Department of Critical Care Medicine Peking Union Medical College Hospital<?xml:namespace prefix = o ns = "urn:schemas-microsoft-com:office:office" />

Bin DU，MD Dechang CHEN，MD Dawei LIU，MD Yun LONG，MD Yan SHI，MD Hao WANG，MD Xi RUI，MD Na CUI，MD

1 Shuai Fu Yuan，Beijing 100730，P. R. China

Correspondence：Bin DU，MD Department of Critical Care Medicine Peking Union Medical College Hospital 1 Shuai Fu Yuan，Beijing 100730 P. R. China

Tel （8610） 6529－6094  Fax （8610） 6512－4875

E－mail：dubin98@yahoo.com

　　Key Words：Cephalosporin Resistance； Cephalosporins，therapeutic use； Comparative Study； Cross Infection，prevention & control； Critical illness； Drug Resistance，microbial； Drug Utilization Review，statistics & numerical data； Gram－negative bacteria； Hospital mortality； Intensive care units.

ABSTRACT

　　Objectives：To determine the effect of restriction of third－generation cephalosporin use on antibiotic resistance and the outcome of patients with infection.

　　Design：A prospective，before－after comparative study.

　　Settings：A general intensive care unit with 14 beds at a university－affiliated teaching hospital.

　　Patients：All patients admitted to ICU within 2 years.

　　Intervention： A new antibiotic treatment strategy was implemented during phase II. All patients with confirmed or suspected Gram－negative bacterial infections were treated mainly with antibiotics other than third－generation cephalosporins.

　　Measurements and Main Results：Antibiotic resistance among common Gram－negative bacilli and infection－related hospital mortality during phase I were compared with phase II. A 26.6％ reduction in third－generation cephalosporin use （from 168.2 ± 48.0 to 123.5 ± 39.3 grams per month，p＝0.021），accompanied by a 277.7％ increase in cefepime use （from 10.3 ± 19.2 to 38.9 ± 31.7 grams per month，p＝0.014） occurred in phase II compared with phase I. This was accompanied by a significant decrease in reduced susceptibility of Gram－negative bacilli to third－generation cephalosporins （p < 0.05），mainly due to the improved susceptibility of Escherichia coli and Klebsiella spp. （p < 0.05）. Infection－related hospital mortality was significantly lower in phase II （19.3％ vs 36.3％，p ＝ 0.014）. Multiple logistic regression analysis demonstrated lower respiratory tract infection，the status of immunocompromise，and continuous venous－venous hemofiltration as independent risk factors for infection－related hospital mortality （p < 0.05），while infection with E. coli or Klebsiella spp. （p ＝ 0.039） and restriction of third－generation cephalosporin use （p ＝ 0.025） were associated with significantly lower mortality rate.<?xml:namespace prefix = o ns = "urn:schemas-microsoft-com:office:office" />

　　Conclusions： Restriction of third－generation cephalosporin use may improve the antibiotic susceptibility and reduce infection－related hospital mortality in critically ill patients.

　　INTRODUCTION

　　Antibiotic resistance among nosocomial pathogens，especially Gram－negative bacilli （GNB），has evolved as a healthcare issue as well as a social problem ^[1]. Studies have demonstrated that increasing antibiotic resistance is related to the selective pressure exerted by the use of these agents ^[2，3]. Guidelines have emphasized aggressive hospital infection control measures to limit the emergence and spread of resistant bacteria within the hospital ^[4]. However，such measures alone often fail to reverse the trend of increasing antibiotic resistance. Therefore，several antibiotic control strategies have been advocated as an adjunctive to improve the antibiotic use by physicians ^[5－9].

　　Although some investigations have shown that change of empiric antibiotics may reduce antibiotic resistance of Enterobacteriaceae ^[5]，or decrease the incidence of ventilator－associated pneumonia attributed to antibiotic－resistant GNB ^[6]，other studies revealed conflicting results concerning the influence of antibiotic change on the resistance profile of different nosocomial pathogens ^[8，9].

　　We performed a prospective study in critically ill patients in an intensive care unit （ICU）. The primary objective of our study is to determine whether restriction of third－generation cephalosporin use，especially ceftazidime，could result in significant reduction in the resistance to commonly used antibiotics，while the secondary objective is to test that such change of antibiotic strategy would improve the outcome of patients with infection.

　　MATERIALS AND METHODS

　　Study Population

　　Peking Union Medical College Hospital is a university－affiliated tertiary care hospital with 1200 beds. The intensive care unit is a 14－bed general ICU，with annual admission of approximately 600 patients. All patients admitted to ICU from January 1，2000 to December 31，2001 were eligible for the study. This study was approved by the institution ethics committee，and the requirement of informed consent was waived.

　　Study Design<?xml:namespace prefix = o ns = "urn:schemas-microsoft-com:office:office" />

　　This is a prospective，two－phase study to test the hypothesis that restriction of third－generation cephalosporin use for confirmed or suspected Gram－negative bacterial infections could improve bacterial resistance as well as patient outcome.

　　During phase I （January 1，2000 to December 31，2000），all patients with confirmed or suspected Gram－negative bacterial infections received definitive or empiric antibiotic treatment mainly with third－generation cephalosporins，including ceftazidime，ceftriaxone，and cefotaxime. Upon recognition of the increased resistance to third－generation cephalosporins among GNB，patients in the phase II （January 1，2001 to December 31，2001） were treated mainly with antibiotics other than third－generation cephalosporins （i.e. fourth－generation cephalosporins or carbapenems） for the same indications. The determination of the indication and duration of antibiotic therapy was left to the intensivists taking care of the patients. However，approval by an investigator （B.D.） was required prior to empiric or definitive use of third－generation cephalosporins，with the exception of the use of ceftriaxone and cefotaxime for surgical prophylaxis. In addition，one of the investigators （D.L.） made daily rounds with the intensivisits to insure full understanding and compliance with the study protocol.

　　Data Collection

　　For all patients，the following data were prospectively recorded： sex，age，major diagnosis，malignancy，length of hospital stay prior to ICU admission，severity of illness assessed by APACHE II （Acute Physiology and Chronic Health Evaluation） score ^[10]，chronic organ dysfunction based on APACHE II score，reasons for ICU admission based on disease categories of APACHE II score，infection focus，type of pathogens，antibiotic resistance profile，length of ICU stay and patient outcome. The patient was considered as admission for organ failure if SOFA （sequential organ failure assessment） score for any individual organ，namely cardiovascular，respiratory，renal，coagulation，hepatic or neurological system，was greater than 2 points ^[11]. The diagnosis of infection－related death was made by the intensivists who did not participate this study.

　　Surveillance of multiresistant pathogens in our ICU has been started for the purpose of infection control since 1994. Cultures were obtained according to clinical indications. One isolate was recorded per body site per patient. All isolates were identified with standard microbiological methods，and susceptibility testing was performed according to the guidelines of the National Committee for Clinical Laboratory Standards （NCCLS） ^[12]. The microbiological laboratory routinely tested isolates of Escherichia coli，Klebsiella spp.，and Pseudomonas aeruginosa for the presence of extended－spectrum beta－lactamase （ESBL）. In brief，a ? 5 mm increase in a zone diameter for ceftazidime or cefotaxime in combination with clavulanic acid versus its zone when tested alone indicated the production of ESBL （e.g. ceftazidime zone＝16 mm，ceftazidime / clavulanic acid zone ＝ 21 mm） ^[12]. Colonization or infection by each isolate was determined by criteria of the Centers for Disease Control and Prevention，Atlanta，Georgia ^[13]. An ICU－acquired infection was defined as an infection that was not present on ICU admission but developed after 72 hours of ICU stay.

18. Pittet B，Thievent B，Wenzel RP，et al. Bedside predction of mortality from bacteremic sepsis： a dynamic analysis of ICU patients. Am J Respir Crit Care Med 1996； 153： 684－93.<?xml:namespace prefix = o ns = "urn:schemas-microsoft-com:office:office" />

19. Quale J，Landman D，Atwood E，et al. Experience with a hospital－wide outbreak of vancomycin－resistant enterococci. Am J Infect Control 1996； 24： 372－9.

20. McGowen JE. Do intensive hospital antibiotic control programs prevent the spread of antibiotic resistance? Infect Control Hosp Epidemiol 1994； 15： 478－83.

21. Torres A，Aznar R，Gatell JM，et al. Incidence，risk，and prognosis factors of nosocomial pneumonia in mechanically ventilated patients. Am Rev Respir Dis 1990； 142： 523－8.

22. Ibrahim EH，Sherman G，Ward S，et al. The influence of inadequate antimicrobial treatment of bloodstream infections on patient outcomes in the ICU setting. Chest 2000； 118： 146－55.

23. Xu YC，Chen MJ，Biedenbach DJ，et al. Evaluation of the in vitro antimicrobial activity of cefepime compared to other broad－spectrum beta－lactams tested against recent clinical isolates from 10 Chinese hospitals. Diagn Microbiol Infect Dis 1999； 35： 135－42.

24. Ehrhardt AF，Sanders CC. Beta－lactam resistance amongst Enterobacter species. J Antimicrob Chemother 1993； 32 （suppl B）：1－11.

25. Joshi M，Brull R，Sompali N，et al. Clinical outcomes of cefepime treatment on infections caused by ESBL－ and AmpC－ producing Enterobacteriaceae. [Abstract #1716 ]. Program and abstracts of the 40^th Interscience Conference on Antimicrobial Agents and Chemotherapy； Sept 17－20，2000； Toronto，Ontario，Canada.

26. Bedenic B，Beader N，Zagar Z. Effect of inoculum size on the antibacterial activity of cefpirome and cefepime against Klebsiella pneumoniae strains producing SHV extended－spectrum beta－lactamases. Clin Microbiol Infect 2001； 7： 626－35.

27. Paterson DL，Ko WC，Mohapatra S，et al. Klebsiella pneumoniae bacteremia：impact of extended spectrum beta－lactamase （ESBL） production in a global study of 216 patients. [Abstract #J－210]. Abstracts of the 37^th Interscience Conference on Antimicrobial Agents and Chemotherapy； Sept 28－Oct 1，1997； Toronto，Ontario，Canada.

28. Lautenbach E，Patel JB，Bilker WB，et al. Extended－spectrum beta－lactamase－producing Escherichia coli and Klebsiella pneumoniae：risk factors for infection and impact of resistance on outcomes. Clin Infect Dis 2001； 32： 1162－71.