a RA Cowley Shock Trauma Center, University of Maryland, Baltimore, MD; b Dayton VA Medical Center, Wright State University, Dayton, OH; c Division of Surgical Infectious Diseases, University of Cincinnati College of Medicine, Cincinnati, OH; d Wyeth-Ayerst Research, Radnor, PA; e Wyeth-Ayerst Research, current address: Pfizer Central Research, Groton, CT, USA
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Abstract |
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Introduction |
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Mortality rates associated with nosocomial pneumonia range from 20% to 70%; 2 it is estimated that as many as 15% of all deaths occurring in hospitalized patients are directly related to nosocomial pneumonia. 3 In addition, there are increases in morbidity, including time in intensive care units. 4
Although the aetiological pathogens implicated in nosocomial LRTI are diverse, aerobic Gram-negative bacilli account for approximately 60% of LRTI and Staphylococcus aureus is the second most frequent individual bacterial aetiological agent. 1 Recently it has been recognized that a substantial number of nosocomial pneumonia cases are polymicrobial in nature. 2
Therapy of nosocomial pneumonia involves the use of iv antibiotics plus supportive measures (pulmonary toilet, oxygen, assisted ventilation, etc.). In most cases, the aetiology of nosocomial pneumonia is unclear initially and the empirical use of broad-spectrum antimicrobial therapy is necessary.
In-vitro testing involving over 50,000 clinical isolates showed that >90% of aerobic Gram-negative strains, 98 of Gram-positive strains and nearly 100% of anaerobes were susceptible to piperacillin/tazobactam. 5
In both comparative and non-comparative, multicentre clinical trials, piperacillin/tazobactam has been shown to be safe and effective in the treatment of serious LRTI in hospitalized patients. 6,7 The present study was designed to compare the safety and efficacy of piperacillin/tazobactam plus tobramycin with ceftazidime plus tobramycin, given iv to patients with nosocomial LRTI.
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Materials and methods |
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Patient selection
Male or female hospitalized patients, with a minimum age of 16 years, suffering from a clinically or bacteriologically confirmed diagnosis of hospital-acquired LRTI caused by bacteria thought to be susceptible to piperacillin/ tazobactam and ceftazidime were eligible for entry into the study. A `hospital-acquired infection' was defined as one that developed >72 h after admission to a hospital or other medical facility. Patients were randomly assigned to one of the two treatment groups based on a computer-generated randomization schedule. The randomization schedule at each centre provided for one patient to receive piperacillin/ tazobactam for every one patient who received ceftazidime. Patients must have had either acute bacterial pneumonia or acute purulent tracheobronchitis.
Clinical criteria for enrolment included: the recent onset of, or significant increase in, purulent sputum; a temperature of >38°C; and/or a peripheral white blood cell count of >10 x 109/L with >5% immature neutrophils. A pre-enrolment Gram's stain of respiratory secretions must have shown >25 polymorphonuclear cells and <10 squamous epithelial cells per field at 100x magnification and a predominant pathogen. Female patients of childbearing potential must have had a negative pregnancy test within 48 h before enrolment into the study. Also, within 48 h before enrolment, two sets of blood cultures, for both aerobic and anaerobic incubation were obtained, and a chest X-ray was used to differentiate between pneumonia and bronchitis.
Patients were excluded in cases of: known or suspected hypersensitivity to penicillins,
cephalosporins, other ß-lactam antibiotics, ß-lactamase inhibitors, or aminoglycosides;
moderate to severe renal dysfunction (creatinine clearance <40 mL/min or serum creatinine
>225 µmol/L), haemodialysis, peritoneal dialysis, plasmapheresis or haemoperfusion;
evidence of active liver disease (serum transaminases, alkaline phosphatase or bilirubin
>2x the normal upper limit); peripheral granulocyte counts 1 x 109/L or platelet counts <50 x 109/L; more than two doses of another
non-study antibacterial agent within 72 h before enrolment (unless this agent had proved to be
clinically and bacteriologically ineffective); recovery of a pathogen resistant to
piperacillin/tazobactam, ceftazidime or tobramycin; treatment with probenecid; presence of
septic shock, cystic fibrosis, active or treated leukaemia, acquired immune deficiency syndrome
or known seropositivity for HIV antigen or antibody, active tuberculosis, lung cancer or
metastatic lung disease or bronchial obstruction; a history of pneumonia, lung abscess, empyema
or pleural effusion >500 mL; administration of another investigational drug within 1 month
before enrolment; presence of concomitant infection other than hospital-acquired LRTI and
associated bacteraemia; patients requiring positive end-expiratory pressure ventilation >5 cm
H2O, patients requiring FiO2 >60% to maintain arterial haemoglobin
oxygen saturation 90%; no bacterial pathogen in pre-treatment culture of sputum or other
respiratory secretions within 72 h before enrolment; any concomitant condition which could
preclude evaluation of response or make it unlikely that the patient could complete the study.
Administration of drug
Patients were randomized to receive either piperacillin (3 g/375 mg) administered every 4 h or ceftazidime (2 g) administered every 8 h. Each dose of study medication was to be given by iv infusion over 30 min. All patients were to receive tobramycin administered iv at a dose of 5 mg/ kg/day given in divided doses every 8 h. In those patients with P. aeruginosa isolated from sputum at baseline, tobramycin was to be continued for the duration of the study. When a baseline isolate of P. aeruginosa was resistant to tobramycin, amikacin at a dose of 15 mg/kg/day could be substituted. Tobramycin could be discontinued in other patients after the baseline culture results were known. Each patient was to be treated for a minimum of 5 days, although it was recommended that in patients with a satisfactory clinical response, treatment be continued for at least 48 h after the resolution of signs and symptoms.
Study procedures
A complete medical history, physical examination and chest X-ray were performed before study entry. The severity of infection, as determined by the investigator, was assessed by a rating of mild, moderate or severe and by APACHE II score rating scale. 8 Evaluations to determine the clinical response to therapy were performed daily for the first week of therapy, every 2 to 3 days thereafter during therapy, 24 to 72 h after completion of therapy (early follow-up), and 10 to 14 days after completion of therapy (late follow-up). The endpoint was the last validated response of each patient and pathogen. A validated clinical response was any unfavourable response at any time during or after therapy, or a favourable response within 1 to 6 days post-treatment or 7 to 24 days post-treatment. A repeat chest X-ray was required only in patients with persisting clinical signs of active infection or in those who were withdrawn because of treatment failure or adverse event.
Aerobic and anaerobic cultures of blood and aerobic cultures of respiratory secretions were obtained before the start of treatment. Respiratory secretions were obtained by deep expectoration, nasotracheal aspiration, intubation with endotracheal suction, bronchoscopy with suction or brushing, transtracheal aspiration or percutaneous lung aspiration. Blood cultures were also obtained on day 3 or 4 and day 5 or 6 of therapy only if the previous blood cultures were positive. Cultures of respiratory secretions for bacteriological evaluation were obtained after 3 or 4 days on therapy, 24 to 72 h post-therapy, and 10 to 14 days post-therapy, if secretions were available. Additional blood and respiratory cultures were required only in patients with persisting clinical signs of active infection, or in those who were withdrawn because of treatment failure or adverse event. Micro-organisms were isolated and identified according to standard bacteriological methods. All isolated pathogens were tested at the study centre for susceptibility to piperacillin, piperacillin/tazobactam, ceftazidime, tobramycin and amikacin. All isolated pathogens were subcultured and sent to Lederle Laboratories, Inc., (Pearl River, NY, USA) for identification and susceptibility testing.
The safety of piperacillin/tazobactam and ceftazidime was evaluated by the following laboratory parameters: haematology including haematocrit, haemoglobin, WBC with differential, platelet count, prothrombin time, PTT and direct Coomb's test; serum chemistries including creatinine, BUN, SGOT, SGPT, alkaline phosphatase, bilirubin, albumin, total protein, glucose, calcium, sodium, potassium, chloride, arterial pH and/or venous HCO3; and urinalysis with microscopy of the sediment. Laboratory evaluations were performed before treatment, every 3 to 5 days during treatment, 24 to 72 h post-treatment, and on the last day of treatment if a patient was withdrawn early from the study. If haematology results were abnormal on a previous determination, they were repeated 10 to 14 days post-treatment, if results were normal only a full blood count with differential WBC count was performed at that time. Serum chemistries and urinalysis were repeated 10 to 14 days post-treatment only if abnormal on a previous determination.
Clinical adverse experiences were recorded and the severity and relationship to the study drugs assessed by the treating clinician.
Evaluation of therapy
A patient was considered evaluable for efficacy if each of the following criteria was met: (i) presence of a baseline pathogen(s) susceptible to the study medications that the patient was randomized to receive, and the absence of a resistant baseline pathogen(s); (ii) availability of susceptibility data (MICs, zone diameters); (iii) treatment with either study medication(s) for at least 5 days (three for a failure); (iv) at least one validated early follow-up or late follow-up evaluation. Patients who received concomitant antibacterial therapy were categorized as failures.
Clinical response was categorized as follows: (i) curedcompleted a full course of therapy and showed complete recovery from the acute infection at post-therapy evaluation; (ii) improvedimproved in at least three of 10 clinical efficacy parameters and showed no clinically significant worsening or reversal in the course of any parameter; (iii) relapsedclinical improvement followed by deterioration during therapy or during the follow-up period; (iv) failedtherapeutic failure, requiring a change in, or addition of, antibacterial therapy. The cured and improved groups were defined as the success group.
Bacteriological response was assessed on both the individual pathogen level and the patient level. Bacteriological response with respect to individual baseline pathogens was graded as follows: (i) eradicationthe baseline pathogen eradicated in cultures taken during or after therapy (or presumptively eradicated based on a favourable clinical response); (ii) persistencepresence of the baseline pathogen(s) in cultures taken during or after treatment, regardless of whether any new pathogens were isolated (or presumptive persistence in a patient with an unfavourable clinical outcome based on a negative culture or where culture data were not available); (iii) superinfection (early follow-up)all baseline pathogens eradicated, but one or more new pathogens present in cultures taken at early follow-up (lower respiratory tract as well as new sites of infection); (iv) new infection (late follow-up)all baseline pathogens eradicated, but one or more new pathogens present in cultures taken from a site of infection other than the lower respiratory tract at late follow-up; (v) reinfection (late follow-up)all baseline pathogens eradicated, but one or more new pathogens present in a lower respiratory tract specimen taken at late follow-up.
Statistical methods
Study design.The study was designed as a randomized, open-label, parallel comparative trial with randomization stratified by centre.
Sample size. The study plan was to enroll 240 patients. Assuming 50% of the enrolled patients are evaluable (i.e. 60 patients per group) and clinical response rates of 75% for both study drugs, there is 71% probability (power) that the distance to the lower bound of a two-sided 95% CI will not exceed 20%. Assuming 75% of the enrolled patients are evaluable (i.e. 90 patients per group), there is 87% probability (power) that the distance to the bound of a two-sided 95% CI will not exceed 20%.
For the primary analyses of efficacy, all evaluable patients with an assessable patient-level (clinical and bacteriological) or pathogen-level (bacteriological) response at early follow-up were pooled across centres. Separate analyses of the treatment difference for each of the three response measures were performed at each follow-up visit employing the Wilcoxon two sample test, using averaged ranks for ties, when ordered response distributions included three or more categories. When the responses were binomially distributed, a chi-square test with continuity adjustment was used.
These analyses were also applied to the endpoint re-sponses for evaluable patients. The confirmatory analyses, based on the subset of all treated patients, assessed endpoint treatment differences for the investigator-assigned clinical outcomes with the Wilcoxon two sample test.
All tests of statistical significance of treatment differences were two-sided and a 5% level of significance was employed.
Ninety-five percent confidence intervals, using the normal approximations to the binomial distribution, were calculated for the true treatment difference in the clinical cure/improvement rates and in the patient-level eradication (documented or presumed) rates at each follow-up visit.
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Results |
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Three hundred patients were randomized into the trial, 155 into the piperacillin/tazobactam group and 145 in the ceftazidime group. Both treatment groups were balanced with respect to each of the baseline demographic characteristics: gender, race, age and number of patients from nursing homes (Table I). Primary diagnosis, duration of treatment with study drugs and severity of infection were distributed equally among both treatment groups (Table II).
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The predominant reason for exclusion for the analysis of evaluable patients was an absence of a baseline pathogen (35 patients; 20 in the piperacillin/tazobactam group and 15 in the ceftazidime group) (Table III). Patients could be excluded from analysis for more than one reason.
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One hundred and thirty-two (85%) of the piperacillin/ tazobactam-treated patients and 122 (85%) of the ceftazidime-treated patients had at least one baseline pathogen. Sixty-four (41%) of the piperacillin/tazobactam-treated patients and 68 (47%) of the ceftazidime-treated patients had two or more baseline pathogens.
Piperacillin/tazobactam-treated patients with P. aeruginosa isolated at baseline received a mean duration of therapy with an aminoglycoside of 10.5 days compared with a mean duration of therapy with an aminoglycoside of 4.6 days for patients who did not have P. aeruginosa isolated at baseline (P = 0.01). The mean duration of therapy with an aminoglycoside for ceftazidime-treated patients with P. aeruginosa isolated at baseline was also greater (7.4 days) than the mean duration of therapy with an aminoglycoside (5.3 days) for patients without P. aeruginosa isolated at baseline (P = 0.01).
Clinical efficacyevaluable patients
The clinical responses of the 136 evaluable patients are shown by the treatment groups in Table IV. The favourable clinical response rate at endpoint was 74% for piperacillin/ tazobactam-treated patients versus 50% for ceftazidime-treated patients. This difference in clinical response between the two treatment groups was statistically significant (P = 0.006).
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Clinical efficacyall treated patients (intent-to-treat)
Any potential for introducing bias by selecting a subset of evaluable patients was addressed by a separate analysis of all treated patients using the investigator assigned clinical outcome. If a patient was not evaluated and, therefore, not assigned a response for at least one of the two evaluation points, the patient was included in the analysis as a `default failure'. One hundred and fifteen (74.2%) of 155 piperacillin/tazobactam-treated patients and 84 (57.9%) of 145 ceftazidime-treated patients had a favourable response (Table V, P = 0.004).
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To further address possible bias, responses for all treated patients with a validated clinical response were analysed. Ninety-eight (72.6%) of 135 piperacillin/tazobactam-treated patients versus 65 (53.7%) of 121 ceftazidime-treated patients had a favourable response (P = 0.002).
Piperacillin/tazobactam, therefore, had a response rate that was greater than that of ceftazidime whether the data were analysed using the intent-to-treat principle, or using patient subsets (evaluable patient subset, or subset of patients with a validated clinical responses).
Bacteriological responseevaluable patients
The bacteriological responses of the 78 evaluable piperacillin/tazobactam-treated patients and 58 evaluable ceftazidime-treated patients are shown in Table V. The differences in distribution of bacteriological responses between the two treatment groups for evaluable patients was statistically significant at endpoint, 65% (51/78) for piperacillin/tazobactam and 38% (22/58) for ceftazidime (P = 0.003).
Bacteriological responsepathogen response
A total of 128 pathogens were isolated in evaluable piperacillin/tazobactam-treated patients, compared to 89 in ceftazidime-treated patients. The baseline pathogen was eradicated in 77% (99/128) of isolates of patients treated with piperacillin/tazobactam compared with only 57% (51/89) of isolates of ceftazidime-treated patients (Table VI).
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Pneumonia and bronchitisevaluable patients
A subset analysis was performed of those evaluable patients diagnosed with pneumonia. The clinical success rate for evaluable patients with pneumonia was 73% (51/70) and 52% (22/42) for the piperacillin/tazobactam and ceftazidime treatment groups, respectively (P = 0.046). The success rate for evaluable patients with polymicrobial pneumonia was 67% (24/36) in the piperacillin/ tazobactam treatment group and 58% (14/24) for the ceftazidime treatment group (P = 0.702). The favourable clinical response in patients with bronchitis was 88% (7/8) and 44% (7/16) for the piperacillin/tazobactam and ceftazidime treatment groups, respectively (P = 0.107).
Nosocomial pneumonia patients also had a favourable bacteriological response; 64% (45/70) and 40% (17/42) of the pathogens in the piperacillin/tazobactam and ceftazidime treatment groups, respectively were eradicated (P = 0.024).
The bacteriological eradication rate for evaluable patients with bronchitis was 75% (6/8) within the piperacillin/tazobactam treatment group, versus 31% (5/16) for ceftazidime treated patients (P = 0.111).
Adverse events
Eighty-seven (56%) of the 155 piperacillin/tazobactam-treated patients and 77 (53%) of the 145 ceftazidime-treated patients reported at least one adverse experience (P = 0.682). Of these 164 patients, five (four in the piperacillin/tazobactam group and one in the ceftazidime group) had adverse experiences which were considered severe and drug-related. Three of the four piperacillin/ tazobactam-treated patients had severe diarrhoea; in none of these patients was pseudomembranous colitis or Clostridium difficile detected. The other piperacillin/ tazobactam-treated patient had severe thrombophlebitis which resolved after treatment. A diffuse maculopapular rash persisting for 4 days was reported in one ceftazidime-treated patient.
Four (2.6%) of the 155 piperacillin/tazobactam-treated patients did not complete the trial due to adverse experiences. These included pancreatitis, fever in two patients and diarrhoea. Two of these patients also had laboratory abnormalities: decreased platelet counts and elevated liver function tests. Seven (4.8%) of the 145 ceftazidime-treated patients did not complete the study due to adverse experiences or laboratory abnormalities consisting of respiratory arrest, erythema multiforme, cardiac arrest, rash in two patients, cerebral haemorrhage and elevated liver function tests.
Patients who received piperacillin/tazobactam had a higher rate of positive direct Coomb's tests than those who received ceftazidime (21% versus 12%), (P = 0.083). There were no clinical sequelae attributed to these changes and no therapy changes were necessary.
Mortality
Thirty-six patients (12 in the piperacillin/tazobactam group; 24 in the ceftazidime group) died during the study or within 30 days of the end of treatment. This difference between treatment groups was statistically significant (P = 0.03). Seven of the 24 deaths in the ceftazidime treatment group appeared to be directly related to failure to control infection, while only one of the 12 deaths in the piperacillin/ tazobactam treatment group was due to progression of pneumonia and failure to control infection. Only one death, in a ceftazidime-treated patient, was judged probably drug-related by the investigator.
Co-morbid conditions were not statistically significantly different between the evaluable subsets of the two groups of patients, with the exception of dermatological symptoms (P = 0.040). The mean Apache II score for the evaluable piperacillin/tazobactam subset group was 11.9 and the mean Apache II score for the ceftazidime evaluable subset group (excluding one patient whose Apache II score was nine points higher than any other patient) was 13.7. These also were not statistically significantly different (P = 0.074).
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Discussion |
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Nosocomial LRTI is often polymicrobial, with P. aeruginosa, H. influenzae, S. aureus, Enterobacter spp., and Klebsiella pneumoniae the most common pathogens. Treatment is usually initiated empirically with broad-spectrum iv antibiotics effective against both Gram-positive and Gram-negative pathogens, including ß-lactamase-producing strains.
Infections caused by P. aeruginosa provide an additional challenge. Data from several studies have shown that LRTI due to P. aeruginosa may require therapy with two antibiotics active against this pathogen for optimal response. 9,10 Several other Gram-negative bacilli, such as Acinetobacter and Enterobacter spp., also tend to be more resistant, in which case empirical therapy with two antibiotics is appropriate pending final susceptibility data.
The present study evaluated the use of piperacillin/ tazobactam (a ß-lactam antibiotic combined with a ß-lactamase inhibitor) versus ceftazidime in patients with LRTI. By protocol design, tobramycin was added to both treatment regimens until P. aeruginosa was excluded as a pathogen.
For several pathogens there was increased efficacy of piperacillin/tazobactam as compared with ceftazidime (Table VI). Although the authors are not aware of any isolates of H. influenzae which are resistant to either ceftazidime or piperacillin/tazobactam, the coincident presence of other unidentified, ß-lactamase-producing bacteria is conceivable. 11 Brook 12 has shown that Bacteroides spp. in the oropharynx may produce detectable amounts of ß-lactamase which may inactivate ß-lactam antibiotics, leading to the persistence of streptococcal pharyngitis. Thus anaerobes, in addition to being intrinsically resistant to ceftazidime, may elaborate ß-lactamase which destroys ceftazidime, thereby rendering it ineffective against H. influenzae. The results for S. aureus are not surprising; several third-generation cephalosporins, especially ceftazidime, have only modest activity against staphylococci, including S. aureus.
The design of this study was to show equivalence of the two arms. The results presented herein were surprising insofar as demonstrating superiority of the piperacillin/ tazobactam arm of the study. Several factors may have contributed to this improved outcome. Ceftazidime has been extensively used over the past 10 years and susceptibility patterns have indicated declining MICs for various Gram-negative bacilli. In addition, there has been an increase in strains producing extended spectrum or chromosomally mediated inducible ß-lactamases. 13 The increase in the prevalence of these strains has been linked to the widespread use of third-generation cephalosporins. 14 ß-lactamase inhibitor combinations such as piperacillin/ tazobactam remain active against these bacteria. Recent data have suggested that some extended spectrum ß-lactamase strains, while appearing susceptible to third-generation cephalosporins, are not effectively killed by these antibiotics. 15 The presence of these strains may have accounted for the increased efficacy seen with piperacillin/ tazobactam.
A large proportion of LRTIs are believed to be polymicrobial. Anaerobic bacteria may have played a larger role in the pneumonias described in this study as they are not detected by routine sputum culture techniques. Superior anaerobic coverage with piperacillin/tazobactam may have added to the improved therapeutic outcome seen with piperacillin/tazobactam.
Both treatments were well tolerated. The overwhelming majority of adverse experiences were not considered drug-related, and were attributed to the patient's underlying disease.
We conclude that, in this study, piperacillin/tazobactam was as safe as ceftazidime and was therapeutically superior in the treatment of nosocomial pneumonia.
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Acknowledgments |
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Notes |
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The Piperacillin/tazobactam Nosocomial Pneumonia Study Group: A. Erickson, Providence,
RI; R. A. Khakoo, Morgantown, WV; B. Suh, Philadelphia, PA; J. Wellman, Atlanta, GA; S.
Jenkinson, San Antonio, TX; C. Crim, St Louis, MO; N. Kirmani, Maywood, IL, D. Smith,
Kansas City, MO; D. W. Gump, Burlington, VT; G. T. Valainis, Spartanburg, SC; L. A. Von
Behren, Springfield, IL; W. J. Holloway, Wilmington, DE; B. E. Sieger, Orlando, FL; M. A.
Young, Washington, DC; S. J. Goodnight-White, Houston, TX; P. S. Barie, New York, NY; L.
D. Thrupp, Orange, CA, USA; T. J. Louie, Calgary, Alberta; D. Grimard, Chicoutimi, Quebec;
A. Y. Martel, Ste-Foy, Quebec; S. Lambert, Quebec, Quebec; R. Boileau, Sherbrooke, Quebec,
Canada.
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References |
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2 . Bradley, S. F. & Lynch, J. P. (1995). Hospital acquired pneumonia: evolving concepts. Internal Medicine 16, 32-8 and 43-4.
3 . Pennington, J. E. (1992). Nosocomial pneumonias. Current Opinion in Infectious Diseases 5, 505-11.[ISI]
4 . Pennington, J. E. (1988). Hospital acquired pneumonia. In Respiratory Infections: Diagnosis and Management , 2nd edn (Pennington, J. E., Ed.), pp. 171- 86. Raven Press, New York.
5 . Lehn, M. (1992). Microbiological profile of tazobactam/ piperacillinresults of a multicenter study. In Program and Abstracts of the Fourth Biennial Conference on Chemotherapy of Infectious Diseases and Malignancies, European Society for Biomodulation and Chemotherapy, Prague, Czechoslovakia, 1992. Abstract 5.
6 . Mouton, Y., Leroy, O., Beuscart, C., Chidiac, C., Senneville, E., Ajana, F. et al. (1993). Efficacy, safety and tolerance of parenteral piperacillin/tazobactam in the treatment of patients with lower respiratory tract infections. Journal of Antimicrobial Chemotherapy 31, Suppl. A, 87-95.
7 . Vogel, F. (1992). The efficacy and safety of piperacillin/ tazobactam in the treatment of lower respiratory tract infections. In Program and Abstracts of the Fourth Biennial Conference on Chemotherapy of Infectious Diseases and Malignancies, European Society for Biomodulation and Chemotherapy, Prague, Czechoslovakia, 1992. Abstract 131.
8 . Knaus, W. A., Draper, E. A., Wagner, D. P. & Zimmermann, J. E. (1985). APACHE II: A severity of disease classification system. Critical Care Medicine 13, 818-29.[ISI][Medline]
9 . Hilf, M., Yu, V. L., Sharp, J., Zuravleff, J. J., Korvick, J. A. & Muder, R. R. (1989). Antibiotic therapy for Pseudomonas aeruginosa bacteremia: outcome correlations in a prospective study of 200 patients. American Journal of Medicine 87, 540-6.[ISI][Medline]
10 . Korvick, J. A. & Yu, V. L. (1991). Antimicrobial agent therapy for Pseudomonas aeruginosa. Antimicrobial Agents and Chemotherapy 35, 2167-72.[ISI][Medline]
11 . Parr, T. R. & Bryan, L. E. (1984). Mechanism of resistance to an ampicillin-resistant, ß-lactamase-negative clinical isolate of Haemophilus influenzae type b to ß-lactam antibiotics. Antimicrobial Agents and Chemotherapy 25, 747-53.[ISI][Medline]
12 . Brook, I. (1984). The role of ß-lactamase-producing bacteria in the persistence of streptococcal tonsillar infection. Reviews of Infectious Diseases 6, 601-7.[ISI][Medline]
13 . Sirot, D. (1995). Extended-spectrum plasmid-mediated ß-lactamases. Journal of Antimicrobial Chemotherapy 36, Suppl. A, 19-34.[ISI][Medline]
14 . Rice, L. B., Carias, L. L., Bonomo, R. A. & Shlaes, D. M. (1996). Molecular genetics of resistance to both ceftazidime and ß-lactam- ß-lactamase inhibitor combinations in Klebsiella pneumoniae and in vivo response to ß-lactam therapy. Journal of Infectious Diseases 173, 151-8.[ISI][Medline]
15 . Karas, J. A., Pillay, D. G., Muckart, D. & Sturm, A. W. (1996). Treatment failure due to extended spectrum ß-lactamase. Journal of Antimicrobial Chemotherapy 37, 203-4.[ISI][Medline]
Received 13 October 1997; returned 21 July 1998; revised 16 November 1998; accepted 26 November 1998