Imipenem plus Netilmicin for Treatment of Severe Infections ... to compare imipenem monotherapy with a combination of imipenem plus netilmicin in the empiric ...
Vol. 38, No. 6
ANTIMICROBIAL AGENTS AND CHEMOTHERAPY, June 1994, p. 1309-1313
0066-4804/94/$04.00+0 Copyright C) 1994, American Society for Microbiology
Prospective Randomized Comparison of Imipenem Monotherapy with Imipenem plus Netilmicin for Treatment of Severe Infections in Nonneutropenic Patientst A. COMETTA,l* J. D. BAUMGARTNER,1 D. LEW,2 W. ZIMMERLI,3 D. PIT ET,2 P. CHOPART,2 U. SCHAAD,2 C. HERTER,2 P. EGGIMANN,' 0. HUBER,2 B. RICOU,2 P. SUTER,2 R. AUCKENTHALER,2 R. CHIOLERO,1 J. BILLE,1 C. SCHEIDEGGER,3 R. FREI,3 AND M. P. GLAUSER1
Division of Infectious Diseases, Centre Hospitalier Universitaire Vaudois, 1011 Lausanne,' Division of Infectious Diseases, Hopital Cantonal Universitaire, 1211 Geneva,2 and Division of Infectious Diseases, Universitatskliniken, Kantonssiptal, 4031 Basel,3 Switzerland Received 15 December 1993/Returned for modification 23 January 1994/Accepted 29 March 1994
Nosocomial pneumonia and sepsis, as well as severe diffuse peritonitis, must be treated early in order to prevent complications such as septic shock and organ dysfunctions. With the availability of new broadspectrum and highly bactericidal antibiotics, the need of combining j-lactams with aminoglycosides for the treatment of severe infections should be reassessed. A prospective randomized controlled study was performed to compare imipenem monotherapy with a combination of imipenem plus netilmicin in the empiric treatment of nosocomial pneumonia, nosocomial sepsis, and severe diffuse peritonitis. A total of 313 patients were enrolled, and 280 were assessable. The antibiotic treatment was successful in 113 of 142 patients (80%v) given the monotherapy and in 119 of 138 patients (86%) given the combination (P = 0.19). The failure rates for the most important type of infection, i.e., pneumonia, were similar in the two groups, as well as the number of superinfections. While creatinine increase was associated with factors not related to antibiotic therapy for all eight patients of the monotherapy group, no factor other than the antibiotics could be found for 6 of the 14 cases of nephrotoxicity observed in the combination group (P = 0.014). Finally, the emergence of Pseudomonas aeruginosa resistant to imipenem occurred in 8 monotherapy patients and in 13 combination therapy patients. In conclusion, imipenem monotherapy appeared as effective as the combination of imipenem plus netilmicin for the treatment of severe infection. The addition of netilmicin increased nephrotoxicity, and it did not prevent the emergence of P. aeruginosa resistant to imipenem.
and highly bactericidal antibiotics, the need of combining ,B-lactams with aminoglycosides should be reassessed. The purpose of this prospective randomized study was to compare imipenem monotherapy with a combination of imipenem plus netilmicin in the empiric treatment of nosocomial pneumonia, nosocomial sepsis, and severe diffuse peritonitis. Imipenem was chosen because of its broad spectrum including activity against Pseudomonas aeruginosa, multiresistant members of the family Enterobactenaceae, anaerobes, and most of the gram-positive cocci. Clinical efficacy and tolerance were the main focus of the study, but emergence of resistance and incidence of superinfections were also examined. (This work was presented in part at the 32nd Interscience Conference on Antimicrobial Agents and Chemotherapy, Anaheim, Calif., 11 to 14 October 1992.)
Nosocomial pneumonia and sepsis are major causes of morbidity and mortality in patients hospitalized in intensive care units. These infections must be treated early in order to prevent complications such as septic shock and organ dysfunctions and in order to decrease the associated costs due to increased length of hospital stay (9, 15). Kreger et al. (10) showed that early appropriate empiric treatment for gramnegative sepsis reduced by half the occurrence of shock in 612 episodes of gram-negative sepsis. Empiric treatment is also mandatory for severe diffuse peritonitis and often consists of antibiotic combinations designed to cover polymicrobial infections including those caused by anaerobes. In most cases of infections in intensive care unit patients, antimicrobial treatment must start before the results of the microbiological cultures are known. Thus, the use of a combination of a 1-lactam with an aminoglycoside is a common practice in the treatment of nosocomial pneumonia and sepsis, as well as of severe diffuse peritonitis. The rationale for using combination therapy (5) is not only to broaden the antimicrobial spectrum, but also to achieve enhanced bacterial killing by synergism (11) and to prevent the emergence of antibiotic resistance. However, the addition of an aminoglycoside is associated with increased costs and drug-related toxicities. Therefore, with the availability of new broad-spectrum
MATERUILS AND METHODS Criteria for eligibility. Patients were eligible if they were at least 16 years old and presented nosocomial pneumonia, nosocomial sepsis, or severe diffuse peritonitis. Nosocomial pneumonia was diagnosed as a new or progressive infiltrate seen on chest X ray 48 or more h after admission in the presence of two or more symptoms, signs, or values such as a fever of .380C, cough, sputum, a leukocyte count of 210,000/liter, or hypoxemia (defined as a partial pressure of arterial oxygen of :390C, or hypothermia (
