Infections in the Surgical Setting: Epidemiology and Effect of Treatment With Cefotaxime in a Multicenter Trial Including 3 , 0 3 2 Patients Gaetano Privitera, MD, Francesco Auxilia, MD, Giuseppe Ortisi, MD, Caterina Matinato, MS, Silvana Castaldi, MD, Antonio Pagano, MD, Milan, Italy
Hospital-acquired infections still represent a serious threat to the surgical patient. A nationwide survey of 2 5 9 Italian surgical wards involving 1 1 , 3 4 3 patients was conducted in October 1 9 8 8 . Hospitalacquired infections were r e c o r d e d in 5 6 5 (5%) patients: the microorganisms most commonly involved were gram-negative rods ( 6 0 % of all isolates), 4 1 % of the infected patients presented one or more intrinsic predisposing factor, and 6 5 % had undergone some invasive procedure. The studied group represented 2 3 % of all surgical patients in the country on the days of the survey. Following the epidemiologic survey, an open multicenter study was conducted in the same wards to e v a l u a t e the efficacy and tolerability of cefotaxime (1 g, 2 or 3 times per day) in the treatment of nosocomial surgical infections. Among 3 , 0 3 2 evaluable patients, 1 , 2 9 5 intra-abdominal, 6 1 0 wound and soft tissue, 5 5 4 urinary, and 3 6 7 respir a t o r y infections were observed. Treatment was judged to be clinically effective in 9 4 % of patients, and side effects, mostly involving the gastrointestinal tract, were observed in 1.4% of patients; but interruption of the treatment was required only in 19 patients (0.6%). This study confirms that cefotaxime, after over a decade of use, retains high efficacy in the treatment for nosocomial infections and induces a low rate of side effects.
mpiric treatment of severe infections occurring in hospitalized patients is one of the main indications E for the use of third-generation cephalosporins. These compounds have proved to be highly effective in the treatment of hospital-acquired pneumonia, urinary infections, selected intraabdominal infections, and meningitis; with exception of the latter, all other infections are commonly diagnosed in surgical patients. Surgical patients are particularly prone to develop infections because of the type of invasive procedures to which they are subjected, such as urinary catheterization, intravascular cannulation, wound drainage, or the presence of other indwelling medical devices. Intrinsic factors also influence the risk of developing an infection: age, malignancy, poor nutritional status, and the presence of other underlying diseases. While most postoperative wound infections are effectively prevented by perioperative administration of antibiotics, other infections not directly related to the surgical procedure also are prevented to a lesser extent by antibiotics. Infection remains a common occurrence in the surgical patient and the timely institution of adequate antimicrobial therapy is essential to good patient management. This report presents the results of a national epidemiogic study of nosocomial infections in surgical wards and the results of an open, multicenter trial conducted in these same wards to examine the efficacy of cefotaxime in treating postoperative infections.
PATIENTS AND METHODS
From the Institute of Hygiene and Preventive Medicine, University of Milan, IRCCS Ospedale Maggioreand Ospedale Niguarda Ca' Granda, Milan, Italy. This work was supported in part by a grant from Roussel Pharma S.p.A., Italy. Requests for reprints should be addressed to Professor Gaetano Privitera, Istituto di Igiene e Medicina Preventiva, Universith di Milano, Via F. Sforza, 35, 20122 Milan, Italy. 6S
Epidemiologic survey: The survey was designed as a point-prevalence study; the population investigated was hospitalized in 259 surgical wards in as many health care institutions all over Italy. Thirty-nine hospitals had > 1,000 beds, 85 hospitals had between 1,000 and 400 beds, and 135 had < 400 beds. Data were collected during October 26-28, 1988, from a total of 11,343 patients representing about 23% of the total number of patients hospitalized in surgical wards in Italy at the time of the survey. Nosocomial infections were reported by the wards' physicians, supported by specially trained supervisors. Infections were considered to be acquired in the hospital if they developed at least 48 hours after admission and were not known to be present or incubating at the time of admission. The definition of the infection was based on clinical criteria and often documented microbiologically. A form divided into two sections was compiled by the
THE AMERICAN JOURNAL OF SURGERY VOLUME 164 NO. 4A (SUPPL) OCTOBER1992
INFECTIONS IN SURGICALSETTING
supervisors of each ward. In the first section, information about the hospital was noted, e.g., number of beds, availability of microbiology laboratory, presence of an infection control committee, and bed occupancy rate at the time of the survey. The second section included demographic data on patients who presented with a nosocomial infection, e.g., age, sex, diagnosis at admission, surgical procedures, antibiotic prophylaxis, site of infection, pathogens isolated from culture materials associated with the infection, and risk factors. Clinical trial: The study was conducted over a 5-month period from November 1988 to March 1989. The study was approved by the institutional review boards of the participating hospitals and informed consent was obtained from all patients. This was an open, multicenter, noncomparative trial in which only patients admitted in the wards surveyed in the previous epidemiologic study and presenting with an infection were enrolled. Criteria for exclusion were the following: penicillin, cephalosporin, or lidocaine hypersensitivity or life-threatening infection. At enrollment, an arbitrary severity-of-illness index was determined for each patient by scoring the intensity of signs and symptoms. Appropriate specimens (blood, wound exudates, intraperitoneal fluid, sputum, urine) were collected for aerobic and anaerobic culture; in vitro susceptibility testing of the isolates was done by the Kirby-Bauer disk-diffusion method. The absence of a cultured pathogen did not exclude a patient from the study. Patients were assessed daily throughout the study and the scoring of signs and symptoms was determined again at day 3, day 5 and at the end of treatment. An overall evaluation for success or failure of the therapeutic regimen was also performed by the treating physician. Success was defined as recovery without either clinical or microbiological evidence of infection at the end of treatment; failure was defined as clinical evidence of continued or new infection, temperature > 38~ abscess formation, wound infection, or positive culture. Antibiotic treatment with cefotaxime was started after the diagnosis: schedule, route (either intramuscular or intravenous), and duration of drug administration were left to the discretion of the treating physician. The combination of cefotaxime with other antimicrobial drugs was permitted in the case of suspected or proven polymicrobial or mixed aerobic-anaerobic infection. Patients were monitored throughout the treatment for the occurrence of side effects related to drug administration. Patients' records were analyzed by an independent statistician using parametric and nonparametric methods, depending on the variables considered. The changes over time of the severity score assigned to the symptoms of each patient were evaluated by the Friedman nonparametric test and by the multiple comparison test (Newman-Keuls). RESULTS Epidelniologic survey: In the 11,343 patients surveyed, 565 infections were observed, giving an overall
TABLE I Distribution of Hospital-Acquired Infections by Size of Hospital No, of Hospital Beds
No. of Hospitals
No. of Patients
HAl
Prevalence (%)
> 1,000
39
1,765
105
5.9
400-1,000
85
4,132
199
4.8
133
5,421
259
4.8
2
25
2
259
11,343
565
1,000 beds, the prevalence of nosocomial infections was 6% compared with 5% in hospitals with 400-1,000 beds and 5% in smaller ones (Table I). Only 49 (19%) of the participating centers were conducting an active surveillance program of nosocomial infections through an infection control committee; the prevalence in these hospitals was 6% compared with 5% in the ones where the committee had not been instituted yet or was not active. Conversely, the presence of a clinical microbiology laboratory in the hospital did not influence the rate of diagnosed infections. The classification of hospital-acquired infections by site is reported in Table II. A total of 518 of 565 (92%) infections were grouped into four major categories: surgical wound infections, urinary tract infections, lower respiratory tract infections, and deep suppurative abdominal collections. The relative prevalence of septicemia was < 3%. An etiologic organism was isolated from 203 infec-
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PRIVITERA ET AL
TABLE III Distribution of Microorganisms Recorded as Causing Hospital-Acquired Infections
Cause of Infection
TABLE V Distribution of Extrinsic Risk Factors for Hospital-Acquired Infections Among the 565 Affected Patients
No. of Patients (%)
No. of Patients (%)
Gram-positive Staphylococcus aureus
12 (5)
Staphylococcus spp
27 (12)
Streptococcus pneumoniae
4 (2)
Streptococcus spp
11 (5)
Enterococcus faecalis
14 (6)
Unspecified gram-positive Total gram-positive
Indwelling catheter Central i.v. catheter i.v. devices Drainages Other* None reported
251 76 113 254 4 199
(44) (13) (20) (45) (1) (35)
i.v. = intravenous. *Endotrachealintubation,dialysis,etc.
7 (3) 75 (33)
Gram-negative Escherichia coil
72 (32)
Pseudomonas aeruginosa
24 (11)
Proteus spp
14 (6)
KES
7 (3)
Other Enterobacteriaceae
2 (1)
Unspecified gram-negative
17 (8)
Total gram-negative
TABLE Vl Demographic Characteristics of 3,130 Surgical Patients Treated with Cefotaxime Characteristic Sex Male (%) Female (%) Age years (range) Age > 60 yrs (%) Weight (kg; range) Length of stay (days; range)
136 (60)
Anaerobes Clostridium spp
3 (1)
Bacteroides spp
2 (1)
Unspecified anaerobe
2 (1)
Total anaerobes
Viruses 7 (3)
Other
2 (1)
Total
227 (100)
Intraabdominal Deep purulent collection Biliary tract infection Peritonitis
Skin and soft tissue
No. of Patients (%)
Diabetes
56 (10)
Anatomic abnormality
14 (3)
Neoplastic disease Other* None reported
25 (4) 335 (59)
THE AMERICAN JOURNAL OF SURGERY
386 141 43 40 554 (18)
Cystitis Pyelonephritis Prostatitis-epididymitis
176 (31)
*Obesity, dysproteinemia,chronic obstructivelung disease, cardiopathy,etc.
8S
Urinary tract
7 (1)
1,295 (43) 558 453 284
610 (21)
Surgical wound infection Abscess Necrotizing ulcer Cellulitis-pyodermatitis
TABLE IV Distribution of Intrinsic Risk Factors for Hospital-Acquired Infection Among the Affected Patients
Granulocytopenia
(53) (47) (1-96) (46) (6-116) (1-91)
No. of Patients (%)
Site
spp = species; KES = Klebsiella species, Enterobacterspecies, Serratia species.
Risk Factor
1,656 1,474 53 t ,389 65 16
TABLE VII Sites of Infection of 3,032 Surgical Patients Treated with Cefotaxime
7 (3)
Candida spp
Quantity
439 73 42
Lower respiratory tract Pneumonia-bronchopneumonia Bronchitis Empyema
367 (12) 265 67 35
Miscellaneous*
206 (7)
*Including genital, bone and joint, and multiple organ infections,and septicemia.
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tions (36%); a single pathogen was cultured in 183 patients, while multiple organisms were cultured in 20 patients. The cultured microorganisms are shown in Table III. Underlying predisposing conditions were widespread among the patients surveyed: 230/565 (41%) of the infected patients presented with one or more intrinsic risk factors, such as granulocytopenia, anatomic abnormality, diabetes, malignancy (Table IV). In this study, 366 (65%) patients with a nosocomial infection were considered to be at higher risk because of an indwelling medical device, most with more than one catheter or wound drain (Table V). Out of the 503 (89%) patients who had undergone a surgical procedure, 433 had received prophylactic antibiotics, mainly a cephalosporin. Clinical study: Of the 3,130 patients, 1,656 males and 1,474 females, who had enrolled in the study, 3,032 were evaluable for efficacy and tolerability. The demographic characteristics of the study population are summarized in Table VI. The infections that were diagnosed included intraabdominal, skin and soft tissue, urinary tract, and lower respiratory tract infections (Table VII). Peritonitis, primary or postoperative suppurative collections, and biliary tract infections are included among intraabdominal infections. The most commonly diagnosed infections, according to frequency, were: intraabdominal abscesses, biliary tract infections, cystitis, surgical wound infections, peritonitis, and pneumonia. Besides surgical procedures and other supportive treatments, all patients received cefotaxime, most (94%) as single antimicrobial therapy, but occasionally in combination with other antimicrobial agents that were mainly active against gram-negative bacilli (agents such as aminoglycosides or aztreonam) or anaerobic bacteria (agents such as clindamycin or metronidazole). The mean duration of cefotaxime therapy was 8 _+ 4 days and the mean daily dose was 2.5 g (Table VIII). An etiologic diagnosis was carried out in 622 patients, and 688 microorganisms were isolated; Escherichia cell and other Enterobacteriaceae belonging to miscellaneous species were the most commonly isolated, along with staphylococci (Table IX). Cefotaxime was highly effective, with an overall cure rate of 92% rising up to 94% when patients with incomplete follow-up were excluded (Table X). The treatment was equally effective regardless of the site of infection; success rates were based on the clinical response, which was judged to be either excellent or satisfactory depending on the basis of the regression of the score of the severity index assessed before, during, and at the end of therapy for each patient. Success rates were approximately 85-94% (Table XI). Treatment with cefotaxime was safe and well tolerated; only 73 of 2,578 evaluable patients (2.8%) had pain at the site of injection. Side effects were reported in 45 patients, consisting mainly in hypersensitivity reactions (16) or gastrointestinal discomfort (23) (Table XlI). The
TABLE VIII Summary, of Regimens and Dosage of Cefotaxime for 3,032 Surgical Patients Route of administration(no. of patients) Intramuscular
Intravenous Mean durationof therapy in days (range) Mean daily dose in g (range)* Mean no. of daily injections(range) No. of combinationtreatmentst
1,508
1,524 7.7 (1-66) 2.5 (2-6) 2.6 (2-6) 173
*Adult patients.
rAminoglycosides = 98; antianaerobic drugs = 25; a z t r e o n a m = 19; others = 3 ! .
TABLE IX Summary of the Microbiology Results for the 3,032 Infected Surg!cal Patients Treated with Cefotaxime No pathogensisolated Pathogensisolated
2,410 622 688
Organisms cultured Escherichia coil
311 112 66 61
Other Enterobacteriacaae Staphylococcus aureus
Coagu!ase-negativestaphylococci
42
Enterococcus faecalis Pseudomonas aemginosa
39 29 16 12
Streptococci Bacteroides fragilis Other organisms
TABLE X Overall Clinical Outcome for the 3,032 Surgical Patients Treated with Cefotaxime No. of Outcome
Patients (%)
Cure or improvement Failure Follow-up incomplete
2,776 (92)
173 (6) 83 (3)
side effects observed were generally mild; the treatment was discontinued only in 19 patients (0.6%). DISCUSSION The prevalence rate (5%) for nosocomial infections in Italian surgical wards shown in our multicenter study appears to be lower than the rates of some recently published European and U.S. studies [1]. There may be several factors accounting for this finding. Although infection control committees have been instituted in Italy since 1985 [2], only 19% of the surveyed centers had implemented a regular surveillance program for nosocomial infections. Therefore, some infections may not have been recognized as nosocomial in their origin because of the physician's lack of familiarity with surveil-
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PRIVITERA ET AL
T A B L E XI
Clinical Response by Site of Infection for the 3,032 Surgical Patients Treated with Cefotaxime
Site
Excellent (%)
Satisfactory (%)
Failure (%)
Not Evaluable {%)
Lower respiratory tract
195 (53)
146 (40)
13 (4)
7 (2)
Urinary tract
329 (59)
194 (35)
19 (3)
6 (1)
6 (1)
Intraabdominal Skin and soft tissue
784 (61) 294 (48)
424 (33) 234 (38)
50 (4) 30 (5)
17 (1) 12 (2)
20 (2) 40 (7)
Miscellaneous Total
TABLE
1O0 (49)
76 (37)
16 {2)
3 (2)
11 (5)
1,074 (35)
128 {4)
45 (2)
83 (3)
XII
No. of Side Effect
Patients
Hypersensitivity reactions
16
Nausea, abdominal cramps Diarrhea
4 19
Others Total
6 (2)
1,702 (56)
Side Effects Reported for Total 3,130 Surgical Patients Treated With Cefotaxime
6 45 (1.4%)
lance activities, despite the presence of an external supervisor. Indeed, some wards reported unexpectedly low infection prevalences. < 2%, in 26% of the participating hospitals. Another factor may be related to the methodology of the study itself, which was designed as a point-prevalence survey, implying specific limitations. In spite of these factors, the results observed are comparable with those from surveys conducted in other countries with respect to general patterns [1,3, 4]. Infection rates appeared to increase with the size of the hospital, as previously described [3]. This is probably related to differences in the patient selection in the patterns of hospital care among different hospitals; larger hospitals are usually referral centers, providing advanced medical or surgical treatment to high-risk patients. The etiologic agents identified follow the same pattern shown in other similar studies, with a predominance of gram-negative bacilli: however, gram-positive isolates, mostly staphylococci and enterococci, account for 33% of the total [1,3-5]. Infections occurring at the surgical site represent 49% of all infections diagnosed in our epidemiologic survey. These are, among hospital-acquired infections. those inducing the highest direct costs because they prolong the hospital stay by an average of 6 days, requiring specific treatment and sometimes further surgical intervention [6, 7]. These results of our open. noncomparative, multi: center clinical study on the use of cefotaxime in the treatment of infections in the surgical patient confirm the efficacy and safety of the drug in a large number of patients in a wide range of clinical indications. These 10S
Poor (%)
may be grouped in four major classes: intraabdominal, soft tissue, urinary tract, and lower respiratory tract infections, with clinical success rates in the range of 85-94% in treated patients. These results are consistent with other published data; in three multicenter trials of cefotaxime for treatment of lower respiratory infection reviewed by Perkins [8], the overall rates of bacteriologic and clinical cures were 90% and 94%, respectively. In an open multicenter trial involving 271 evaluable patients who received 2 g of cefotaxime intravenously or intramuscularly daily for 5-10 days for urinary tract infection, 84% of all causative pathogens were eradicated [9]. Cefotaxime was also reported to be clinically effective in 94% of 260 hospitalized patients with bacterial wound infections, cellulitis. abscesses, or necrotizing ulcers of the skin or subcutaneous tissues [10]. Concerning intraabdominal infections, early noncomparative studies indicated that cefotaxime at high daily doses might be useful as monotherapy in the treatment of peritonitis, biliary, pancreatic, and hepatic infections: in a single study it appeared as effective as a combination Of clindamycin and gentamicin in patients with peritonitis [11]. The consensus, however, was that following this indication, cefotaxime should be used with another antibiotic such as metronidazole, clindamycin. or piperacillin because of the relatively frequent isolation of Bacteroides strains resistant to cefotaxime. More experimental and clinical data concerning this indication have b e e n recently reported. Desacetylcefotaxime, the in vivo metabolite of cefotaxime possessing significant antimicrobial activity, has been shown to act synergistically against Bacteroides fragilis and strains belonging to o t h e r Bacteroides species, raising the activity of cefotaxime on these anaerobic organisms to 80-90% of tested isolates [12,13]. Recent studies also have confirmed that both cefotaxime and desacetylcefotaxime achieve effective antibacterial concentrations in several tissues and body fluids, such as bile. ascitic fluid, and peritoneal exudate [1416], and that treatment with cefotaxime, either alone o r in combination, may be as effective as standard regimens against intraabdominal sepsis [17,18]. These findings may explain the excellent results observed in our study in the treatment of intraabdominal infections, even when
THE AMERICAN JOURNAL OF SURGERY VOLUME 164 NO. 4A (SUPPL) OCTOBER 1992
INFECTIONS IN SURGICALSE'I~ING
cefotaxime was administered as a single antimicrobial agent every 8 or 12 hours. Cefotaxime appears to be a safe and well-tolerated antimicrobial agent. The most commonly observed side effects were hypersensitivity reactions and gastrointestinal symptoms. This study confirms that, among thirdgeneration cephalosporins, cefotaxime is associated with the lowest frequency of serious adverse effects. This excellent tolerability is also related to the fact that cefotaxime is excreted only slightly into the bile and does not possess the N-methylthiotetrazole side chain on its molecule, to which coagulation defects and disulfiramlike reactions are related following the administration of other compounds [19]. After one decade of clinical use and continuing experimentation, cefotaxime is not only effective and well tolerated in the empiric treatment of serious infections in the surgical patient, but it has now been shown to be highly effective in surgical prophylaxis, selective digestive decontamination, and treatment of pelvic inflammatory disease.
REFERENCES 1. Haley WR, Culver DH, White JW, Morgan WM, Emori TG. The nationwide nosocomial infection rate--a new need for vital statistics. Am J Epidemiol 1985; 121: 159-67. 2. Ministero della SanitY. Lotta contro le infezioni ospedaliere. Circ Min 1985; 52. 3. Mertens R, Kegels G, Stroobant A, et at. The national prevalence survey Of nosocomial infections in Belgium, 1984. J Hosp Infect 1987; 9: 21-229. 4. Moro ML, Stazi MA, Marasca G, Greco D, Zampieri A. National prevalence surveyof hospital-aequired infections in Italy. J Hosp Infect 1986; 8: 72-85. 5, LuscoG; Pasargiklian I, Signore!liC, Lunghi G, Mascheroni E. Infezioni nosocomiali:risultati di indagini di prevalenza in tre anni consecutivi (i983-85). Ig Mod 1986; 204-9. 6. Dixon RE. Cost of n0socomial infections and benefits of infections control programs. In: Wenzel RP; editor. Prevention and
control of nosocomial infections. Baltimore: William & Wilkins, 1987:19-25. 7. Saenz Gonzalez MC, Sanchez NR, Gonzales Celador R. Epidemiological study of surgical wound infections. Eur J Epidemiol 1986;2: 312-5. 8. Perkins RL. Clinical trials of cefotaxime for treatment of the lower respiratory tract. Rev Infect Dis 1982; 4 (suppl): $421-31. 9. Madsen PO, Treatment of urinary tract infectious with cefotaxime: non comparative and prospective comparative trials. Rev Infect Dis 1982; 4 (suppl): $416-20. 10. McCloskey RV, Goren N, Bissett D, Bentley J, Tutlane V. Cefotaxime in the treatment of infections of skin and skin structure. Rev Infect Dis 1982; 4 (suppl): $444-7. 11. Carmine AA, Brogden RN, Heel RC, Speight TM, Avery GS. Cefotaxime: a review of its antibacterial activity, pharmacological properties and therapeutic use. Drugs 1983;25: 223-89. 12. Canawati HN. Comparative in vitro activity of cefoxitin, cefotaxime alone and in combination with desacetylcefotaxime against the Bacteroides species. Diagn Microbiol Infect Dis 1989; 12: 33-37. 13. Aldridge KE. Comparison of the in vitro action and interaction of cefotaxime and desacetylcefotaximeagainst clinical isolates ofBacteroides spp. Diagn Microbiol Infect Dis 1989; 12: 45-50. 14. Jehl F, Peter JD, Picard A, et al. Investigation of biliary clearances of cefotaxime and desacetylcefotaxime by an original procedure in cholecystectomised patients. Infection 1987; 15: 450-4. 15. Hary L, Andrejak M, Leleu S, Orfila J, Capron JP. The pharmacokinetics of ceftriaxone and cefotaxime in cirrhotic patients with ascites. Eur J Clin Pharmacol 1989; 36: 613-6. 1 6. Runyon BA, AkriviadisEA, Sattler FR, Cohen J. Ascitic fluid and serum cefotaxime levels in patients treated for spontaneous peritonitis. Hepatology 1988; 8: 1246. 17, Biron S, Legtes G, Girard R, Lavardiere M, Delorme F. Short-term antibiotic therapy for intra-abdominal sepsis: prospective randomised trial comparing metronidazole-cefotaxime and clindamycin-tobramycin.Curr Ther Res 1988;43: 538-46. 18. Runyon BA, Akriviadis EA, Antillon MR, McHutchinson JG, Montano AA. Short course versus long course therapy of spontaneous bacterial peritonitis: a randomised trial of 70 patients. (Abstr.) Gastroenterology 1989; 96: 651. 19. Fekety FR. Safetyof parenteral third-generation cephalosporins. Am J Med 1990; 88 (suppl 4A): 39S-44S.
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Hospital-acquired infections still represent a serious threat to the surgical patient. A nationwide survey of 2 5 9 Italian surgical wards involving 1 1 , 3 4 3 patients was conducted in October 1 9 8 8 . Hospitalacquired infections were r e c o r d e d in 5 6 5 (5%) patients: the microorganisms most commonly involved were gram-negative rods ( 6 0 % of all isolates), 4 1 % of the infected patients presented one or more intrinsic predisposing factor, and 6 5 % had undergone some invasive procedure. The studied group represented 2 3 % of all surgical patients in the country on the days of the survey. Following the epidemiologic survey, an open multicenter study was conducted in the same wards to e v a l u a t e the efficacy and tolerability of cefotaxime (1 g, 2 or 3 times per day) in the treatment of nosocomial surgical infections. Among 3 , 0 3 2 evaluable patients, 1 , 2 9 5 intra-abdominal, 6 1 0 wound and soft tissue, 5 5 4 urinary, and 3 6 7 respir a t o r y infections were observed. Treatment was judged to be clinically effective in 9 4 % of patients, and side effects, mostly involving the gastrointestinal tract, were observed in 1.4% of patients; but interruption of the treatment was required only in 19 patients (0.6%). This study confirms that cefotaxime, after over a decade of use, retains high efficacy in the treatment for nosocomial infections and induces a low rate of side effects.
mpiric treatment of severe infections occurring in hospitalized patients is one of the main indications E for the use of third-generation cephalosporins. These compounds have proved to be highly effective in the treatment of hospital-acquired pneumonia, urinary infections, selected intraabdominal infections, and meningitis; with exception of the latter, all other infections are commonly diagnosed in surgical patients. Surgical patients are particularly prone to develop infections because of the type of invasive procedures to which they are subjected, such as urinary catheterization, intravascular cannulation, wound drainage, or the presence of other indwelling medical devices. Intrinsic factors also influence the risk of developing an infection: age, malignancy, poor nutritional status, and the presence of other underlying diseases. While most postoperative wound infections are effectively prevented by perioperative administration of antibiotics, other infections not directly related to the surgical procedure also are prevented to a lesser extent by antibiotics. Infection remains a common occurrence in the surgical patient and the timely institution of adequate antimicrobial therapy is essential to good patient management. This report presents the results of a national epidemiogic study of nosocomial infections in surgical wards and the results of an open, multicenter trial conducted in these same wards to examine the efficacy of cefotaxime in treating postoperative infections.
PATIENTS AND METHODS
From the Institute of Hygiene and Preventive Medicine, University of Milan, IRCCS Ospedale Maggioreand Ospedale Niguarda Ca' Granda, Milan, Italy. This work was supported in part by a grant from Roussel Pharma S.p.A., Italy. Requests for reprints should be addressed to Professor Gaetano Privitera, Istituto di Igiene e Medicina Preventiva, Universith di Milano, Via F. Sforza, 35, 20122 Milan, Italy. 6S
Epidemiologic survey: The survey was designed as a point-prevalence study; the population investigated was hospitalized in 259 surgical wards in as many health care institutions all over Italy. Thirty-nine hospitals had > 1,000 beds, 85 hospitals had between 1,000 and 400 beds, and 135 had < 400 beds. Data were collected during October 26-28, 1988, from a total of 11,343 patients representing about 23% of the total number of patients hospitalized in surgical wards in Italy at the time of the survey. Nosocomial infections were reported by the wards' physicians, supported by specially trained supervisors. Infections were considered to be acquired in the hospital if they developed at least 48 hours after admission and were not known to be present or incubating at the time of admission. The definition of the infection was based on clinical criteria and often documented microbiologically. A form divided into two sections was compiled by the
THE AMERICAN JOURNAL OF SURGERY VOLUME 164 NO. 4A (SUPPL) OCTOBER1992
INFECTIONS IN SURGICALSETTING
supervisors of each ward. In the first section, information about the hospital was noted, e.g., number of beds, availability of microbiology laboratory, presence of an infection control committee, and bed occupancy rate at the time of the survey. The second section included demographic data on patients who presented with a nosocomial infection, e.g., age, sex, diagnosis at admission, surgical procedures, antibiotic prophylaxis, site of infection, pathogens isolated from culture materials associated with the infection, and risk factors. Clinical trial: The study was conducted over a 5-month period from November 1988 to March 1989. The study was approved by the institutional review boards of the participating hospitals and informed consent was obtained from all patients. This was an open, multicenter, noncomparative trial in which only patients admitted in the wards surveyed in the previous epidemiologic study and presenting with an infection were enrolled. Criteria for exclusion were the following: penicillin, cephalosporin, or lidocaine hypersensitivity or life-threatening infection. At enrollment, an arbitrary severity-of-illness index was determined for each patient by scoring the intensity of signs and symptoms. Appropriate specimens (blood, wound exudates, intraperitoneal fluid, sputum, urine) were collected for aerobic and anaerobic culture; in vitro susceptibility testing of the isolates was done by the Kirby-Bauer disk-diffusion method. The absence of a cultured pathogen did not exclude a patient from the study. Patients were assessed daily throughout the study and the scoring of signs and symptoms was determined again at day 3, day 5 and at the end of treatment. An overall evaluation for success or failure of the therapeutic regimen was also performed by the treating physician. Success was defined as recovery without either clinical or microbiological evidence of infection at the end of treatment; failure was defined as clinical evidence of continued or new infection, temperature > 38~ abscess formation, wound infection, or positive culture. Antibiotic treatment with cefotaxime was started after the diagnosis: schedule, route (either intramuscular or intravenous), and duration of drug administration were left to the discretion of the treating physician. The combination of cefotaxime with other antimicrobial drugs was permitted in the case of suspected or proven polymicrobial or mixed aerobic-anaerobic infection. Patients were monitored throughout the treatment for the occurrence of side effects related to drug administration. Patients' records were analyzed by an independent statistician using parametric and nonparametric methods, depending on the variables considered. The changes over time of the severity score assigned to the symptoms of each patient were evaluated by the Friedman nonparametric test and by the multiple comparison test (Newman-Keuls). RESULTS Epidelniologic survey: In the 11,343 patients surveyed, 565 infections were observed, giving an overall
TABLE I Distribution of Hospital-Acquired Infections by Size of Hospital No, of Hospital Beds
No. of Hospitals
No. of Patients
HAl
Prevalence (%)
> 1,000
39
1,765
105
5.9
400-1,000
85
4,132
199
4.8
133
5,421
259
4.8
2
25
2
259
11,343
565
1,000 beds, the prevalence of nosocomial infections was 6% compared with 5% in hospitals with 400-1,000 beds and 5% in smaller ones (Table I). Only 49 (19%) of the participating centers were conducting an active surveillance program of nosocomial infections through an infection control committee; the prevalence in these hospitals was 6% compared with 5% in the ones where the committee had not been instituted yet or was not active. Conversely, the presence of a clinical microbiology laboratory in the hospital did not influence the rate of diagnosed infections. The classification of hospital-acquired infections by site is reported in Table II. A total of 518 of 565 (92%) infections were grouped into four major categories: surgical wound infections, urinary tract infections, lower respiratory tract infections, and deep suppurative abdominal collections. The relative prevalence of septicemia was < 3%. An etiologic organism was isolated from 203 infec-
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TABLE III Distribution of Microorganisms Recorded as Causing Hospital-Acquired Infections
Cause of Infection
TABLE V Distribution of Extrinsic Risk Factors for Hospital-Acquired Infections Among the 565 Affected Patients
No. of Patients (%)
No. of Patients (%)
Gram-positive Staphylococcus aureus
12 (5)
Staphylococcus spp
27 (12)
Streptococcus pneumoniae
4 (2)
Streptococcus spp
11 (5)
Enterococcus faecalis
14 (6)
Unspecified gram-positive Total gram-positive
Indwelling catheter Central i.v. catheter i.v. devices Drainages Other* None reported
251 76 113 254 4 199
(44) (13) (20) (45) (1) (35)
i.v. = intravenous. *Endotrachealintubation,dialysis,etc.
7 (3) 75 (33)
Gram-negative Escherichia coil
72 (32)
Pseudomonas aeruginosa
24 (11)
Proteus spp
14 (6)
KES
7 (3)
Other Enterobacteriaceae
2 (1)
Unspecified gram-negative
17 (8)
Total gram-negative
TABLE Vl Demographic Characteristics of 3,130 Surgical Patients Treated with Cefotaxime Characteristic Sex Male (%) Female (%) Age years (range) Age > 60 yrs (%) Weight (kg; range) Length of stay (days; range)
136 (60)
Anaerobes Clostridium spp
3 (1)
Bacteroides spp
2 (1)
Unspecified anaerobe
2 (1)
Total anaerobes
Viruses 7 (3)
Other
2 (1)
Total
227 (100)
Intraabdominal Deep purulent collection Biliary tract infection Peritonitis
Skin and soft tissue
No. of Patients (%)
Diabetes
56 (10)
Anatomic abnormality
14 (3)
Neoplastic disease Other* None reported
25 (4) 335 (59)
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386 141 43 40 554 (18)
Cystitis Pyelonephritis Prostatitis-epididymitis
176 (31)
*Obesity, dysproteinemia,chronic obstructivelung disease, cardiopathy,etc.
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Urinary tract
7 (1)
1,295 (43) 558 453 284
610 (21)
Surgical wound infection Abscess Necrotizing ulcer Cellulitis-pyodermatitis
TABLE IV Distribution of Intrinsic Risk Factors for Hospital-Acquired Infection Among the Affected Patients
Granulocytopenia
(53) (47) (1-96) (46) (6-116) (1-91)
No. of Patients (%)
Site
spp = species; KES = Klebsiella species, Enterobacterspecies, Serratia species.
Risk Factor
1,656 1,474 53 t ,389 65 16
TABLE VII Sites of Infection of 3,032 Surgical Patients Treated with Cefotaxime
7 (3)
Candida spp
Quantity
439 73 42
Lower respiratory tract Pneumonia-bronchopneumonia Bronchitis Empyema
367 (12) 265 67 35
Miscellaneous*
206 (7)
*Including genital, bone and joint, and multiple organ infections,and septicemia.
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tions (36%); a single pathogen was cultured in 183 patients, while multiple organisms were cultured in 20 patients. The cultured microorganisms are shown in Table III. Underlying predisposing conditions were widespread among the patients surveyed: 230/565 (41%) of the infected patients presented with one or more intrinsic risk factors, such as granulocytopenia, anatomic abnormality, diabetes, malignancy (Table IV). In this study, 366 (65%) patients with a nosocomial infection were considered to be at higher risk because of an indwelling medical device, most with more than one catheter or wound drain (Table V). Out of the 503 (89%) patients who had undergone a surgical procedure, 433 had received prophylactic antibiotics, mainly a cephalosporin. Clinical study: Of the 3,130 patients, 1,656 males and 1,474 females, who had enrolled in the study, 3,032 were evaluable for efficacy and tolerability. The demographic characteristics of the study population are summarized in Table VI. The infections that were diagnosed included intraabdominal, skin and soft tissue, urinary tract, and lower respiratory tract infections (Table VII). Peritonitis, primary or postoperative suppurative collections, and biliary tract infections are included among intraabdominal infections. The most commonly diagnosed infections, according to frequency, were: intraabdominal abscesses, biliary tract infections, cystitis, surgical wound infections, peritonitis, and pneumonia. Besides surgical procedures and other supportive treatments, all patients received cefotaxime, most (94%) as single antimicrobial therapy, but occasionally in combination with other antimicrobial agents that were mainly active against gram-negative bacilli (agents such as aminoglycosides or aztreonam) or anaerobic bacteria (agents such as clindamycin or metronidazole). The mean duration of cefotaxime therapy was 8 _+ 4 days and the mean daily dose was 2.5 g (Table VIII). An etiologic diagnosis was carried out in 622 patients, and 688 microorganisms were isolated; Escherichia cell and other Enterobacteriaceae belonging to miscellaneous species were the most commonly isolated, along with staphylococci (Table IX). Cefotaxime was highly effective, with an overall cure rate of 92% rising up to 94% when patients with incomplete follow-up were excluded (Table X). The treatment was equally effective regardless of the site of infection; success rates were based on the clinical response, which was judged to be either excellent or satisfactory depending on the basis of the regression of the score of the severity index assessed before, during, and at the end of therapy for each patient. Success rates were approximately 85-94% (Table XI). Treatment with cefotaxime was safe and well tolerated; only 73 of 2,578 evaluable patients (2.8%) had pain at the site of injection. Side effects were reported in 45 patients, consisting mainly in hypersensitivity reactions (16) or gastrointestinal discomfort (23) (Table XlI). The
TABLE VIII Summary, of Regimens and Dosage of Cefotaxime for 3,032 Surgical Patients Route of administration(no. of patients) Intramuscular
Intravenous Mean durationof therapy in days (range) Mean daily dose in g (range)* Mean no. of daily injections(range) No. of combinationtreatmentst
1,508
1,524 7.7 (1-66) 2.5 (2-6) 2.6 (2-6) 173
*Adult patients.
rAminoglycosides = 98; antianaerobic drugs = 25; a z t r e o n a m = 19; others = 3 ! .
TABLE IX Summary of the Microbiology Results for the 3,032 Infected Surg!cal Patients Treated with Cefotaxime No pathogensisolated Pathogensisolated
2,410 622 688
Organisms cultured Escherichia coil
311 112 66 61
Other Enterobacteriacaae Staphylococcus aureus
Coagu!ase-negativestaphylococci
42
Enterococcus faecalis Pseudomonas aemginosa
39 29 16 12
Streptococci Bacteroides fragilis Other organisms
TABLE X Overall Clinical Outcome for the 3,032 Surgical Patients Treated with Cefotaxime No. of Outcome
Patients (%)
Cure or improvement Failure Follow-up incomplete
2,776 (92)
173 (6) 83 (3)
side effects observed were generally mild; the treatment was discontinued only in 19 patients (0.6%). DISCUSSION The prevalence rate (5%) for nosocomial infections in Italian surgical wards shown in our multicenter study appears to be lower than the rates of some recently published European and U.S. studies [1]. There may be several factors accounting for this finding. Although infection control committees have been instituted in Italy since 1985 [2], only 19% of the surveyed centers had implemented a regular surveillance program for nosocomial infections. Therefore, some infections may not have been recognized as nosocomial in their origin because of the physician's lack of familiarity with surveil-
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T A B L E XI
Clinical Response by Site of Infection for the 3,032 Surgical Patients Treated with Cefotaxime
Site
Excellent (%)
Satisfactory (%)
Failure (%)
Not Evaluable {%)
Lower respiratory tract
195 (53)
146 (40)
13 (4)
7 (2)
Urinary tract
329 (59)
194 (35)
19 (3)
6 (1)
6 (1)
Intraabdominal Skin and soft tissue
784 (61) 294 (48)
424 (33) 234 (38)
50 (4) 30 (5)
17 (1) 12 (2)
20 (2) 40 (7)
Miscellaneous Total
TABLE
1O0 (49)
76 (37)
16 {2)
3 (2)
11 (5)
1,074 (35)
128 {4)
45 (2)
83 (3)
XII
No. of Side Effect
Patients
Hypersensitivity reactions
16
Nausea, abdominal cramps Diarrhea
4 19
Others Total
6 (2)
1,702 (56)
Side Effects Reported for Total 3,130 Surgical Patients Treated With Cefotaxime
6 45 (1.4%)
lance activities, despite the presence of an external supervisor. Indeed, some wards reported unexpectedly low infection prevalences. < 2%, in 26% of the participating hospitals. Another factor may be related to the methodology of the study itself, which was designed as a point-prevalence survey, implying specific limitations. In spite of these factors, the results observed are comparable with those from surveys conducted in other countries with respect to general patterns [1,3, 4]. Infection rates appeared to increase with the size of the hospital, as previously described [3]. This is probably related to differences in the patient selection in the patterns of hospital care among different hospitals; larger hospitals are usually referral centers, providing advanced medical or surgical treatment to high-risk patients. The etiologic agents identified follow the same pattern shown in other similar studies, with a predominance of gram-negative bacilli: however, gram-positive isolates, mostly staphylococci and enterococci, account for 33% of the total [1,3-5]. Infections occurring at the surgical site represent 49% of all infections diagnosed in our epidemiologic survey. These are, among hospital-acquired infections. those inducing the highest direct costs because they prolong the hospital stay by an average of 6 days, requiring specific treatment and sometimes further surgical intervention [6, 7]. These results of our open. noncomparative, multi: center clinical study on the use of cefotaxime in the treatment of infections in the surgical patient confirm the efficacy and safety of the drug in a large number of patients in a wide range of clinical indications. These 10S
Poor (%)
may be grouped in four major classes: intraabdominal, soft tissue, urinary tract, and lower respiratory tract infections, with clinical success rates in the range of 85-94% in treated patients. These results are consistent with other published data; in three multicenter trials of cefotaxime for treatment of lower respiratory infection reviewed by Perkins [8], the overall rates of bacteriologic and clinical cures were 90% and 94%, respectively. In an open multicenter trial involving 271 evaluable patients who received 2 g of cefotaxime intravenously or intramuscularly daily for 5-10 days for urinary tract infection, 84% of all causative pathogens were eradicated [9]. Cefotaxime was also reported to be clinically effective in 94% of 260 hospitalized patients with bacterial wound infections, cellulitis. abscesses, or necrotizing ulcers of the skin or subcutaneous tissues [10]. Concerning intraabdominal infections, early noncomparative studies indicated that cefotaxime at high daily doses might be useful as monotherapy in the treatment of peritonitis, biliary, pancreatic, and hepatic infections: in a single study it appeared as effective as a combination Of clindamycin and gentamicin in patients with peritonitis [11]. The consensus, however, was that following this indication, cefotaxime should be used with another antibiotic such as metronidazole, clindamycin. or piperacillin because of the relatively frequent isolation of Bacteroides strains resistant to cefotaxime. More experimental and clinical data concerning this indication have b e e n recently reported. Desacetylcefotaxime, the in vivo metabolite of cefotaxime possessing significant antimicrobial activity, has been shown to act synergistically against Bacteroides fragilis and strains belonging to o t h e r Bacteroides species, raising the activity of cefotaxime on these anaerobic organisms to 80-90% of tested isolates [12,13]. Recent studies also have confirmed that both cefotaxime and desacetylcefotaxime achieve effective antibacterial concentrations in several tissues and body fluids, such as bile. ascitic fluid, and peritoneal exudate [1416], and that treatment with cefotaxime, either alone o r in combination, may be as effective as standard regimens against intraabdominal sepsis [17,18]. These findings may explain the excellent results observed in our study in the treatment of intraabdominal infections, even when
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cefotaxime was administered as a single antimicrobial agent every 8 or 12 hours. Cefotaxime appears to be a safe and well-tolerated antimicrobial agent. The most commonly observed side effects were hypersensitivity reactions and gastrointestinal symptoms. This study confirms that, among thirdgeneration cephalosporins, cefotaxime is associated with the lowest frequency of serious adverse effects. This excellent tolerability is also related to the fact that cefotaxime is excreted only slightly into the bile and does not possess the N-methylthiotetrazole side chain on its molecule, to which coagulation defects and disulfiramlike reactions are related following the administration of other compounds [19]. After one decade of clinical use and continuing experimentation, cefotaxime is not only effective and well tolerated in the empiric treatment of serious infections in the surgical patient, but it has now been shown to be highly effective in surgical prophylaxis, selective digestive decontamination, and treatment of pelvic inflammatory disease.
REFERENCES 1. Haley WR, Culver DH, White JW, Morgan WM, Emori TG. The nationwide nosocomial infection rate--a new need for vital statistics. Am J Epidemiol 1985; 121: 159-67. 2. Ministero della SanitY. Lotta contro le infezioni ospedaliere. Circ Min 1985; 52. 3. Mertens R, Kegels G, Stroobant A, et at. The national prevalence survey Of nosocomial infections in Belgium, 1984. J Hosp Infect 1987; 9: 21-229. 4. Moro ML, Stazi MA, Marasca G, Greco D, Zampieri A. National prevalence surveyof hospital-aequired infections in Italy. J Hosp Infect 1986; 8: 72-85. 5, LuscoG; Pasargiklian I, Signore!liC, Lunghi G, Mascheroni E. Infezioni nosocomiali:risultati di indagini di prevalenza in tre anni consecutivi (i983-85). Ig Mod 1986; 204-9. 6. Dixon RE. Cost of n0socomial infections and benefits of infections control programs. In: Wenzel RP; editor. Prevention and
control of nosocomial infections. Baltimore: William & Wilkins, 1987:19-25. 7. Saenz Gonzalez MC, Sanchez NR, Gonzales Celador R. Epidemiological study of surgical wound infections. Eur J Epidemiol 1986;2: 312-5. 8. Perkins RL. Clinical trials of cefotaxime for treatment of the lower respiratory tract. Rev Infect Dis 1982; 4 (suppl): $421-31. 9. Madsen PO, Treatment of urinary tract infectious with cefotaxime: non comparative and prospective comparative trials. Rev Infect Dis 1982; 4 (suppl): $416-20. 10. McCloskey RV, Goren N, Bissett D, Bentley J, Tutlane V. Cefotaxime in the treatment of infections of skin and skin structure. Rev Infect Dis 1982; 4 (suppl): $444-7. 11. Carmine AA, Brogden RN, Heel RC, Speight TM, Avery GS. Cefotaxime: a review of its antibacterial activity, pharmacological properties and therapeutic use. Drugs 1983;25: 223-89. 12. Canawati HN. Comparative in vitro activity of cefoxitin, cefotaxime alone and in combination with desacetylcefotaxime against the Bacteroides species. Diagn Microbiol Infect Dis 1989; 12: 33-37. 13. Aldridge KE. Comparison of the in vitro action and interaction of cefotaxime and desacetylcefotaximeagainst clinical isolates ofBacteroides spp. Diagn Microbiol Infect Dis 1989; 12: 45-50. 14. Jehl F, Peter JD, Picard A, et al. Investigation of biliary clearances of cefotaxime and desacetylcefotaxime by an original procedure in cholecystectomised patients. Infection 1987; 15: 450-4. 15. Hary L, Andrejak M, Leleu S, Orfila J, Capron JP. The pharmacokinetics of ceftriaxone and cefotaxime in cirrhotic patients with ascites. Eur J Clin Pharmacol 1989; 36: 613-6. 1 6. Runyon BA, AkriviadisEA, Sattler FR, Cohen J. Ascitic fluid and serum cefotaxime levels in patients treated for spontaneous peritonitis. Hepatology 1988; 8: 1246. 17, Biron S, Legtes G, Girard R, Lavardiere M, Delorme F. Short-term antibiotic therapy for intra-abdominal sepsis: prospective randomised trial comparing metronidazole-cefotaxime and clindamycin-tobramycin.Curr Ther Res 1988;43: 538-46. 18. Runyon BA, Akriviadis EA, Antillon MR, McHutchinson JG, Montano AA. Short course versus long course therapy of spontaneous bacterial peritonitis: a randomised trial of 70 patients. (Abstr.) Gastroenterology 1989; 96: 651. 19. Fekety FR. Safetyof parenteral third-generation cephalosporins. Am J Med 1990; 88 (suppl 4A): 39S-44S.
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