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A multicenter, open comparative study of parenteral cefotaxime and ceftriaxone in the treatment of nosocomial lower respiratory tract infections
DIAGN MICROBIOLINFECTDIS 1992;15:85-88
85
A Multicenter, Open Comparative Study of Parenteral Cefotaxime and Ceftriaxone in the Treatment of Nosocomial Lower Respiratory Tract Infections Gary E. Garber, Pierre Auger, Robert M.T. Chan, John M. Conly, Stephen D. Shafran, and Marvin Gerson
A multicenter Canadian study enrolled 74 persons to compare low-dose cefotaxime at 1 g every 8 hr to ceftriaxone 1 g every 12 hr in patients with nosocomial pneumonia. Of 57 evaluable patients (30 cefotaxime and 27 ceftriaxone) in this preliminary report, 93% responded to therapy in both groups. Ceftriaxone patients tended to have more side effects (14.2%). This study
is continuing to accrue patients to achieve 100 evaluable patients. Interim data, however, support the continued use of low-dose cefotaxime as an appropriate alternative for clinically effective and cost-effective management of nosocomially acquired pneumonia.
INTRODUCTION
Cefotaxime has a half-life of - 1 hr. A l t h o u g h this would ordinarily suggest a dosing regime of every 4-6 hr, administering cefotaxime at the advised 1-2 g every 8-12 hr resulted in serum bactericidal titers of 1:512-1:1024 and a trough of 1:64-1:1024 to most of the infecting Enterobacteriaceae. In addition, cefotaxime's metabolite (desacetylcefotaxime) acts synergistically with the parent c o m p o u n d to further enhance activity (Goodpasture et al., 1988; Neu, 1984; Trenholme et al., 1989). In an outbreak of Acinetobacter calcoaceticus in the intensive care unit at the Ottawa General Hospital in 1986, cefotaxime at a dose of 3-6 g/day was used successfully to treat a n u m b e r of patients with this severe nosocomial p n e u m o n i a (Contant et al., 1990). This experience p r o m p t e d the design of a more systematic approach to evaluate lowerdose cefotaxime at 3 g/day in a comparison to ceftriaxone 1 g every 12 hr, a c o m m o n l y used regimen for treating nosocomial p n e u m o n i a . The questions that we w a n t e d to answer in this study were (a) is a 3-g dose of cefotaxime a safe and effective treatment for nosocomial p n e u m o n i a , (b) would this lower dose result in more treat-
W h e n first released for clinical use, the third-generation cephalosporins were used to treat patients with serious, life-threatening infections. Inevitably, high-dose treatment was employed, for example, with cefotaxime at 8-12 g/day. It was soon found, however, that the exquisite sensitivity profile of a broad range of bacteria to these antibiotics resulted in similar clinical efficacy being achieved with a lower dose or less frequent dosing. This led to the possibility of significant cost savings. From the Department of Medicine, University of Ottawa (G.E.G.), Ottawa; the University of Montreal (P.A.) and McGill University (M.G.), Montreal; the University of British Columbia (R.M.T.C.), Vancouver; the University of Saskatchewan 0.C.), Saskatoon; and the University of Alberta (S.S.), Edmonton, Canada. Address reprint requests to Dr. G.E. Garber, Head, Division of Infectious Diseases, Ottawa General Hospital, 501 Smyth Road, Ottawa, Ontario KIH 8L6, Canada. Received 20 June 1991; revised and accepted 15 August 1991. © 1992 Elsevier Science Publishing Co., Inc. 655 Avenue of the Americas, New York, NY 10010 0732-8893/92/$3.50
86
ment failures or relapses, and (c) could cost savings be realized compared with other third-generation cephalosporins?
METHODS This is a multicenter, open, randomized comparative trial in four Canadian medical centers. The protocol was approved by the local H u m a n Experimentation Committee of each center, and informed consent was obtained from each patient prior to enrollment. For the purposes of this trial, hospital-acquired pneumonia was defined as occurring > 48 hr after admission. Inclusion criteria included (a) patients/> 18 years old, (b) radiographic evidence of pulmonary infiltrate suggestive of pneumonia, and (c) physical signs consistent with pulmonary infection (such as shortness of breath, crackles, and bronchial breath sounds) and clinical signs of infection including fever, leucocytosis, and purulent sputum. Exclusion criteria were (a) known hypersensitivity to cephalosporins or penicillins, (b) a known resistant bacterial pathogen, (c) pregnancy or nursing women, (d) concomitant major infection requiring additional antibiotic treatment, (e) antimicrobial therapy within 48 hr unless the pathogen was resistant to therapy, and (f) renal failure or serious liver disease (AST twice nor-
real). Patients were randomized to receive either cefotaxime I g intravenously (i.v.) every 8 hr or ceftriaxone 1 g i.v. every 12 hr for 7-10 days. No other antimicrobial therapy was allowed while on study. Patients who did not improve clinically after 3 days of treatment were considered treatment failures and withdrawn from the study. Patients were evaluated at the end of treatment and 2 weeks after treatment. Clinical response was classified as (a) cure--no evidence of infection at end of treatment, (b) improved--clinical signs and symptoms have subsided, but there is incomplete resolution of infection according to clinical and radiological criteria, (c) failure---signs and symptoms unchanged or worsened, and (d) relapse--patient develops similar clinical symptoms within 5 days after therapy is discontinued. Bacteriologic response was classified as (a) cure--pretreatment culture is eradicated, (b) failure----causative organism persists, (c) relapse--symptoms and isolate recur within 5 days of discontinuing therapy, and (d) reinfection--a repeat infection, but with a different organism. Side effects were monitored by daily clinical examination, and chest radiographs were performed on admission to the study, at day 3, at end of therapy, and at follow-up. A hemoglobin, white blood
G.E. Garber et al.
cell (WBC) and differential, platelet count as well as biochemical parameters of creatinine, blood urea nitrogen (BUN), globulin, albumen, bilirubin, alkaline phosphatase, ALT, AST, PO4, Ca, glucose, K +, Cl-, and Na + were all performed upon admission to the study and at the end of treatment, as well as when clinically indicated. All blood, urine, and sputum cultures were processed at the local microbiology laboratory at the university teaching hospital participating in the study, using standard methods for identification and determination of sensitivity data.
RESULTS This study is currently ongoing to achieve 100 evaluable patients. At the present time, 74 patients have been enrolled, of which 57 are clinically evaluable; 39 were enrolled in the cefotaxime arm and 35 received ceftriaxone (Table 1). Four patients in each group were eliminated from the study for protocol violations such as treatment with antibiotics in the 48-hr period preceding the study, no chest radiographic finding of pneumonia, or hospital stay of < 48 hr. Two patients receiving cefotaxime and three on ceftriaxone were on study medication for < 72 hr and were omitted from analysis. The two cefotaxime patients were withdrawn when at 24-hr blood cultures indicated Gram-positive cocci (susceptible to cefotaxime in vitro) and treatment with cloxacillin was started. Of the three ceftriaxone patients, two died within 24 hr of enrollment and the third with bacteremia caused by Staphylococcus aureus (susceptible to ceftriaxone in vitro) was withdrawn and treatment with cloxacillin was started. Three additional cefotaxime and one ceftriaxone patient were unevaluable because of concurrent medical problems such as aspiration pneumonia, cardiac failure, and withdrawal on day 5 at patient's request. The remaining 30 cefotaxime and 27 ceftriaxone patients were then analyzed for clinical and bacteriologic efficacy. In the cefotaxime group, 23 patients (76.7%) were cured by days 7-10, five were improved, and two (6.7%) were considered treatment failures (Table 2). In the ceftriaxone group, only 12 (44.4%) were cured, 13 improved, and two (7.4%) failed. Combining cured and improved results in 93.4% successful cefotaxime treatment versus 92.6% on ceftriaxone (p > 0.05). The side-effect profile (excluding death) indicates that only one patient in the cefotaxime group developed diarrhea compared with five patients on ceftriaxone who developed side effects (Table 3). Although not statistically significant, the odds ratio was > 6, indicating a strong trend toward a higher incidence of side effects with ceftriaxone. Four patients were defined as treatment failures
Low-Dose Cefotaxime in Nosocomial Pneumonia
TABLE 1
87
Patient Demographics and Organism Responses Cefotaxime Demographic Enrolled Male/female Age (mean) (years) Age range Bacteremia Organism/response Staphylococcus aureus Streptococcus pneumoniae Haemophilus influenzae Klebsiella pneumoniae Enterobacter cloacae Klebsiella oxytoca Moraxella catarrhalis Coagulase-negative staphylococci Enterobacter aerogenes Xanthomonas maltophilia Escherichia coli
by the on-site investigator. Of the two failures in the cefotaxime group, one patient had Streptococcus pneumoniae isolated (susceptible to cefotaxime in vitro) and, after an initial response, deteriorated on day 7 and tobramycin was added. This patient died of heart failure 25 days later of purulent pericarditis. The other patient was treated for 4 days and then withdrawn as a clinical failure with S. aureus isolated from sputum. In the ceftriaxone group, one patient grew Staphylococcus epidermidis and Klebsiella pneumoniae and, after initial improvement, relapsed radiologically. Another patient with congestive heart failure and pneumonia with K. pneumoniae and S. aureus was doing well on ceftriaxone, but on day 7 was switched to imipenem for failure. Since there was a concern that low-dose treatment may not be effective, we systematically continued to study our subjects for 2 weeks after antibiotic treatment. One patient on cefotaxime relapsed with S. aureus in sputum. In the ceftriaxone arm, four patients had clinical relapse, two had recurrence of S. aureus, and two developed superinfection, one
39 24/15 62.2 18-92 3
35 20/15 71.2 18-96 6
7/7 5/5 3/3 2/2 2/2 1/1 2/2 1/1 -1/1 1/1
4/4 4/4 4/4 3/3 --1/1 1/1 1/1 -2/2
with Acinetobacter calcoaceticus, and the other developed nosocomially acquired Legionella.
DISCUSSION In this preliminary analysis, cefotaxime at 1 g i.v. every 8 hr was as effective as ceftriaxone at 1 g i.v. every 12 hr, with a trend for less side effects, reinfections, and superinfections on cefotaxime. Surprisingly, no patients with Pseudomonas aeruginosa, who would have then required withdrawal due to antibiotic resistance, were entered into the study. This may reflect the relative lack of nosocomial P. aeruginosa seen in the participating centers as well as a tendency of the investigator not to enroll patients colonized with P. aeruginosa. The number of S. aureus to date (11 of 57, or 19%) is higher than expected. Although clearly effective, three patients (one cefotaxime and two ceftriaxone) relapsed with
TABLE 3
TABLE 2
Clinical Evaluation of 57 Patients
Clinical Response
Cefotaxime (n = 30)
Ceftriaxone (n = 27)
Cure Improved Failure Relapse/superinfection
23 (76.7%) 5 (16.7%) 2 (6.7%) 2 (6.7%)
12 (44.4%) 13 (48.1%) 2 (7.4%) 4 (14.8%)
Ceftriaxone
Side Effects Observed During the Study
Side Effect
Cefotaxime (n = 39)
Ceftriaxone (n = 35)
Diarrhea UTIa Elevated LFTb
1 (2.6%) 0 0
3 (8.6%) 1 (2.8%) 1 (2.8%)
Total (%)
2.6%
~Urinarytract infection. ~Liverfunctiontests.
14.2%
88
S. aureus. Low investigator confidence in the thirdgeneration cephalosporins appeared during the study with several patients being removed from the trial within the first 72 hr for Gram-positive cocci in blood or sputum. Lower-dose cefotaxime has been shown to be effective in lower respiratory tract infection in a study of 2 g i.v. every 12 hr for 7-14 days. In this study by Kosmidis et al. (1988) of 121 patients, 114 responded with an efficacy of 94%, similar to that seen in our interim data. The safety and efficacy of the third-generation cephalosporins in the treatment of a wide array of infections is well established. In nosocomial pneumonia, third-generation cephalosporins are the drugs of choice because of a high degree of clinical and microbiological activity, tissue penetration, and safety. With their broad spectrum against Klebsiella pneumoniae, Escherichia coli, Enterobacter spp., Haemophilus influenzae, and even S. aureus, they are effective in treating the majority of nosocomially acquired re-
G.E. Garber et al.
spiratory pathogens (Modai, 1990). Our preliminary data suggest that low-dose (3 g/day) cefotaxime is as effective as ceftriaxone in nosocomial pneumonia. The clinical and bacteriologic response to S. aureus is excellent, but relapse occurred. Most failures are associated with underlying medical problems. Cefotaxime I g i.v. every 8 hr costs -$36.50 (Can)/ day compared with $72 (Can) for ceftriaxone 2 g/ day. We are continuing our accrual of patients to achieve a total of 100 evaluable patients. If the trend of equal efficacy continues, low-dose cefotaxime may be both a clinically effective and cost-effective w a y to manage nosocomial pneumonia in a university hospital with a low incidence of P. aeruginosa.
This study was supported by an educational grant from Roussel Canada Inc.
REFERENCES Contant J, Kemeny E, Oxley C, Perry E, Garber GE (1990) Investigation of an outbreak of Acinetobacter calcoaceticus in patients in an ICU. Am J Infect Control 18:288-291. Goodpasture HC, Gerlach HE, Jones RN, Peterie JD (1988) Optimal cefotaxime dosing for Gram-negative bacteremia. Diagn Microbiol Infect Dis 9:97-103. Kosmidis J, Tsougranis A, Kastanakis S, Doudoulaki P, Kavakas H, Diamantis T (1988) Value of twice daily cefotaxime in lower respiratory tract infections. Drugs 35(Suppl 2):214-215.
Modai J (1990) Empiric therapy of serious infections in adults. Am J Med 88(Suppl 4):12-17. Neu HC (1984) The pharmacokinetics of new cephalosporins: significance in clinical practice. Bull NY Acad Med 60:327-339. Trenholme GM, Schmitt BA, Nelson JA, Gvazdinskas IC, Harrison BB, Parkhurst GW (1989) Comparison study of 3 different dosing regimens of cefotaxime for Gramnegative bacteremia. Diagn Microbiol Infect Dis 12:107112.
85
A Multicenter, Open Comparative Study of Parenteral Cefotaxime and Ceftriaxone in the Treatment of Nosocomial Lower Respiratory Tract Infections Gary E. Garber, Pierre Auger, Robert M.T. Chan, John M. Conly, Stephen D. Shafran, and Marvin Gerson
A multicenter Canadian study enrolled 74 persons to compare low-dose cefotaxime at 1 g every 8 hr to ceftriaxone 1 g every 12 hr in patients with nosocomial pneumonia. Of 57 evaluable patients (30 cefotaxime and 27 ceftriaxone) in this preliminary report, 93% responded to therapy in both groups. Ceftriaxone patients tended to have more side effects (14.2%). This study
is continuing to accrue patients to achieve 100 evaluable patients. Interim data, however, support the continued use of low-dose cefotaxime as an appropriate alternative for clinically effective and cost-effective management of nosocomially acquired pneumonia.
INTRODUCTION
Cefotaxime has a half-life of - 1 hr. A l t h o u g h this would ordinarily suggest a dosing regime of every 4-6 hr, administering cefotaxime at the advised 1-2 g every 8-12 hr resulted in serum bactericidal titers of 1:512-1:1024 and a trough of 1:64-1:1024 to most of the infecting Enterobacteriaceae. In addition, cefotaxime's metabolite (desacetylcefotaxime) acts synergistically with the parent c o m p o u n d to further enhance activity (Goodpasture et al., 1988; Neu, 1984; Trenholme et al., 1989). In an outbreak of Acinetobacter calcoaceticus in the intensive care unit at the Ottawa General Hospital in 1986, cefotaxime at a dose of 3-6 g/day was used successfully to treat a n u m b e r of patients with this severe nosocomial p n e u m o n i a (Contant et al., 1990). This experience p r o m p t e d the design of a more systematic approach to evaluate lowerdose cefotaxime at 3 g/day in a comparison to ceftriaxone 1 g every 12 hr, a c o m m o n l y used regimen for treating nosocomial p n e u m o n i a . The questions that we w a n t e d to answer in this study were (a) is a 3-g dose of cefotaxime a safe and effective treatment for nosocomial p n e u m o n i a , (b) would this lower dose result in more treat-
W h e n first released for clinical use, the third-generation cephalosporins were used to treat patients with serious, life-threatening infections. Inevitably, high-dose treatment was employed, for example, with cefotaxime at 8-12 g/day. It was soon found, however, that the exquisite sensitivity profile of a broad range of bacteria to these antibiotics resulted in similar clinical efficacy being achieved with a lower dose or less frequent dosing. This led to the possibility of significant cost savings. From the Department of Medicine, University of Ottawa (G.E.G.), Ottawa; the University of Montreal (P.A.) and McGill University (M.G.), Montreal; the University of British Columbia (R.M.T.C.), Vancouver; the University of Saskatchewan 0.C.), Saskatoon; and the University of Alberta (S.S.), Edmonton, Canada. Address reprint requests to Dr. G.E. Garber, Head, Division of Infectious Diseases, Ottawa General Hospital, 501 Smyth Road, Ottawa, Ontario KIH 8L6, Canada. Received 20 June 1991; revised and accepted 15 August 1991. © 1992 Elsevier Science Publishing Co., Inc. 655 Avenue of the Americas, New York, NY 10010 0732-8893/92/$3.50
86
ment failures or relapses, and (c) could cost savings be realized compared with other third-generation cephalosporins?
METHODS This is a multicenter, open, randomized comparative trial in four Canadian medical centers. The protocol was approved by the local H u m a n Experimentation Committee of each center, and informed consent was obtained from each patient prior to enrollment. For the purposes of this trial, hospital-acquired pneumonia was defined as occurring > 48 hr after admission. Inclusion criteria included (a) patients/> 18 years old, (b) radiographic evidence of pulmonary infiltrate suggestive of pneumonia, and (c) physical signs consistent with pulmonary infection (such as shortness of breath, crackles, and bronchial breath sounds) and clinical signs of infection including fever, leucocytosis, and purulent sputum. Exclusion criteria were (a) known hypersensitivity to cephalosporins or penicillins, (b) a known resistant bacterial pathogen, (c) pregnancy or nursing women, (d) concomitant major infection requiring additional antibiotic treatment, (e) antimicrobial therapy within 48 hr unless the pathogen was resistant to therapy, and (f) renal failure or serious liver disease (AST twice nor-
real). Patients were randomized to receive either cefotaxime I g intravenously (i.v.) every 8 hr or ceftriaxone 1 g i.v. every 12 hr for 7-10 days. No other antimicrobial therapy was allowed while on study. Patients who did not improve clinically after 3 days of treatment were considered treatment failures and withdrawn from the study. Patients were evaluated at the end of treatment and 2 weeks after treatment. Clinical response was classified as (a) cure--no evidence of infection at end of treatment, (b) improved--clinical signs and symptoms have subsided, but there is incomplete resolution of infection according to clinical and radiological criteria, (c) failure---signs and symptoms unchanged or worsened, and (d) relapse--patient develops similar clinical symptoms within 5 days after therapy is discontinued. Bacteriologic response was classified as (a) cure--pretreatment culture is eradicated, (b) failure----causative organism persists, (c) relapse--symptoms and isolate recur within 5 days of discontinuing therapy, and (d) reinfection--a repeat infection, but with a different organism. Side effects were monitored by daily clinical examination, and chest radiographs were performed on admission to the study, at day 3, at end of therapy, and at follow-up. A hemoglobin, white blood
G.E. Garber et al.
cell (WBC) and differential, platelet count as well as biochemical parameters of creatinine, blood urea nitrogen (BUN), globulin, albumen, bilirubin, alkaline phosphatase, ALT, AST, PO4, Ca, glucose, K +, Cl-, and Na + were all performed upon admission to the study and at the end of treatment, as well as when clinically indicated. All blood, urine, and sputum cultures were processed at the local microbiology laboratory at the university teaching hospital participating in the study, using standard methods for identification and determination of sensitivity data.
RESULTS This study is currently ongoing to achieve 100 evaluable patients. At the present time, 74 patients have been enrolled, of which 57 are clinically evaluable; 39 were enrolled in the cefotaxime arm and 35 received ceftriaxone (Table 1). Four patients in each group were eliminated from the study for protocol violations such as treatment with antibiotics in the 48-hr period preceding the study, no chest radiographic finding of pneumonia, or hospital stay of < 48 hr. Two patients receiving cefotaxime and three on ceftriaxone were on study medication for < 72 hr and were omitted from analysis. The two cefotaxime patients were withdrawn when at 24-hr blood cultures indicated Gram-positive cocci (susceptible to cefotaxime in vitro) and treatment with cloxacillin was started. Of the three ceftriaxone patients, two died within 24 hr of enrollment and the third with bacteremia caused by Staphylococcus aureus (susceptible to ceftriaxone in vitro) was withdrawn and treatment with cloxacillin was started. Three additional cefotaxime and one ceftriaxone patient were unevaluable because of concurrent medical problems such as aspiration pneumonia, cardiac failure, and withdrawal on day 5 at patient's request. The remaining 30 cefotaxime and 27 ceftriaxone patients were then analyzed for clinical and bacteriologic efficacy. In the cefotaxime group, 23 patients (76.7%) were cured by days 7-10, five were improved, and two (6.7%) were considered treatment failures (Table 2). In the ceftriaxone group, only 12 (44.4%) were cured, 13 improved, and two (7.4%) failed. Combining cured and improved results in 93.4% successful cefotaxime treatment versus 92.6% on ceftriaxone (p > 0.05). The side-effect profile (excluding death) indicates that only one patient in the cefotaxime group developed diarrhea compared with five patients on ceftriaxone who developed side effects (Table 3). Although not statistically significant, the odds ratio was > 6, indicating a strong trend toward a higher incidence of side effects with ceftriaxone. Four patients were defined as treatment failures
Low-Dose Cefotaxime in Nosocomial Pneumonia
TABLE 1
87
Patient Demographics and Organism Responses Cefotaxime Demographic Enrolled Male/female Age (mean) (years) Age range Bacteremia Organism/response Staphylococcus aureus Streptococcus pneumoniae Haemophilus influenzae Klebsiella pneumoniae Enterobacter cloacae Klebsiella oxytoca Moraxella catarrhalis Coagulase-negative staphylococci Enterobacter aerogenes Xanthomonas maltophilia Escherichia coli
by the on-site investigator. Of the two failures in the cefotaxime group, one patient had Streptococcus pneumoniae isolated (susceptible to cefotaxime in vitro) and, after an initial response, deteriorated on day 7 and tobramycin was added. This patient died of heart failure 25 days later of purulent pericarditis. The other patient was treated for 4 days and then withdrawn as a clinical failure with S. aureus isolated from sputum. In the ceftriaxone group, one patient grew Staphylococcus epidermidis and Klebsiella pneumoniae and, after initial improvement, relapsed radiologically. Another patient with congestive heart failure and pneumonia with K. pneumoniae and S. aureus was doing well on ceftriaxone, but on day 7 was switched to imipenem for failure. Since there was a concern that low-dose treatment may not be effective, we systematically continued to study our subjects for 2 weeks after antibiotic treatment. One patient on cefotaxime relapsed with S. aureus in sputum. In the ceftriaxone arm, four patients had clinical relapse, two had recurrence of S. aureus, and two developed superinfection, one
39 24/15 62.2 18-92 3
35 20/15 71.2 18-96 6
7/7 5/5 3/3 2/2 2/2 1/1 2/2 1/1 -1/1 1/1
4/4 4/4 4/4 3/3 --1/1 1/1 1/1 -2/2
with Acinetobacter calcoaceticus, and the other developed nosocomially acquired Legionella.
DISCUSSION In this preliminary analysis, cefotaxime at 1 g i.v. every 8 hr was as effective as ceftriaxone at 1 g i.v. every 12 hr, with a trend for less side effects, reinfections, and superinfections on cefotaxime. Surprisingly, no patients with Pseudomonas aeruginosa, who would have then required withdrawal due to antibiotic resistance, were entered into the study. This may reflect the relative lack of nosocomial P. aeruginosa seen in the participating centers as well as a tendency of the investigator not to enroll patients colonized with P. aeruginosa. The number of S. aureus to date (11 of 57, or 19%) is higher than expected. Although clearly effective, three patients (one cefotaxime and two ceftriaxone) relapsed with
TABLE 3
TABLE 2
Clinical Evaluation of 57 Patients
Clinical Response
Cefotaxime (n = 30)
Ceftriaxone (n = 27)
Cure Improved Failure Relapse/superinfection
23 (76.7%) 5 (16.7%) 2 (6.7%) 2 (6.7%)
12 (44.4%) 13 (48.1%) 2 (7.4%) 4 (14.8%)
Ceftriaxone
Side Effects Observed During the Study
Side Effect
Cefotaxime (n = 39)
Ceftriaxone (n = 35)
Diarrhea UTIa Elevated LFTb
1 (2.6%) 0 0
3 (8.6%) 1 (2.8%) 1 (2.8%)
Total (%)
2.6%
~Urinarytract infection. ~Liverfunctiontests.
14.2%
88
S. aureus. Low investigator confidence in the thirdgeneration cephalosporins appeared during the study with several patients being removed from the trial within the first 72 hr for Gram-positive cocci in blood or sputum. Lower-dose cefotaxime has been shown to be effective in lower respiratory tract infection in a study of 2 g i.v. every 12 hr for 7-14 days. In this study by Kosmidis et al. (1988) of 121 patients, 114 responded with an efficacy of 94%, similar to that seen in our interim data. The safety and efficacy of the third-generation cephalosporins in the treatment of a wide array of infections is well established. In nosocomial pneumonia, third-generation cephalosporins are the drugs of choice because of a high degree of clinical and microbiological activity, tissue penetration, and safety. With their broad spectrum against Klebsiella pneumoniae, Escherichia coli, Enterobacter spp., Haemophilus influenzae, and even S. aureus, they are effective in treating the majority of nosocomially acquired re-
G.E. Garber et al.
spiratory pathogens (Modai, 1990). Our preliminary data suggest that low-dose (3 g/day) cefotaxime is as effective as ceftriaxone in nosocomial pneumonia. The clinical and bacteriologic response to S. aureus is excellent, but relapse occurred. Most failures are associated with underlying medical problems. Cefotaxime I g i.v. every 8 hr costs -$36.50 (Can)/ day compared with $72 (Can) for ceftriaxone 2 g/ day. We are continuing our accrual of patients to achieve a total of 100 evaluable patients. If the trend of equal efficacy continues, low-dose cefotaxime may be both a clinically effective and cost-effective w a y to manage nosocomial pneumonia in a university hospital with a low incidence of P. aeruginosa.
This study was supported by an educational grant from Roussel Canada Inc.
REFERENCES Contant J, Kemeny E, Oxley C, Perry E, Garber GE (1990) Investigation of an outbreak of Acinetobacter calcoaceticus in patients in an ICU. Am J Infect Control 18:288-291. Goodpasture HC, Gerlach HE, Jones RN, Peterie JD (1988) Optimal cefotaxime dosing for Gram-negative bacteremia. Diagn Microbiol Infect Dis 9:97-103. Kosmidis J, Tsougranis A, Kastanakis S, Doudoulaki P, Kavakas H, Diamantis T (1988) Value of twice daily cefotaxime in lower respiratory tract infections. Drugs 35(Suppl 2):214-215.
Modai J (1990) Empiric therapy of serious infections in adults. Am J Med 88(Suppl 4):12-17. Neu HC (1984) The pharmacokinetics of new cephalosporins: significance in clinical practice. Bull NY Acad Med 60:327-339. Trenholme GM, Schmitt BA, Nelson JA, Gvazdinskas IC, Harrison BB, Parkhurst GW (1989) Comparison study of 3 different dosing regimens of cefotaxime for Gramnegative bacteremia. Diagn Microbiol Infect Dis 12:107112.