic penicillins, cephalosporins, and aminoglycosides by the agar dilution method against 3,600 isolates of facultative gram-negative bacilli, Bacteroides fragilis, and enterococci. At 64 mug/ml, piperacillin inhibited 90% of the isolates in each group of organisms tested except for Escherichia coli (83% inhibited by 64 mug/ml). Compared with carbenicillin, piperacillin had a 16-fold increase in activity by weight against Pseudomonas aeruginosa and the enterococcus, an 8-fold increase against Serratia marcescens, and a 4-fold increase against B. fragilis and Enterobacter species. Piperacillin was highly active against carbenicillin-resistant Klebsiella pneumoniae and inhibited many aminoglycoside-resistant organisms. Except for P. aeruginosa, the minimum bactericidal concentration of piperacillin was usually within one tube dilution of the minimum inhibitory concentration. Approximately one-third of the gram-negative bacilli were inhibited synergistically by piperacillin plus amikacin, but no synergy could be demonstrated against enterococci. Piperacillin's in vitro activity against gram-negative bacilli was similar to gentamicin's except that it also included B. fragilis, and piperacillin was decidedly superior to presently available penicillins against K. pneumoniae.

Piperacillin, a new penicillin active against many bacteria resistant to other penicillins.

The in vitro activity of piperacillin, a new semisynthetic piperazine penicillin derivative, was evaluated against 626 clinical isolates and compared with the activity of other beta-lactam antibiotics. At a concentration of 0.1 microgram/ml, piperacillin inhibited all streptococci except enterococci. Non-beta-lactamase-producing staphylococci were inhibited by 1.6 microgram or less per ml. Both beta-lactamase- and non-beta-lactamase-producing Haemophilus were inhibited by 0.1 microgram/ml. Piperacillin inhibited non-beta-lactamase-producing Escherichia coli, Salmonella, and Shigella at a concentration of 6.3 micrograms/ml, but 20% of strains of these species containing type III beta-lactamase were not inhibited by 100 micrograms/ml. Piperacillin at 25 micrograms/ml, inhibited 83% of Citrobacter, 58% of Klebsiella, 88% of Enterobacter, and 50% of indole-positive Proteus, Acinetobacter, and Providencia. At 25 micrograms/ml, piperacillin inhibited 95% of Pseudomonas aeruginosa and 78% of Bacteroides fragilis. The minimal inhibitory concentration of piperacillin against Pseudomonas was affected by increasing the inoculum size and by pH. Minimum bactericidal concentrations against Pseudomonas and Serratia often were eightfold greater than the minimum inhibitory concentrations. Piperacillin was equal in activity to ampicillin against enterococci. It was more active than carbenicillin against E. coli, Klebsiella, Enterobacter, and Bacteroides. It was the most active penicillin against Pseudomonas and inhibited many strains of Pseudomonas for which the MICs of carbenicillin were above 200 micrograms/ml. Piperacillin was hydrolyzed by many different beta-lactamases. Synergistic activity of piperacillin was demonstrated when it was combined with amikacin, gentamicin, and cefazolin against P. aeruginosa and members of the Enterobacteriaceae. No antagonism was observed when piperacillin was combined with aminoglycosides; however, antagonism was observed rarely against E. coli when piperacillin was combined with cefazolin.