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Activities of piperacillin, ceftazidime, cefepime and cefpirome against Pseudomonas aeruginosa strains with intrinsic ticarcillin resistance.

The in vitro activities of cefepime and cefpirome against 44 intrinsically ticarcillin-resistant strains of Pseudomonas aeruginosa were compared to their activities against 20 ticarcillin-susceptible strains by MIC determination and the disk test. Time-killing curves were constructed for piperacillin, ceftazidime, cefepime and cefpirome against two susceptible and two resistant strains. The activities of cefepime and cefpirome against the resistant strains were impaired, and most of the strains were of intermediate sensitivity to these agents. The time-killing curves of the four beta-lactams were similar, with a modest decline in viable cell counts over the first 6 h followed by regrowth. There was no difference between the susceptible and resistant strains.

Anti-Bacterial Agents↗

Superior effect of tazobactam/piperacillin compared to piperacillin on beta-lactamase-producing Pseudomonas aeruginosa.

To evaluate the synergistic antimicrobial effects of tazobactam (TAZ), a beta-lactamase inhibitor, and piperacillin (PIPC) on Pseudomonas aeruginosa, we compared the antimicrobial effects of TAZ/PIPC with those of PIPC alone on bacteria inducibly or constitutively producing beta-lactamase. TAZ/PIPC had more potent antimicrobial effects compared with PIPC on clinical isolates producing beta-lactamase. In the treatment of mouse systemic infection, the therapeutic effect of PIPC was markedly decreased by beta-lactamase, but that of TAZ/PIPC was only slightly decreased. In the treatment of local infections in mice, the therapeutic effects of PIPC were decreased due to the induction of beta-lactamase and the emergence of bacterial strains constitutively producing beta-lactamase, while those of TAZ/ PIPC were not affected.

Animals↗

Piperacillin Sodium (a phase III clinical trial).

Twenty-one patients with a variety of clinical infections were treated with Piperacillin Sodium intravenously. One case was considered to be a therapeutic failure. Two further cases were incapable of scientific assessment with respect to their response as no satisfactory pathogen could be identified in spite of a significant febrile illness. In all the other patients in the study a good clinical response was deemed to have been achieved. In nine of these patients, a microbiological cure was also achieved. In the remainder, because of the nature of their clinical problem, no final microbiological sample was available for culture due to the absence of any infective material. Only one adverse incident was encountered (a thrombo-phlebitis, in relation to the intravenous avenue of administration.

Adolescent↗

Neutropenia associated with mezlocillin and piperacillin.

Neutropenia associated with beta-lactam antibiotics has been widely reported since the first case was described in 1946. Cross-reactivity between beta-lactam antibiotics for this phenomenon rarely has been reported. This case describes the development of neutropenia after a course of mezlocillin, resolution upon discontinuation, and recurrence promptly after initiation of piperacillin, with resolution subsequent to discontinuation. Clinical practitioners should be aware that this adverse drug reaction has been associated with the newer beta-lactam antibiotics and that cross-reactivity may occur between these antibiotics.

Adult↗

A beneficial interaction between imipenem and piperacillin possibly through their renal excretory process.

In order to assess the beneficial mechanism of the concomitant use of imipenem (IPM) with piperacillin (PIPC) for the treatment of serious infectious diseases such as sepsis, the effects of PIPC on the uptake of IPM by rat renal cortical slices and on the plasma concentrations of IPM after intravenous infusion to rabbits were studied. The uptake of IPM by the rat renal cortical slices was significantly inhibited by p-aminohippurate, probenecid and PIPC whereas the uptake of PIPC by the slices was slightly decreased in the presence of IPM. When IPM was administered together with PIPC by 1-h infusion, the plasma concentrations of IPM were significantly increased during the infusion. These results imply that PIPC possibly interferes with the renal transport of IPM mediated by an organic anion transporter across the renal basolateral membranes, which leads to a longer period above the minimum inhibitory concentrations of IPM.

Animals↗

[Antigenicity tests of tazobactam/piperacillin, tazobactam and piperacillin].

The antigenicity tests of Tazobactam/piperacillin (TAZ/PIPC), tazobactam (TAZ:beta-lactamase inhibitor) and piperacillin (PIPC:penicillin antibiotic) were performed in mice and guinea pigs. The following results were obtained. 1. TAZ/PIPC, TAZ or PIPC had no immunogenicity and allergenicity in either passive cutaneous anaphylaxis (PCA) test using BALB/c and C3H/He mice or in PCA test using guinea pigs. 2. Guinea pigs sensitized with TAZ/PIPC, TAZ or PIPC showed no anaphylactic symptoms in active systemic anaphylaxis (ASA) test. 3. Guinea pig PCA tests using protein conjugates as sensitizing and challenging antigens showed positive reactions. Immunological cross-reactivity tests were performed by using these conjugates in guinea pig PCA reaction. Results showed that TAZ/PIPC and PIPC cross-reacted with penicillin G (PCG) and ampicillin (ABPC), but not with cephalothin (CET) and cephmetazol (CMZ). TAZ did not cross-react with PCG, ABPC, CET or CMZ. 4. From the results of the passive hemagglutination (PHA) test, no antibody against TAZ/PIPC, TAZ or PIPC was detected. 5. In direct Coombs' test using human blood, TAZ/PIPC, TAZ, PCG and CET showed positive reactions at 20-80, 5-20, 80 and 10-20 mg/ml, respectively. 6. The results of a test on in vitro covalent binding activity with human serum albumin indicated that the order of binding potency was CET > CMZ > ABPC > PCG = PIPC > TAZ under the physiological condition (pH 7.2-7.4), and was CMZ > CET > ABPC > PIPC > TAZ > PCG under the alkaline condition (pH 10.0-10.5), respectively.

Animals↗

[Single-dose toxicity study and twenty-eight-days intravenously repeated dose toxicity study of desethyl-piperacillin in rats].

Desethyl-piperacillin (desethyl-PIPC) is an active metabolite of PIPC which was newly found in clinical field. We carried out a single intravenous toxicity study at the dosage of 2000 mg/kg, and 28-days intravenous toxi-city study at the daily dosage of 400 mg/kg followed by 28-days recovery study using both sexes of rats. The following results were obtained. In the single dose toxicity study, no deaths occurred in rats injected 2000 mg/kg of desethyl-PIPC, therefore it is presumed that minimal lethal dose of desethyl-PIPC is over 2000 mg/kg in both sexes. As clinical signs, decrease in locomotor activity, deep breath and loose stool were observed. In the patho-logical study, dilatation of cecal lumen was observed macroscopically, but no significant changes were observed histologically. In the repeated dose toxicity study, loose stool, increase in water consumption, dilatation of cecal lumen and increase in its weight were noted. These abnormal findings were considered to be due to antimicrobial activity of desethyl-PIPC. In addition, decrease in the ratio of serum gamma-globulin and increase in the ratio of alpha 1-globulin were observed, but A/G ratio was not affected. After withdrawal of desethyl-PIPC administration, these abnormal findings tended to disappear. As mentioned above, the minimal lethal dose of desethyl-PIPC is over 2000 mg/kg in the single dose toxicity study and abnormal signs were slight in the repeated dose toxicity study at the dosage of 400 mg/kg of desethyl-PIPC for 28 days in rats. It is, therefore, concluded that desethyl-PIPC is a low toxic metabolite of PIPC.

Alpha-Globulins↗

Hypercoagulopathy with piperacillin administration in osteomyelitis.

A 51-year-old man with osteomyelitis developed acute renal failure and superior mesenteric venous (SMV) thrombosis after piperacillin (PIPC) treatment. Coagulation profile disclosed disseminated intravascular coagulation (DIC). The serum levels of IgE and eosinophil cationic protein showed significant increases, while a lymphocyte stimulation test with PIPC also demonstrated an extremely high index. These observations suggest that hypersensitivity to PIPC might play a role in the pathogenesis of acute renal failure and SMV thrombosis due to hypercoagulopathy. Withdrawal of PIPC and anticoagulation therapy resulted in clinical improvement and normalization of the affected laboratory data. This is the first report to describe PIPC-induced hypercoagulopathy.

Acute Kidney Injury↗

Amikacin plus piperacillin versus ceftazidime as initial therapy in granulocytopenic patients with presumed bacteremia.

69 febrile granulocytopenic episodes without an initial focus of infection were assessed for empiric treatment either with high-dose amikacin plus piperacillin or ceftazidime. 90% of patients in each group survived the granulocytopenic episode; 15 (44 +/- 17%) episodes treated with the combination and 23 (66 +/- 16%) given ceftazidime responded without any modification of initial therapy and half defervesced within 72 h. Persistent fever was the most frequent reason for altering treatment which was done empirically in 90% of cases, but two-thirds of patients required further treatment modification. An infectious focus mainly involving the lung developed during granulocytopenia in 21 patients (30%), of which 17 occurred during antimicrobial therapy. Only 1 infection was shown to be due to bacteria, while 7 were due to fungi. Amikacin levels were similar to those expected following a normal dose (mean peak of 34.7 and mean trough of 12.6 mg/l). Therapy with the combination resulted in a higher serum creatinine (p less than 0.001) and a lower potassium level (p less than 0.001) in comparison with monotherapy. Potassium supplementation was required in 45 +/- 17% of patients given the combination compared with only 4 +/- 7% of those treated with ceftazidime. While both regimens appeared to be equally effective as initial therapy, the need for modification was high in both patient groups. Monotherapy being both simpler to administer and less toxic seems therefore to be the logical choice although the period of empiric therapy must be fully exploited in order to improve diagnosis and therefore antimicrobial management.

Adolescent↗

A randomised comparison of ceftazidime and piperacillin, both in combination with flucloxacillin for treatment of febrile episodes in neutropenic children. Finnish Three-Centre Study.

111 febrile episodes in 98 neutropenic children were randomly treated with either ceftazidime (CAZ) 150 mg/kg/day or with piperacillin (PIP) 200 mg/kg/day, both combined with flucloxacillin (FLUC) 50 mg/kg/day. A total of 37/47 (79%) eligible episodes in the CAZ group and 41/53 (77%) in the PIP group were cured without needing to stop the initial therapy. The success without modification of the treatment in the verified septicaemias in the CAZ group was 8/18 (44%) and in the PIP group 5/18 (28%). Of the bacteriologically documented infections, 13/24 (54%) in the CAZ group and 11/24 (46%) in the PIP group were cured without modification of the therapy. Similarly, 17/31 (55%) of all the isolated bacteria in the CAZ group and 14/33 (42%) in the PIP group were eradicated with the initial therapy. Overall there were 13 deaths of which 4 in the CAZ group and 5 in the PIP group occurred during the infection. An increasing granulocyte count exceeding 0.25 x 10(9)/l at the end of the therapy was a good prognostic sign for the outcome of the infection. This study indicates that CAZ is as effective as PIP in the treatment of infections in neutropenic children.

Adolescent↗

Enhanced liposome-mediated antibacterial activity of piperacillin and gentamicin against gram-negative bacilli in vitro.

This study showed that encapsulation of piperacillin (PIP) and gentamicin (GE) by liposomes prepared with phosphatidylcholine and cholesterol (1:1) enhanced the antibiotic activity against gram negative bacilli. This was demonstrated by growth inhibition of Escherichia coli and Pseudomonas aeruginosa in the presence of the liposomal preparations containing either PIP or GE at 50 per cent MIC. Mixtures of liposomes containing buffer and either PIP or GE also exhibited an enhanced activity of the drug against the micro-organisms.

Drug Carriers↗

A randomized prospective multicentre trial of cefpirome versus piperacillin-tazobactam in febrile neutropenia.

Fever is frequently the only clinical sign of infection in patients with chemo-induced neutropenia. In this setting, empirical administration of broad spectrum antibiotics must be rapid. The aim of this work was to compare, for the first time, cefpirome (CPO) and piperacillin-tazobactam (PT) in a large randomized trial. Two hundred-eight febrile neutropenic episodes (FNE) (> or = 38.5 degrees C and ANC < or = 0.5 giga/l) were treated by randomization, as first line therapy, using either CPO 2 g x 2/day (105 cases) or PT 4 g x 3/day (103 cases), alone (CPO: 15/PT: 15), or plus aminoglycoside (165 cases, CPO: 82/PT: 83) or quinolone (CPO: 2/PT: 2). There were 131 men and 77 women aged between 17 and 83 years (median: 49) who received chemotherapy (n = 160) or allogeneic (n = 10) or autologous (n = 38) stem cell transplantations. Underlying diseases were: acute leukemia (n = 131), lymphoma (n = 33), myeloma (n = 16), solid tumor (n = 8), myeloproliferative disorder (n = 9), chronic lymphoid leukemia (n = 5), aplastic anemia (n = 3), myelodysplasia (n = 3). Distribution of age, neutropenia duration (median: 17 days), underlying disease, and protocol therapy duration (median: 11 days) was comparable in both arms. A microbiologically documented infection (MDI) was evidenced in 57 cases (27%). Bacteria were isolated from blood cultures in 54 cases (Gram positive: 32 cases). Their in vitro susceptibility rates to CPO and PT were not different. Two days after antibiotics initiation, clinical (fever disappearance) and microbiological (culture negativation) success rates (SR) were 62% for CPO versus 61% for PT and 50% versus 55% respectively in case of MDI (p = 0.89). Two deaths and 77 failures were registered. At the end of protocol, SR (no antibiotic change/absence of superinfection) was 59% with CPO versus 50% with PT (p = 0.27) and 53% versus 40% respectively in the 151 cases with neutropenia > or = 10 days (p = 0.17). The occurrence of side effects was similar in both arms. In our hands, the efficacy of CPO and PT was comparable for treating FNE.

Adolescent↗

Pharmacokinetics of piperacillin in renal failure.

Patients with chronic renal failure who received bolus doses of piperacillin maintained high serum levels for up to six hours. The percentage of the injected dose which was detectable in the urine in 24 hours was reduced proportionately to the severity of the renal failure.

Female↗

The mechanism of action of piperacillin-analogues in vitro; effect of the carbon number at the N-4 position of 2,3-dioxopiperazine on the outer membrane permeability, stability to beta-lactamase and binding affinity to penicillin-binding proteins.

The relationship between the chemical structure and the mode of action of piperacillin-analogues (PIPC-analogues) against Escherichia coli and Klebsiella pneumoniae were investigated. The antibacterial activity of PIPC-analogues increased with an increase in the number of carbon atoms at the N-4 position of 2,3-dioxopiperazine. Their mode of action is discussed on the basis of the results of studies on outer membrane permeability, stability to beta-lactamase and binding affinity to penicillin-binding proteins (PBPs). The outer membrane permeability and stability to beta-lactamase were hardly affected by the chain length of the alkyl group at the N-4 position. On the other hand, the affinity to PBPs, especially to PBP 3, became stronger with increase of the number of carbon atoms at N-4 position. These results suggest that increased affinity to PBPs is the main reason for the increased antibacterial activity of the PIPC-analogues reported here.

Bacterial Proteins↗

[In vitro interaction of piperacillin and imipenem/cilastatin combined with aminoglycosides against Pseudomonas aeruginosa].

The in vitro interactions of piperacillin (PIPC) and imipenem/cilastatin (IPM/CS) combined with 5 kinds of aminoglycosides (gentamicin, tobramycin, amikacin (AMK), isepamicin and netilmicin) were investigated against IPM/CS-susceptible (MIC of IPM/CS was < or = 3.13 micrograms/ml) and IPM/CS-resistant (MIC of IPM/CS was > or = 12.5 micrograms/ml) Pseudomonas aeruginosa. The following results were obtained. 1. In the checkerboard dilution studies, the combinations of PIPC with aminoglycosides showed synergistic effect for more than 50% of the each 54 strains of IPM/CS-susceptible and IPM/CS-resistant P. aeruginosa. The synergistic/additive effects of PIPC with aminoglycosides were demonstrated for all tested strains. 2. In the checkerboard dilution studies, the combinations of IPM/CS with aminoglycosides showed no antagonism against any strains. The synergistic effects of IPM/CS with aminoglycosides were demonstrated for 0 to 14.8%, and these values were smaller than the combinations of PIPC with aminoglycosides. 3. Corresponding to the results of checkerboard dilution studies, the combination of PIPC with AMK was more effective than the combination of IPM/CS with AMK on the killing curve for IPM-resistant P. aeruginosa. In conclusion, PIPC showed the synergistic effects in combinations with aminoglycosides against IPM/CS-resistant P. aeruginosa. These results suggest that the combination therapies of PIPC with aminoglycosides are useful for the clinical treatment of serious infections due to P. aeruginosa.

Amikacin↗

[Antibacterial activities of piperacillin for several resistant strains from respiratory infections--in reference to MRSA, PRSP, BLNAR and P. aeruginosa].

We investigated antibacterial activities of piperacillin (PIPC) for several resistant strains of bacteria isolated from patients with respiratory infections from 1998 to 1999 in comparison with reference drugs and obtained the following results: 1. The majority of methicillin resistant strains of Staphylococcus aureus (MRSA) showed high resistance to beta-lactam antibiotics including PIPC. 2. MIC90 of PIPC was 1 and 4 micrograms/ml for penicillin intermediate and penicillin resistant strains of Streptococcus pneumoniae (PISP/PRSP), respectively. 3. MIC90 of PIPC was 0.25 microgram/ml for beta-lactamase negative ampicillin resistant strains of Haemophilus influenzae (BLNAR), showing higher antibacterial activity than the reference drugs. 4. PIPC exhibited the MICs of 8 micrograms/ml or less in 19 out of 40 IPM resistant (MIC > or = 16 micrograms/ml) strains of Pseudomonas aeruginosa. From these results, PIPC is proved to possess extremely favorable antibacterial activities for BLNAR, and it was suggested that PIPC might be a drug of choice even for PISP/PRSP and IPM resistant strains of P. aeruginosa.

Ampicillin↗

[Antibacterial activities of piperacillin in several fresh clinical isolates].

We investigated activity of piperacillin (PIPC) in comparison with 8 antibacterial reference drugs against several fresh clinical strains isolated from patients with infectious diseases in the respiratory tract and after surgical interventions in 1999. The following results were obtained: 1. PIPC had its MIC90 of 0.12-6 micrograms/ml in Gram-positive bacteria (Methicillin susceptible Staphylococcus aureus, Staphylococcus epidermidis, Streptococcus pyogenes, Streptococcus agalactiae, Streptococcus pneumoniae, Enterococcus faecalis) and showed its MIC of 1 microgram/ml or higher in 9 possible PRSP strains out of 38 isolates of S. pneumoniae but there were no possible isolates with evident resistance in other species of bacteria. 2. PIPC showed favorable antibacterial activities as its MIC90 were 2-8 micrograms/ml in Gram-negative bacteria (Escherichia coli, Klebsiella pneumoniae, Serratia marcescens, Citrobacter freundii, Pseudomonas aeruginosa, Moraxella (Branhamella) catarrhalis, Haemophilus influenzae), except for P. mirabilis in which its MIC90 was as high as 64 micrograms/ml. 11 out of 39 isolates of P. mirabilis were resistant to other drugs such as PIPC, ABPC, CTM and CZOP. 3. PIPC had its MIC90 of > 128 micrograms/ml in Bacteroides fragilis. From these results, PIPC was considered highly effective in several infections in view of maintaining its favorable antibacterial activities in several causative bacteria even today when 20 years had passed since its first application to clinical practice.

Bacteroides fragilis↗

[Nephrotoxicity of piperacillin combined with furosemide in rats].

Nephrotoxicity of piperacillin (PIPC) was evaluated in rats after combined administration with furosemide. After intravenous administration of PIPC (1600 mg/kg), the rats showed no change in urinalysis, biochemical analysis of plasma and histopathological analysis. The rats receiving furosemide (100 mg/kg) showed elevation of urinary NAG, BUN and creatinine concentrations, and showed slight degeneration of the renal proximal tubules. The rats receiving PIPC (1600 mg/kg) and furosemide (100 mg/kg) showed elevation of BUN and creatinine concentrations, and showed slight degeneration of the proximal tubules. These changes were comparable to those in rats receiving furosemide alone. The rats receiving cephaloridine (1600 mg/kg) showed elevation of urinary protein, BUN and creatinine concentrations, and showed moderate degeneration and necrosis of the proximal tubules. The nephrotoxicity was enhanced by combination with furosemide. In conclusion, no enhanced effect of nephrotoxicity was observed by combination of PIPC with furosemide.

Animals↗