piperacillin--tazobactam-drug-combination and Disease-Models--Animal

As Bacillus anthracis spores pose a proven bio-terror risk, the treatment focus has shifted from exposed populations to anthrax patients and the need for effective antibiotic treatment protocols increases. The CDC recommends carbapenems and Linezolid (oxazolidinone), for the treatment of anthrax, particularly for the late, meningeal stages of the disease. Previously we demonstrated that treatment with Meropenem or Linezolid, either as a single treatment or in combination with Ciprofloxacin, fails to protect rabbits from anthrax-meningitis. In addition, we showed that the failure of Meropenem was due to slow BBB penetration rather than low antibacterial activity. Herein, we tested the effect of increasing the dose of the antibiotic on treatment efficacy. We found that for full protection (88% cure rate) the dose should be increased four-fold from 40 mg/kg to 150 mg/kg. In addition, B. anthracis is a genetically stable bacterium and naturally occurring multidrug resistant B. anthracis strains have not been reported. In this manuscript, we report the efficacy of classical β-lactams as a single treatment or in combination with β-lactamase inhibitors in treating anthrax meningitis. We demonstrate that Ampicillin based treatment of anthrax meningitis is largely efficient (66%). The high efficacy (88-100%) of Augmentin (Amoxicillin and Clavulonic acid) and Unasyn (Ampicillin and Sulbactam) makes them a favorable choice due to reports of β-lactam resistant B. anthracis strains. Tazocin (Piperacillin and Tazobactam) proved inefficient compared to the highly efficient Augmentin and Unasyn.

Topics: Amoxicillin-Potassium Clavulanate Combination; Ampicillin; Animals; Anthrax; Anti-Bacterial Agents; Bacillus anthracis; Bacteria; beta-Lactamase Inhibitors; beta-Lactams; Disease Models, Animal; Dose-Response Relationship, Drug; Humans; Meropenem; Microbial Sensitivity Tests; Piperacillin, Tazobactam Drug Combination; Rabbits; Sulbactam

Implementing a mouse model of Acinetobacter baumannii (AB) digestive colonization and studying the propensity of an intestinal reservoir of AB to be at the origin of pneumonia.. After a disruption of the digestive flora by piperacillin-tazobactam, two multidrug-resistant AB strains were intranasally inoculated to two cohorts of ten mice daily. For each strain, five mice were rendered transiently neutropenic.. One strain persisted several weeks in the digestive tract, even after stopping piperacillin-tazobactam injections, leading to the hypothesis that some AB strains can authentically colonize the gut. Most of the immunocompromised mice experienced clinical signs and positive lung cultures, which were associated with positive spleen cultures, an argument in favor of bacterial translocation.

Topics: Acinetobacter; Acinetobacter Infections; Animals; Anti-Bacterial Agents; Bacterial Translocation; Disease Models, Animal; Drug Resistance, Multiple, Bacterial; Gastrointestinal Tract; Immunosuppression Therapy; Lung; Mice; Neutropenia; Penicillanic Acid; Piperacillin; Piperacillin, Tazobactam Drug Combination; Pneumonia, Bacterial

Sub-inhibitory concentrations of antibiotics are always generated as a consequence of antimicrobial therapy and the effects of such residual products in bacterial morphology are well documented, especially the filamentation generated by beta-lactams. The aim of this study was to investigate some morphological and pathological aspects (virulence factors) of Escherichia coli cultivated under half-minimum inhibitory concentration (1.0 µg/mL) of piperacillin-tazobactam (PTZ sub-MIC). PTZ sub-MIC promoted noticeable changes in the bacterial cells which reach the peak of morphological alterations (filamentation) and complexity at 16 h of antimicrobial exposure. Thereafter the filamentous cells and a control one, not treated with PTZ, were comparatively tested for growth curve; biochemical profile; oxidative stress tolerance; biofilm production and cell hydrophobicity; motility and pathogenicity in vivo. PTZ sub-MIC attenuated the E. coli growth rate, but without changes in carbohydrate fermentation or in traditional biochemical tests. Overall, the treatment of E. coli with sub-MIC of PTZ generated filamentous forms which were accompanied by the inhibition of virulence factors such as the oxidative stress response, biofilm formation, cell surface hydrophobicity, and motility. These results are consistent with the reduced pathogenicity observed for the filamentous E. coli in the murine model of intra-abdominal infection. In other words, the treatment of E. coli with sub-MIC of PTZ suggests a decrease in their virulence.

Topics: Animals; Anti-Bacterial Agents; Biofilms; Disease Models, Animal; Escherichia coli; Escherichia coli Infections; Intraabdominal Infections; Locomotion; Metabolism; Mice; Microbial Sensitivity Tests; Penicillanic Acid; Piperacillin; Piperacillin, Tazobactam Drug Combination; Virulence

Recent findings have identified Escherichia coli strains that are pan-β-lactam susceptible (PBL-S) but piperacillin-tazobactam resistant (TZP-R) in vitro We assessed the in vivo significance of this resistance profile in a neutropenic murine pneumonia model using humanized exposures of TZP with 18 clinical E. coli isolates, 8 TZP-S/PBL-S and 10 genotypically confirmed TZP-R/PBL-S. Despite phenotypically and genotypically defined resistance, TZP displayed efficacy against these isolates. Additional studies are required to define the clinical implications of these TZP-R/PBL-S strains.

Topics: Animals; Anti-Bacterial Agents; Cephalosporins; Colistin; Culture Media; Disease Models, Animal; Drug Administration Schedule; Drug Resistance, Bacterial; Escherichia coli; Escherichia coli Infections; Female; Humans; Mice; Mice, Inbred ICR; Microbial Sensitivity Tests; Neutropenia; Penicillanic Acid; Piperacillin; Piperacillin, Tazobactam Drug Combination; Tobramycin; Treatment Outcome

Negligible in vivo growth of enterococci and high-level dispersion of data have led to inaccurate estimations of antibiotic pharmacodynamics (PD). Here we improved an in vivo model apt for PD studies by optimizing the in vitro culture conditions for enterococci. The PD of vancomycin (VAN), ampicillin-sulbactam (SAM), and piperacillin-tazobactam (TZP) against enterococci were determined in vivo, comparing the following different conditions of inoculum preparation: aerobiosis, aerobiosis plus mucin, and anaerobiosis plus mucin. Drug exposure was expressed as the ratio of the area under the concentration-time curve for the free, unbound fraction of the drug to the MIC (fAUC/MIC) (VAN) or the time in a 24-h period that the drug concentration for the free, unbound fraction exceeded the MIC under steady-state pharmacokinetic conditions (fT(>MIC)) (SAM and TZP) and linked to the change in log10 CFU/thigh. Only anaerobiosis plus mucin enhanced the in vivo growth, yielding significant PD parameters with all antibiotics. In conclusion, robust in vivo growth of enterococci was crucial for better determining the PD of tested antibacterial agents, and this was achieved by optimizing the procedure for preparing the inoculum.

Topics: Ampicillin; Anaerobiosis; Animals; Anti-Bacterial Agents; Disease Models, Animal; Enterococcus faecalis; Female; Gram-Positive Bacterial Infections; Mice, Inbred ICR; Microbial Sensitivity Tests; Mucins; Penicillanic Acid; Piperacillin; Piperacillin, Tazobactam Drug Combination; Sulbactam; Vancomycin

Evidence from a recent randomized study of our group suggests that intravenous clarithromycin resulted in earlier resolution of ventilator-associated pneumonia. The need to understand the mechanism of action of clarithromycin guided to the study of a model of experimental empyema by multidrug-resistant Pseudomonas aeruginosa in 40 rabbits. Animals were randomized into controls (group A); treatment with clarithromycin (group B); treatment with piperacillin/tazobactam (group C); and treatment with both agents (group D). Pleural fluid was collected at regular time intervals for quantitative culture, estimation of cell apoptosis and of concentrations of tumour necrosis factor-alpha (TNFα). After 7 days, animals were euthanized for estimation of tissue growth. Bacterial growth in the pleural fluid of group D was significantly decreased compared with the other groups on day 5. Lung growth of group D was lower than group A. That was also the case of cytokine stimulation by pleural fluid samples on U937 monocytes. It is concluded that administration of clarithromycin enhanced the antimicrobial efficacy of piperacillin/tazobactam and decreased bacterial growth in the pleural fluid and in tissues. It also attenuated the pro-inflammatory phenomena induced by the β-lactam.

Topics: Adjuvants, Immunologic; Animals; Anti-Bacterial Agents; Apoptosis; Clarithromycin; Disease Models, Animal; Drug Resistance, Multiple, Bacterial; Drug Therapy, Combination; Empyema, Pleural; Humans; Interleukin-6; Male; Penicillanic Acid; Piperacillin; Piperacillin, Tazobactam Drug Combination; Pleural Effusion; Pseudomonas aeruginosa; Pseudomonas Infections; Rabbits; Tumor Necrosis Factor-alpha; U937 Cells

The inoculum effect is a laboratory phenomenon in which the minimal inhibitory concentration (MIC) of an antibiotic is increased when a large number of organisms are exposed. Due to the emergence of extended-spectrum β-lactamase-producing Klebsiella pneumoniae (ESBL-Kpn) infections, the inoculum effect of ESBL-Kpn on β-lactams was studied in vitro and in vivo using an experimental model of pneumonia. The in vitro inoculum effect of 45 clinical ESBL-Kpn isolates on β-lactams was evaluated at standard (10(5) CFU/mL) and high (10(7) CFU/mL) organism concentrations. The MIC50 of piperacillin-tazobactam, cefotaxime and cefepime was increased eight-fold or more and that of meropenem was increased two-fold. The in vivo inoculum effect was evaluated in an ESBL-Kpn pneumonia mouse model treated with bacteriostatic effect-adjusted doses of piperacillin-tazobactam (1000 mg/kg four times daily, %T>MIC; 32.60%) or meropenem (100 mg/kg twice daily, %T>MIC; 28.65%) at low/standard (10(4) CFU/mouse) and high (10(6) CFU/mouse) inocula. In mice administered a low inoculum, no mice died after treatment with piperacillin-tazobactam or meropenem, whereas all the control mice died. In contrast, in the high inoculum model, all mice in the piperacillin-tazobactam-treated group died, whereas all meropenem-treated mice survived and had a decreased bacterial load in the lungs and no invasion into the blood. In conclusion, meropenem was more resistant to the inoculum effect of ESBL-Kpn than piperacillin-tazobactam both in vitro and in vivo. In the management of severe pneumonia caused by ESBL-Kpn, carbapenems may be the drugs of choice to achieve a successful outcome.

Topics: Animals; Anti-Bacterial Agents; Bacterial Load; Disease Models, Animal; Klebsiella Infections; Klebsiella pneumoniae; Lung; Male; Meropenem; Mice, Inbred BALB C; Microbial Sensitivity Tests; Penicillanic Acid; Piperacillin; Piperacillin, Tazobactam Drug Combination; Pneumonia, Bacterial; Survival Analysis; Thienamycins

The aim of this study was to compare ceftolozane with ceftazidime, piperacillin/tazobactam (TZP) and imipenem in an experimental rabbit model of Pseudomonas aeruginosa pneumonia. Efficacy was assessed following 2 days of treatment by total colony counts in different tissues (lung, spleen and blood culture). Mean ± standard deviation pulmonary bacterial loads were 4.9 ± 0.3, 3.6 ± 0.3, 4.8 ± 0.2, 5.5 ± 0.8 and 3.9 ± 0.3 log₁₀CFU/g of lung for ceftolozane (1g), ceftolozane (2g), ceftazidime, TZP and imipenem, respectively, compared with 6.3 ± 0.9 log₁₀CFU/g of lung for control animals. The higher ceftolozane dose [2g three times daily (t.i.d.)] showed significantly better efficacy than the lower dose (1g t.i.d.). In conclusion, in this rabbit model of P. aeruginosa pneumonia, ceftolozane had an efficacy equivalent to that of comparator agents at a dose of 1g t.i.d. and had better efficacy at a higher dose (2g t.i.d.).

Topics: Animal Structures; Animals; Anti-Bacterial Agents; Bacterial Load; Ceftazidime; Cephalosporins; Colony Count, Microbial; Disease Models, Animal; Female; Humans; Imipenem; Penicillanic Acid; Piperacillin; Piperacillin, Tazobactam Drug Combination; Pneumonia, Bacterial; Pseudomonas aeruginosa; Pseudomonas Infections; Rabbits; Treatment Outcome

Dodecapeptide SC4 is a broad-spectrum bactericidal agent that functions by disintegrating bacterial membranes and neutralizing endotoxins. For insight into which SC4 amino acids are functionally important, we assessed Gram-negative bactericidal effects in structure-activity relationship experiments. Subsequently, SC4 was tested in a murine bacteremia model to combine and compare the efficacy with Zosyn, a first-line antibiotic against Pseudomonas aeruginosa (P. aeruginosa).. SC4 alanine-scanning analogs and their activities on were tested on P. aeruginosa. Survival studies in P. aeruginosa challenged mice were executed to monitor overall efficacy of SC4 and Zosyn, as a single modality and also as combination treatment. ELISAs were used to measure blood serum levels of selected inflammatory cytokines during treatment.. Cationic residues were found to play a crucial role in terms of bactericidal activity against P. aeruginosa. In vivo, while only 9% (3/34) of control animals survived to day two and beyond, 44% (12/27) to 41% (14/34) of animals treated with SC4 or Zosyn, respectively, survived beyond one week. Combination treatment of SC4 and Zosyn demonstrated improved survival, i.e. 60% (12/20). The TNFα, IL-1, and IL-6 serum levels were attenuated in each treatment group compared to the control group.. These data show that combination treatment of SC4 and Zosyn is most effective at killing P. aeruginosa and attenuating inflammatory cytokine levels in vivo.. Combination treatment of SC4 and Zosyn may be useful in the clinic as a more effective antibiotic therapy against Gram-negative infectious diseases.

Topics: Animals; Anti-Bacterial Agents; Bacteremia; Cytokines; Disease Models, Animal; Inflammation Mediators; Male; Mice; Penicillanic Acid; Peptide Fragments; Piperacillin; Piperacillin, Tazobactam Drug Combination; Pseudomonas aeruginosa; Pseudomonas Infections; Time Factors

Topics: Animals; Anti-Bacterial Agents; beta-Lactamases; Disease Models, Animal; Drug Resistance, Bacterial; Escherichia coli; Escherichia coli Infections; Humans; Mice; Microbial Sensitivity Tests; Nociceptive Pain; Penicillanic Acid; Piperacillin; Piperacillin, Tazobactam Drug Combination; Staphylococcal Infections

CXA-101 is a novel antipseudomonal cephalosporin with enhanced activity against Gram-negative organisms displaying various resistance mechanisms. This study evaluates the efficacy of exposures approximating human percent free time above the MIC (%fT > MIC) of CXA-101 with or without tazobactam and piperacillin-tazobactam (TZP) against target Gram-negative organisms, including those expressing extended-spectrum β-lactamases (ESBLs). Sixteen clinical Gram-negative isolates (6 Pseudomonas aeruginosa isolates [piperacillin-tazobactam MIC range, 8 to 64 μg/ml], 4 Escherichia coli isolates (2 ESBL and 2 non-ESBL expressing), and 4 Klebsiella pneumoniae isolates (3 ESBL and 1 non-ESBL expressing) were used in an immunocompetent murine thigh infection model. After infection, groups of mice were administered doses of CXA-101 with or without tazobactam (2:1) designed to approximate the %fT > MIC observed in humans given 1 g of CXA-101 with or without tazobactam every 8 h as a 1-h infusion. As a comparison, groups of mice were administered piperacillin-tazobactam doses designed to approximate the %fT > MIC observed in humans given 4.5 g piperacillin-tazobactam every 6 h as a 30-min infusion. Predicted piperacillin-tazobactam %fT > MIC exposures of greater than 40% resulted in static to >1 log decreases in CFU in non-ESBL-expressing organisms with MICs of ≤32 μg/ml after 24 h of therapy. Predicted CXA-101 with or without tazobactam %fT > MIC exposures of ≥37.5% resulted in 1- to 3-log-unit decreases in CFU in non-ESBL-expressing organisms, with MICs of ≤16 μg/ml after 24 h of therapy. With regard to the ESBL-expressing organisms, the inhibitor combinations showed enhanced CFU decreases versus CXA-101 alone. Due to enhanced in vitro potency and resultant increased in vivo exposure, CXA-101 produced statistically significant reductions in CFU in 9 isolates compared with piperacillin-tazobactam. The addition of tazobactam to CXA-101 produced significant reductions in CFU for 7 isolates compared with piperacillin-tazobactam. Overall, human simulated exposures of CXA-101 with or without tazobactam demonstrated improved efficacy versus piperacillin-tazobactam.

Topics: Animals; Anti-Bacterial Agents; beta-Lactamases; Cephalosporins; Colony Count, Microbial; Disease Models, Animal; Drug Combinations; Drug Resistance, Bacterial; Escherichia coli; Escherichia coli Infections; Female; Humans; Klebsiella Infections; Klebsiella pneumoniae; Mice; Mice, Inbred ICR; Microbial Sensitivity Tests; Penicillanic Acid; Phenotype; Piperacillin; Piperacillin, Tazobactam Drug Combination; Pseudomonas aeruginosa; Pseudomonas Infections; Tazobactam; Thigh

β-Tricalcium phosphate (TCP) has good biodegradability and osteoconductivity as a scaffold material for bone tissue engineering. Both block and granular forms are available; however, it has been associated with risk of infection and exposure. To this end, the study evaluated the effect of piperacillin-tazobactam coated β-TCPs for mastoid obliteration in otitis media.. Ten guinea pigs were divided into the experimental (piperacillin-tazobactam coated β-TCP granules, n=5) and control groups (uncoated β-TCP granules, n=5). After mastoid obliteration, transtympanic injection with a saline suspension of lipopolysaccharide established inflammation. The animals were sacrificed 5 weeks later. Tissue sections were stained with hematoxylin and eosin and examined.. Encapsulation and formation of fibrous capsule by foreign material in the bulla were not evident. The histological evaluation did not reveal inflammatory cells and fibrosis in the piperacillin-tazobactam coated β-TCP group. In contrast, the control group showed numerous inflammatory cells around the implanted uncoated β-TCP granules and incomplete new bone formation.. β-TCP is an effective carrier material for piperacillin-tazobactam. The use of piperacillin-tazobactam coated β-TCP may be optimal for mastoid obliteration.

Topics: Animals; Calcium Phosphates; Coated Materials, Biocompatible; Disease Models, Animal; Guinea Pigs; Male; Mastoid; Otitis Media; Penicillanic Acid; Piperacillin; Piperacillin, Tazobactam Drug Combination; Plastic Surgery Procedures; Random Allocation; Reference Values; Tissue Scaffolds; Treatment Outcome; Tympanoplasty

In this study, an appropriate sepsis model was created in rats. Additionally, the effects of steroid treatments on survival, in connection with antibiotic treatment, were investigated. The sepsis model performed via intraperitoneal injection of 3 ml/kg fecal suspension was determined as the most appropriate model for our study. Fifteen rats were used to investigate the effect of piperacillin-tazobactam on sepsis treatment. Forty-five randomly selected rats were used to investigate the efficacy of the antibiotic-plus-steroid combination. The rats were divided into three groups of 15 rats each. Twelve hours after the administration of fecal suspension, methylprednisolone (MP) at the dose of 0.25, 0.5, and 2 mg/kg/day was given to each group, respectively, in addition to an antibiotic administered intravenously. In order to investigate the effect of steroids alone in the treatment of sepsis, 0.5 mg/kg/day MP was given intravenously to 15 rats, 12 h after the fecal suspension was administered. It was concluded that administration of MP alone shortens survival time in rats with sepsis, whereas antibiotic therapy alone increases survival time significantly in rats with sepsis. It was seen that the antibiotic-plus-steroid treatment increases survival significantly compared to rats with no treatment (p < 0.05). In addition, steroids, when added to an antibiotic treatment in sepsis, affect survival positively when compared to the group with antibiotic therapy alone, depending on the dose given. Although, not statistically significant, high doses decrease survival (p > 0.05), and very low doses increase survival and mean survival time (p > 0.05) on the basis of clinical observation and average life time. However, low doses were found to increase survival significantly (p < 0.05). We concluded that low-dose MP, in addition to the appropriate antibiotic therapy, is the optimal in the treatment of rats with intraabdominal sepsis.

Topics: Animals; Disease Models, Animal; Methylprednisolone; Penicillanic Acid; Piperacillin; Piperacillin, Tazobactam Drug Combination; Rats; Rats, Sprague-Dawley; Sepsis

We investigated the efficacy of Tachyplesin III alone or combined with piperacillin-tazobactam (TZP) to prevent biofilm formation in vitro and in a rat model of Pseudomonas aeruginosa ureteral stent infection. We have observed that in vitro TZP, in presence of Tachyplesin III, showed minimal inhibitory concentrations (MIC)s twofold and minimal bactericidal concentrations (MBC)s eightfold lower. The in vivo study showed that rats that received intraperitoneal TZP showed the lowest bacterial numbers. Tachyplesin III combined with TZP showed efficacies higher than that of each single compound. Coating ureteral stents with Tachyplesin III is able to inhibit bacterial growth up to 1,000 times.

Topics: Animals; Anti-Bacterial Agents; Antimicrobial Cationic Peptides; Bacterial Adhesion; Biofilms; Colony Count, Microbial; Disease Models, Animal; DNA-Binding Proteins; Drug-Eluting Stents; In Vitro Techniques; Male; Penicillanic Acid; Peptides, Cyclic; Piperacillin; Piperacillin, Tazobactam Drug Combination; Pseudomonas aeruginosa; Pseudomonas Infections; Rats; Rats, Wistar; Ureteral Diseases

Chronic bone and soft tissue suppurations have become more frequent recently due to the increasing number of high-energy injuries. There are certain antibiotic beads available for local administration, but they cannot always be applied specifically against the pyogenic microorganisms. In the present study, a new technique of local antibiotic therapy for the treatment of infections is described. Polymethylmethacrylate (PMMA) capsules were produced and filled with 0.1 ml Tazocin (0.02 g piperacillin sodium + 0.005 g tazobactam). The efficacy of these Tazocin-filled capsules was examined in vivo using a rabbit osteomyelitis model. Chronic osteomyelitis was induced in rabbit tibia by local injection of Staphylococcus aureus. The treatment included surgical debridement and implantation of Tazocin-containing PMMA capsules into the medullar cavity (n = 12). Simple surgical debridement with no antibiotic implantation was performed in control animals (n = 7). Results were evaluated using microbiological, radiological and histological methods 14 weeks after induction of osteomyelitis. Eight weeks after the implantation of PMMA capsules, complete physical, radiological and histological healing was achieved in 7 animals, initiation of the reparative phase was observed histologically in 3 cases and no reparative signs were detected in 2 rabbits. In the control group, no significant sign of reparation could be seen in any of the cases.

Topics: Animals; Anti-Bacterial Agents; Capsules; Chronic Disease; Delayed-Action Preparations; Disease Models, Animal; Drug Implants; Male; Osteomyelitis; Penicillanic Acid; Piperacillin; Piperacillin, Tazobactam Drug Combination; Polymethyl Methacrylate; Rabbits; Staphylococcal Infections; Staphylococcus aureus; Tibia

We compared ceftriaxone and piperacillin-tazobactam at doses ranging from 0.1 to 2 times the human equivalent daily dose (HEDD), to determine their impact on gastrointestinal colonization by ampicillin- and vancomycin-resistant Enterococcus faecium C68 in a mouse model. Ceftriaxone failed to promote colonization at doses up to 0.25 times the HEDD, whereas piperacillin-tazobactam promoted colonization at doses up to 0.5 times the HEDD. Ceftriaxone promoted colonization at doses at least 0.5 times the HEDD, whereas piperacillin-tazobactam inhibited colonization at doses at least 0.75 times the HEDD. Both piperacillin-tazobactam and ceftriaxone inhibited colonization by an enterococcal strain devoid of low-affinity penicillin-binding protein-5 (significantly increasing its susceptibility to these agents), at doses that promoted colonization by E. faecium C68. These results support a model in which the impact that different beta -lactam agents have on colonization by VRE is related to the level of the beta -lactam agent's intrinsic antienterococcal activity against the colonizing strain.

Topics: Animals; Anti-Bacterial Agents; Carrier State; Ceftriaxone; Colony Count, Microbial; Disease Models, Animal; Dose-Response Relationship, Drug; Drug Resistance, Multiple, Bacterial; Enterococcus faecium; Feces; Female; Gastrointestinal Tract; Gram-Positive Bacterial Infections; Mice; Penicillanic Acid; Piperacillin; Piperacillin, Tazobactam Drug Combination

The antibacterial activity of imipenem, cefepime and piperacillin-tazobactam alone or in combination with amikacin against a Pseudomonas aeruginosa strain producing an extended-spectrum beta-lactamase (PER-1) were compared using an experimental model of pneumonia in non-leucopenic rats. Animals were infected intratracheally with 8.0 +/- 0.4 log10 cfu of P. aeruginosa, and therapy was initiated 3 h later, by which time animal lungs showed bilateral pneumonia containing >7 log10 P. aeruginosa cfu/g of tissue. Since rats eliminate antibiotics much more rapidly than humans, renal impairment was induced in all animals to simulate the pharmacokinetic parameters of humans. MICs determined using an inoculum of 4 log10 cfu/mL were as follows: imipenem, 1 mg/L; cefepime, 8 mg/L; piperacillin-tazobactam, 32 mg/L; and amikacin, 16 mg/L. A noticeable inoculum effect was observed with the four antimicrobial agents tested, which was greatest for cefepime and piperacillin-tazobactam. In-vitro studies indicated that imipenem was the beta-lactam with the greatest bactericidal effect and that amikacin was synergic only in combination with cefepime and imipenem. Cefepime and piperacillin-tazobactam alone failed to decrease bacterial counts in the rats' lungs 60 h after therapy onset, whereas imipenem and, to a lesser extent, amikacin significantly reduced the number of viable microorganisms. Combination of amikacin with any of the three beta-lactams tested was synergic, despite a high amikacin MIC for the infecting strain. These results paralleled our in-vitro data showing a marked inoculum effect for cefepime and piperacillin-tazobactam. Based on the results of this study, the best treatment for infections caused by this type of extended-spectrum beta-lactamase-possessing strain would be imipenem plus amikacin.

Topics: Amikacin; Animals; Anti-Bacterial Agents; beta-Lactamases; Cefepime; Cephalosporins; Colony Count, Microbial; Disease Models, Animal; Drug Synergism; Drug Therapy, Combination; Imipenem; Lung; Male; Microbial Sensitivity Tests; Penicillanic Acid; Piperacillin; Piperacillin, Tazobactam Drug Combination; Pneumonia, Bacterial; Pseudomonas aeruginosa; Pseudomonas Infections; Rats; Rats, Wistar