Activity Of Piperacillin Research Articles

6-(1-hydroxyalkyl)penam sulfone derivatives as inhibitors of class a and class C β-lactamases I

Five 6-(1-hydroxyalkyl)penam sulfone derivatives and two 6-(hydroxymethyl)penams were synthesized for β-lactamase inhibitor screens. The substituent effects and stereochemical requirements of 6α- and 6β-(1-hydroxyalkyl) groups for the biological activity of penam sulfone derivatives were investigated. Of these substituents, only the 6β-hydroxymethyl group of 15 improved the activity of sulbactam against both TEM-1 and AmpC β-lactamases. The sulfone moiety is required for the enhancement of the β-lactamase inhibitory activity. 6β-Hydroxymethylsulbactam ( 15) was able to restore the activity of piperacillin in vitro and in vivo against various β-lactamase producing microorganisms.

6-(1-Hydroxyalkyl)penam sulfone derivatives as inhibitors of class A and class C β-lactamases II

Two stereoselective processes for the synthesis of novel 3,6-disubstituted penam sulfone derivatives were developed. One 6β-(1-hydroxyethyl) and four 6β-hydroxymethyl penam sulfone derivatives were synthesized. All four 6β-(hydroxymethyl)penam sulfone derivatives demonstrated good IC 50 against both TEM-1 and AmpC β-lactamases. Of these, 6β-hydroxymethyl penam sulfone derivative 25 was the most active inhibitor which was able to restore the activity of piperacillin in vitro and in vivo against both TEM-1 and AmpC β-lactamases producing organisms.

Comparative in vitro activities of meropenem, imipenem, temocillin, piperacillin, and ceftazidime in combination with tobramycin, rifampin, or ciprofloxacin against Burkholderia cepacia isolates from patients with cystic fibrosis.

We evaluated the activities of meropenem, imipenem, temocillin, piperacillin, and ceftazidime by determination of the MICs for 66 genotypically characterized Burkholderia cepacia isolates obtained from the sputum of cystic fibrosis patients. In vitro synergy assays, as performed by the time-kill methodology, of two- and three-drug combinations of the beta-lactams with tobramycin, rifampin, and/or ciprofloxacin were also performed with 10 strains susceptible, intermediate, or resistant to fluoroquinolones. On the basis of the MICs, meropenem and temocillin were the most active beta-lactam agents, with MICs at which 90% of isolates are inhibited of 8 and 32 micrograms/ml, respectively. The addition of ciprofloxacin significantly enhanced the killing activities of piperacillin, imipenem, and meropenem against the 10 strains tested (P < 0.05). The best killing activity was obtained with the combination of meropenem and ciprofloxacin, with bactericidal activity of 3.31 +/- 0.36 log10 CFU/ml (P < 0.05). Compared to the activity of the two-drug beta-lactam-ciprofloxacin combination, the addition of rifampin or tobramycin did not significantly increase the killing activity (P > 0.05). The three-drug combinations (with or without ciprofloxacin) significantly enhanced the killing activities of piperacillin, imipenem, and meropenem relative to the activities of the beta-lactams used alone (P < 0.05). The combination beta-lactam-ciprofloxacin-tobramycin was the combination with the most consistently synergistic effect.

Bacterial concentrations in pus and infected peritoneal fluid-- implications for bactericidal activity of antibiotics

Little is known about how many bacteria are present at an infectious focus at the onset of antibiotic therapy. The number of cfu was determined in pus and infected peritoneal fluids obtained from 41 patients. Pathogens were detected in 71% of specimens. There were high concentrations of bacteria in culture-positive samples, in both soft-tissue and peritoneal infections, averaging 2 x 10(8) cfu/mL. These concentrations were much higher than the standard inoculum size used in in-vitro susceptibility tests, 5 x 10(5) cfu/mL. The impact of this discrepancy on antibacterial efficacy was studied with amikacin, ciprofloxacin, imipenem and piperacillin against Escherichia coli and Staphylococcus aureus. The inhibitory and bactericidal activities of amikacin and ciprofloxacin determined with high inocula were two to four times lower than with standard inocula, whereas the activity of piperacillin was diminished at least 128-fold. Similar activity was observed with these drugs in Mueller-Hinton broth and peritoneal fluid. The bactericidal activity of imipenem was reduced in peritoneal fluid. Thus, conditions prevailing at the infection site may compromise antibiotic activity determined in vitro.

Beta-lactam/beta-lactamase inhibitor combinations: pharmacodynamic considerations and possible role in the management of bacterial infections in the neutropenic host.

Morbidity and mortality in febrile neutropenic patients result mainly from complications attributable to infectious diseases. Both Gram-negative and Gram-positive bacterial infections have been implicated. The use of antibiotics in combating bacterial infections has been hampered by production by many bacterial pathogens of beta-lactamases that render them resistant to beta-lactam antibiotics. Since susceptibility to the beta-lactam appears crucial in attaining a clinical response in Gram-negative bacteraemia in febrile neutropenic patients, regimens that inhibit the activity of beta-lactamases are desirable. Although many beta-lactamase inhibitors, such as tazobactam, can result in irreversible inhibition of bacterial beta-lactamase in vitro, careful selection of dosage, as well as testing in models of infection mimicking that in patients, is required. Experimental studies in in-vitro models of infection that mimic conditions of absent host response, show that tazobactam restores the activity of piperacillin against beta-lactamase-producing bacteria. Optimal dosage regimens of beta-lactamase inhibitors will provide mean concentrations of beta-lactamase inhibitor at or above those used in in-vitro testing.

Susceptibility of the Anaerobic Gram-negative Non-Sporulating Rod, Bilophila wadsworthia to Beta-Lactams, Beta-Lactamase Inhibitors, Meropenem, Metronidaz

The susceptibility of eighty-seven strain of Bilophila wadsworthia to five beta-lactams, two beta-lactamase inhibitors, meropenem, metronidazole, clindamycin and two quinolones was determined. Tests were performed by the modified reference agar dilution technique using triphenyltetrazolium chloride for endpoint reading. The test strains showed a reduced susceptibility to the beta-lactams, penicillin G (MIC90 4 micrograms/ml), ampicillin (MIC90 32 micrograms/ml), piperacillin (MIC90 64 micrograms/ml), cephalothin (MIC90 2 micrograms/ml and cefotaxim (MIC90 4 micrograms/ml). The activity of ampicillin was increased by addition of the beta-lactamase inhibitor, sulbactam (MIC90 2 micrograms/ml), as was the activity of piperacillin by the addition of tazobactam (MIC90 4 micrograms/ml) 90.8% of the strains were found to produce beta-lactamase by the nitrocefin tube method. All strains were shown to be highly susceptible to meropenem, metronidazole and clindamycin (MICs < or = 1 microgram/ml). Sparfloxacin (MIC90 1 microgram/ml) and ciprofloxacin (MIC90 0.5 microgram/ml) were found to be active against most of the strains tested.

Activities and time-kill studies of selected penicillins, beta-lactamase inhibitor combinations, and glycopeptides against Enterococcus faecalis.

The activities of piperacillin, piperacillin-tazobactam, ticarcillin, ticarcillin-clavulanate, ampicillin, ampicillin-sulbactam, vancomycin, and teicoplanin were tested against 212 Enterococcus faecalis strains (9 beta-lactamase producers) by standard agar dilution MIC testing (10[4] CFU/spot). The MICs at which 50 and 90% of the isolates were inhibited (MIC50s and MIC90s, respectively) were as follows (microg/ml): piperacillin, 4 and 8; piperacillin-tazobactam, 4 and 8; ticarcillin, 64 and 128; ticarcillin-clavulanate, 64 and 128; ampicillin, 2 and 2; ampicillin-sulbactam, 1 and 2; vancomycin, 1 and 4; and teicoplanin, 0.5 and 1. Agar dilution MIC testing of the nine beta-lactamase-positive strains with an inoculum of 10(6) CFU/spot revealed higher beta-lactam MICs (piperacillin, 64 to >256 microg/ml; ticarcillin, 128 to >256 microg/ml; and ampicillin, 16 to 128 microg/ml); however, MICs with the addition of inhibitors were similar to those obtained with the lower inoculum. Time-kill studies of 15 strains showed that piperacillin-tazobactam was bactericidal (99.9% killing) for 14 strains after 24 h at four times the MIC, with 90% killing of all 15 strains at two times the MIC. After 12 and 6 h, 90% killing of 14 and 13 strains, respectively, was found at two times the MIC. Ampicillin gave 99.9% killing of 14 beta-lactamase-negative strains after 24 h at eight times the MIC, with 90% killing of all 15 strains at two times the MIC. After 12 and 6 h, 90% killing of 14 and 13 strains, respectively, was found at two times the MIC. Killing by ticarcillin-clavulanate was slower than that observed for piperacillin-tazobactam, relative to the MIC. For the one beta-lactamase-producing strain tested by time-kill analysis with a higher inoculum, addition of the three inhibitors (including sulbactam) to each of the beta-lactams resulted in bactericidal activity at 24 h at two times the MIC. For an enzyme-negative strain, addition of inhibitors did not influence kinetics. Kinetics of vancomycin and teicoplanin were significantly slower than those of the beta-lactams, with bactericidal activity against 6 strains after 24 h at eight times the MIC, with 90% killing of 12 and 14 strains, respectively, at four times the MIC. Slower-kill kinetics by both glycopeptides were observed at earlier periods.

Tolerability of piperacillin/tazobactam in children and adolescents after high dose radio-/chemotherapy and autologous stem cell transplantation.

The combination of piperacillin with tazobactam (PIP/TAZ) extends the activity of piperacillin against gram-positive, gram-negative, and anaerobic bacteria. The broad-spectrum of this formulation, together with its low degree of organ toxicity observed in adults, makes PIP/TAZ a tempting choice for children with radio-/chemotherapy-induced neutropenia. However, the use of PIP/TAZ is not yet approved for children under 12 years of age. The tolerability of PIP/TAZ was assessed in 19 children and adolescents between 2 and 18 years of age who developed a fever during aplasia after high dose radio-/chemotherapy and autologous stem cell transplantation (HD-SCT) for primary multifocal or relapsed solid tumours. Treatment with PIP/TAZ was initiated on average 3 days after HD-SCT, and the treatment was continued for approximately 10 days. Both clinical observation and laboratory studies showed no relevant alterations that would have been attributable to PIP/TAZ treatment. These results indicate that PIP/TAZ appears to be well tolerated in children during the acute phase of HD-SCT.

The effect of tazobactam on the pharmacokinetics and the antibacterial activity of piperacillin in dogs

Tazobactam (Tazosyn®) is a novel β-lactamase inhibitor belonging to a class of penicillanic acid sulfones. Tazobactam was developed to be used in combination with piperacillin against β-lactamase producing microorganisms. The current study was conducted to determine the effect of tazobactam on the pharmacokinetics and the antibacterial activity of piperacillin in dogs. Three groups of animals consisting of three beagle dogs per group were used for the study. The animals were administered a single I.V. dose of tazobactam (40 mg/kg), piperacillin (320 mg/kg) or the combination in a ratio of 1:8 (tazobactam: piperacillin). Blood samples were drawn at different time intervals. The serum bactericidal titers (SBT) were determined against a plasmid-mediated β-lactamase producing strain of Eschericia coli (LSU-80-8). Serum concentrations of both compounds were determined by high performance liquid chromatography. The mean serum bactericidal titers of the combination was 1:16 against this piperacillin resistant strain of E. coli, 2 h after dosing as compared to less than 1:2 when piperacillin was given alone at the same dose. This indicates that serum concentrations greater than 187 μg/ml of piperacillin (SBT<1:2) were required to kill 99.9% of the piperacillin resistant E. coli inoculum (10 6 CFU/ml) when piperacillin was given alone. However, when piperacillin was administered in combination with tazobactam, concentrations as low as 7 μg/ml of piperacillin and 2 μg/ml of tazobactam were sufficient to exhibit the same bactericidal activity. These results indicate an in-vivo synergistic effect of tazobactam on the piperacillin activity at this dosing ratio which lasted for approximately 5 h after dosing. The coadministration of tazobactam did not appear to affect the pharmacokinetic parameters of piperacillin. However, the elimination of tazobactam was significantly inhibited when coadministered with piperacillin, resulting in a reduction of the clearance (3.5 vs. 7.5 ml/min per kg) and prolongation of the half-life (43 vs. 31 min).

In vitro activity of piperacillin/tazobactam against isolates from patients enrolled in clinical trials

The in vitro activity of piperacillin alone or titrated with a constant concentration of 4 μg/ml tazobactam was evaluated against 3962 baseline pathogens isolated from 1899 patients enrolled in 9 clinical trial studies in North America. Tazobactam increased susceptibility rates of piperacillin for Enterobacteriaceae from 81% to 96%, Staphylococcus (methicillin susceptible) spp. from 6% to 100%, Bacteroides fragilis group from 79% to >99% and Haemophilus from 85% to 98%. The excellent activity of piperacillin against Pseudomonas, Streptococcus and Enterococcus was maintained in the presence of tazobactam. Overall piperacillin/tazobactam had better activity than ticarcillin/clavulanic acid, ceftazidime, and in general equaled the activity of imipenem. The excellent in vitro, extended-spectrum activity of piperacillin/tazobactam suggests its utility for various infections.

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.

An evaluation of the in vitro activity of piperacillin/tazobactam

Tazobactam is a new, irreversible inhibitor of bacterial beta-lactamases of staphylococci, plasmid-mediated beta-lactamases of the TEM and SHV types found in Escherichia coli and Klebsiella species and beta-lactamases of anerobes such as Bacteroides species. Its combination with piperacillin, a broad spectrum ureido-penicillin, would be expected to improve the activity of piperacillin against staphylococci, TEM and SHV beta-lactamase producing Gram negative bacteria and anerobes. Minimal inhibitory concentrations (MIC) of piperacillin/tazobactam were determined for 1952 individual patient isolates of Gram positive and negative bacteria causing significant infections and compared with MIC values for cefotaxime, ceftazidime, ciprofloxacin, imipenem, ticarcillin/clavulanic acid. MICs were determined by agar dilution (NCCLS 1990 and 1992). Piperacillin/tazobactam had excellent activity against methicillin susceptible staphylococci, Streptococcus pneumoniae, Haemophilus influenzae, enterococci and organisms of the Bacteroides fragilis group. It was also active against the majority of Enterobacteriaceae and Pseudomonas aeruginosa isolates tested. It was not active against extended spectrum beta-lactamase (ESBL) producing Klebsiella species and some high level TEM and SHV beta-lactamase producing E. coli and Klebsiella species. Activity against Gram negative organisms capable of producing chromosomally mediated beta-lactamases was good, since in most organisms tested, the enzymes were not induced in sufficient quantities to cause antibiotic resistance. However some Enterobacter species were derepressed hyperproducing mutants; these isolates showed resistance to piperacillin/tazobactam since tazobactam does not inhibit these Class I beta lactamases. Activity was superior to ticarcillin/clavulanic acid for Gram negative rods. Imipenem was the most active agent against ESBL producing Klebsiella species. Piperacillin/tazobactam has a suitable spectrum of activity in vitro to suggest its use in monotherapy of mixed anerobic infections, mixed respiratory infections such as aspiration pneumonia and, in combination with an aminoglycoside, it would provide Gram positive as well as Gram negative cover of febrile episodes in immunosuppressed patients.

Activities of oral and parenteral agents against penicillin-susceptible and -resistant pneumococci.

This study examined bacteriostatic and bactericidal activities of oral and parenteral antibiotics for penicillin-susceptible and intermediately and fully penicillin-resistant pneumococci. beta-Lactamase inhibitors did not affect beta-lactam results. The activities of ampicillin, amoxicillin +/- clavulanate, WY-49605, cefuroxime, cefpodoxime, cefdinir, cefixime, and cefaclor against two penicillin-susceptible, two intermediately penicillin-resistant, and two fully penicillin-resistant pneumococcal strains were tested. For all three groups, bacteriostatic values of amoxicillin and WY-49605 were lower than were those of other beta-lactams tested. Of the cephalosporins, cefdinir, cefuroxime, and cefpodoxime yielded the lowest bacteriostatic values. All beta-lactams were bactericidal (reduced original counts by > or = 3 log10 CFU/ml) at 1 dilution above bacteriostatic values, except for cefpodoxime (bactericidal at 2 dilutions above bacteriostatic values for one susceptible strain and one intermediately resistant strain), cefuroxime (bactericidal at 2 dilutions above bacteriostatic values for one intermediately resistant strain), and ampicillin (bactericidal at 2 dilutions above bacteriostatic values for one intermediately resistant strain). The activities of piperacillin, piperacillin-tazobactam, ticarcillin, ticarcillin-clavulanate, ampicillin, ampicillin-sulbactam, ceftriaxone, ceftazidime, and ciprofloxacin against four penicillin-susceptible, two intermediately penicillin-resistant, and four fully penicillin-resistant pneumococcal strains were evaluated. Bacteriostatic values of piperacillin, ampicillin, and ceftriaxone for all groups were lower than were those of ticarcillin and ceftazidime. Bacteriostatic values of ciprofloxacin were unaffected by penicillin susceptibility. All beta-lactams were bactericidal at 1 dilution above the bacteriostatic value, except for piperacillin (bactericidal at 2 dilutions above the bacteriostatic value for one intermediately resistant strain), ticarcillin (bactericidal at 2 dilutions above the bacteriostatic value for one susceptible strain and one resistant strain), ampicillin (bactericidal at 2 dilutions above the bacteriostatic value for two resistant strains), ceftriaxone (bactericidal at 2 dilutions above the bacteriostatic value for one resistant strain), and ceftazidime (bactericidal at 2 dilutions above the bacteriostatic value for one susceptible strain).

Piperacillin/tazobactam: a new beta-lactam/beta-lactamase inhibitor combination.

To discuss the antimicrobial activity, pharmacokinetics, clinical efficacy, and adverse effect profile of piperacillin/tazobactam, a new beta-lactan/beta-lactamase inhibitor combination. Literature was identified by MEDLINE search of the medical literature, review of selected references, and data provided by the manufacturer. In vitro susceptibility data were surveyed from studies following the methods of the National Committee for Clinical Laboratory Standards. Data evaluating clinical efficacy were selected from all published trials and abstracts. Additional information concerning safety, chemistry, and pharmacokinetics was reviewed. The antimicrobial activity of piperacillin is enhanced by addition of tazobactam against gram-positive, gram-negative, and anaerobic bacteria. Tazobactam is active against a broad spectrum of plasmid and chromosomally mediated enzymes and has minimal ability to induce class I chromosomally mediated beta-lactamase enzymes. Piperacillin/tazobactam's expanded activity appears encouraging in the treatment of mixed aerobic and anaerobic infections. Direct comparisons of ticarcillin/clavulanate and piperacillin/tazobactam for the treatment of lower respiratory tract infections showed piperacillin/tazobactam to be clinically superior, and in the treatment of skin and soft tissue infections the 2 agents were comparable. For the treatment of intraabdominal infections, piperacillin/tazobactam was at least as effective as imipenem/cilastatin and clindamycin plus gentamicin. The combination of tazobactam with piperacillin results in an antimicrobial agent with enhanced activity against most beta-lactamase-producing organisms. Preliminary data indicate that piperacillin/tazobactam has proven clinical efficacy in the treatment of a variety of infections, especially polymicrobic infections.

Evolution of β-lactamase inhibitors

beta-Lactamases present the greatest single challenge to beta-lactam antibiotics, including piperacillin. beta-Lactamase-mediated resistance to supposedly beta-lactamase stable agents such as second- and third-generation cephalosporins is now emerging and inhibitor combinations provide an alternative strategy to overcome this problem. The success of this strategy depends on 1) how efficiently the inhibitor inhibits important beta-lactamases, 2) on how much beta-lactamase the bacteria produce, 3) on the drug that is to be protected, 4) on the permeability and intrinsic susceptibility of the organisms and 5) on the conditions, notably the pH. Tazobactam inhibits most of the clinically important beta-lactamases that give piperacillin resistance, except for the Class I types. Piperacillin itself is a relatively easy drug to protect, particularly against the TEM-type enzymes. The result is that tazobactam greatly extends the activity of piperacillin, notably against enterobacteria, but also against staphylococci and anaerobes. The survey confirmed the very broad spectrum of activity of piperacillin/tazobactam. Resistance occurred in about 17% of the Enterobacter, Citrobacter, Serratia group, where we believe it to have been caused by derepressed Class I enzymes since these strains were cross-resistant to third-generation cephalosporins. Otherwise, resistance was largely confined to such organisms as E. faecium and methicillin-resistant staphylococci, which have piperacillin insensitive penicillin-binding proteins. Finally, some question remains on the antistaphylococcal activity of piperacillin/tazobactam, where MIC tests gave a more favorable impression than disc tests. Nevertheless, early clinical results against staphylococcal infection appear good, with a response rate of nearly 90% [15].

Piperacillin/tazobactam. A review of its antibacterial activity, pharmacokinetic properties and therapeutic potential.

Combining tazobactam, a beta-lactamase inhibitor, with the ureidopenicillin, piperacillin, successfully restores the activity of piperacillin against beta-lactamase-producing bacteria. Tazobactam has inhibitory activity, and therefore protects piperacillin against Richmond and Sykes types II, III, IV and V beta-lactamases, staphylococcal penicillinase and extended-spectrum beta-lactamases. However, tazobactam has only species-specific activity against class I chromosomally-mediated enzymes. Resistant organisms include some Citrobacter spp., Enterobacter spp., Serratia spp., Xanthomonas maltophilia and Enterococcus faecium. Consistent with its in vitro activity, preliminary clinical data indicate that the fixed combination of piperacillin/tazobactam (dose ratio 8:1) is effective in the treatment of moderate to severe polymicrobial infections, including intra-abdominal, skin and soft-tissue and lower respiratory tract infections. In limited comparative trials, piperacillin/tazobactam demonstrated equivalent or better efficacy than standard comparator regimens in these infections. Piperacillin/tazobactam in combination with an aminoglycoside was effective in the empirical treatment of fever in patients with neutropenia and compared favourably with ceftazidime in combination with an aminoglycoside, although second-line therapy with a glycopeptide antibiotic may be indicated in unresponsive episodes. Data from phase III trials indicate that piperacillin/tazobactam has a tolerability profile typical of a penicillin agent. Piperacillin/tazobactam provides a broad spectrum of antibacterial activity in a convenient single formulation suitable for use in the treatment of polymicrobial infections. Possible limitations concern its restricted activity against class I beta-lactamases, enzymes that are becoming increasingly important in the nosocomial environment. Combined therapy with an aminoglycoside may be necessary in more serious infections.

Effect of pH and CO2 on in vitro susceptibility of Pseudomonas cepacia to beta-lactams.

Inhibition of Pseudomonas cepacia (but not Pseudomonas aeruginosa) by beta-lactams was decreased in 5% CO2 in air compared with air alone. The effect of CO2 and pH (range, 6.0 to 8.0) on beta-lactam susceptibility, beta-lactamase expression, and outer membrane proteins was studied in isolates recovered from the sputum of children with cystic fibrosis. Incubation in 5% CO2 decreased the activity of piperacillin, piperacillin/tazobactam, and ceftazidime, although isolates were still clinically sensitive (minimum inhibitory concentrations < 16 mg/L). Cefpirome activity was markedly decreased from a minimum inhibitory concentration of 2.0 to greater than 64 mg/L. On highly buffered 3-(N-morpholino)-propane sulfonic acid media, beta-lactam susceptibility was eliminated at pH greater 7.5. A 2- to 13-fold increase in beta-lactamase activity was demonstrated after growth in 5% CO2 compared with basal aerobic levels for 13 of 15 clinical isolates. beta-Lactamase activity did not vary significantly with pH. Addition of imipenem to media (2.0 mg/L) resulted in hyperproduction of beta-lactamase (180-fold). Isoelectric points varied with cultural conditions, and all beta-lactamases detected were inhibited by clavulanate and tazobactam. Significant hydrolysis of piperacillin and ceftazidime could not be demonstrated. A 36-kD porin was present at all pH tested. Thus, our strains of Pseudomonas cepacia were markedly affected by cultural conditions not normally used in standardized susceptibility tests. However, such conditions may be encountered in the pathologically altered infected lung in cystic fibrosis.

Antimicrobial activity of piperacillin with tazobactam, a new betalactamase inhibitor, in vitro against recent clinical isolates

Antimicrobial activity of piperacillin with tazobactam, a new betalactamase inhibitor, <I>in vitro</I> against recent clinical isolates

Susceptibility of β-lactamase-producing enterococci to piperacillin with tazobactam

The in vitro activity of piperacillin with and without tazobactam was evaluated against different inocula of 12 clinical isolates of β-lactamase-producing Enterococcus faecalis obtained from different geographic areas. Minimum inhibitory concentrations (MICs) of piperacillin alone at ∼10 3 colony-forming units (CFU)/spot ranged from 4 to 8 and from 4 to 8 μg/ml with piperacillin plus tazobactam. When ∼10 7 CFU/spot was used, MICs increased to a range of 128–1024 μg/ml piperacillin. This inoculum effect was reversed by the addition of tazobactam to piperacillin at a fixed concentration of 1 μg/ml or at a ratio of 8 : 1 (piperacillin relative to tazobactam) with an MIC 90 of 16 2 μ g/ml for the combination drug. In time-kill studies, four β-lactamase-producing (Bla +) cisolates were tested and demonstrated a decrease of ≥2 log 10 with 8 or 16 μg/ml of piperacillin in combination with 4 μg of tazobactam, but not with piperacillin alone. A non-β-lactamase-producing isolate was equally inhibited by piperacillin alone and piperacillin plus tazobactam. Against a Bla + isolate, the combination of piperacillin with tazobactam with streptomycin resulted in a synergistic effect relative to that of piperacillin with tazobactam; piperacillin plus streptomycin did not show synergism. Piperacillin in combination with tazobactam is active against enterococci that produce β-lactamase and, in combination with an appropriate aminoglycoside, could be a viable choice for therapy of enterococci that do not have high-level resistance to all aminoglycosides.

Piperacillin, tazobactam, and gentamicin alone or combined in an endocarditis model of infection by a TEM-3-producing strain of Klebsiella pneumoniae or its susceptible variant.

The efficacy of tazobactam, a beta-lactamase inhibitor, in combination with piperacillin, was studied in vitro and in rabbit experimental endocarditis due to a Klebsiella pneumoniae strain (KpR) producing an extended-spectrum beta-lactamase, TEM-3, or its nonproducing variant (KpS). In vitro, piperacillin was active against KpS (MIC = 4 micrograms/ml, MBC = 8 micrograms/ml with 10(7)-CFU/ml inoculum) but not against KpR (MIC = MBC = 256 micrograms/ml). Tazobactam (1 microgram/ml) restored the activity of piperacillin against KpR (MIC = 2 micrograms/ml, MBC = 4 micrograms/ml). Gentamicin was active against both strains (MIC = 0.25 and 0.5 micrograms/ml for KpS and KpR, respectively). The piperacillin-tazobactam-gentamicin combination was synergistic in vitro. The piperacillin/tazobactam ratio in plasma and in vegetations was always lower than the 4/1 injected dose ratio. In vivo, piperacillin (300 mg/kg of body weight four times a day [QID]) was active against KpS but not against KpR. Tazobactam (75 mg/kg QID) was able to restore the in vivo effect of piperacillin (300 mg/kg QID) against KpR (-3.0 log10 CFU/g of vegetation versus that of controls). Gentamicin (4 mg/kg twice a day [BID]) was active against both strains. Compared with controls, the combination of gentamicin plus piperacillin against KpS (-5.6 log10 CFU/g of vegetation), and the gentamicin-piperacillin-tazobactam combination against KpR (-4.4 log10 CFU/g of vegetation) achieved the greatest decrease in bacterial counts in vegetations and were the only regimens that significantly increased the proportion of sterile vegetations. It is concluded that (i) tazobactam was able to restore the effect of piperacillin against a TEM-3 extended-spectrum Beta-lactamase-producing strain of K. pneumoniae, both in vitro and in a severe experimental infection with high inoculum, when used in a 4/1 piperacillin/tazobactam dose ratio; (ii) gentamicin alone was effective because of the high peak/MBC ratio in plasma; (iii) piperacillin-tazobactam-gentamicin, probably because of the effect of gentamicin in reducing bacterial inoculum in vivo, as stressed by the results obtained by piperacillin-gentamicin against KpS, may be the most effective regimen against KpR.