Online Supplement for: INFLUENCE OF COMBINED INTRAVENOUS AND TOPICAL ANTIBIOTIC PROPHYLAXIS ON THE INCIDENCE OF INFECTIONS, ORGAN DYSFUNCTIONS, AND MORTALITY IN CRITICALLY ILL SURGICAL PATIENTS A PROSPECTIVE, STRATIFIED, RANDOMIZED, DOUBLE-BLIND, PLACEBO-CONTROLLED CLINICAL TRIAL Figure E1. Comparison of percent of patients treated with specific antibiotics. Second generation cephalosporins: cefotiame, cefamandole, cefoxitine. Third generation cephalosporins: cefotaxime, ceftriaxone, cefmenoxime, ceftazidime. Acylaminopenicillins: piperacillin, mezlocillin. Carbapenem: imipenem-cilastatin. Quinolones: ciprofloxacin, ofloxacin. Aminoglycosides: tobramycin, gentamicin, amikacin. Figure E1. Therapeutic use of antibiotics. Therapeutic use of antibiotics 25 % of patients treated 20 15 10 5 0 2nd gen. Cephalosporins 3rd gen. Cephalosporins Acylaminopenicillins Carbapenems Quinolones Aminoglycosides Erythromycin Metronidazole Clindamycin Vancomycin prophylaxis placebo
TABLE E1. DEFINITIONS OF ORGAN SYSTEM DYSFUNCTIONS AND OF IRREVERSIBLE ORGAN FAILURES, MODIFIED FROM (E1 E3) Organ System Severe Dysfunction Irreversible Failure* Circulation Heart Lung CNS Coagulation Hematological system SVR < 800 dyne/sec/cm 5 or serum lactate > 2.2 mg/dl or need for catecholamines to keep systolic blood pressure > 90 mmhg despite adequate volume replacement Cardiac index < 2 L/min/m 2 or successful cardiopulmonary resuscitation after ventricular fibrillation / asystole Acute lung injury (ALI) with bilateral infiltrates on chest radiograph without clinical evidence of left heart failure (PCWP < 18 mm Hg) and P a O 2 /FIO 2 < 300 or multilobar pneumonia GCS < 8 for more than 3 days or GCS < 5 for more than 24 h Fibrinogen < 100 mg/dl or partial thromboplastin time prolonged > 1.5 times of normal value or platelet count < 60.000/µL Excessive blood loss leading to systolic blood pressure < 90 mm Hg for more than 2 h and need for inotropic support/ transfusion of packed red blood cells Progressive circulatory failure not responding to fluids and catecholamines Irreversible cardiogenic shock or ventricular fibrillation/asystole or right heart failure following pulmonary embolism Hypoxia/respiratory acidosis (P a O 2 < 40 mm Hg/pH < 7.1) despite all efforts of ventilatory management Brain death Microvascular bleeding despite surgical interventions and/or transfusion of blood products Blood loss not caused by coagulation disorder and not manageable by surgery Liver Bilirubin > 6 mg/dl Progressive liver dysfunction and hepatic encephalopathy/ hepato-renal syndrome Kidney Gastrointestinal tract Creatinine > 5 mg/dl, renal replacement therapy Rupture of bowel or intra-abdominal necrosis amenable to surgery or pancreatitis with shock (systolic blood pressure < 90 mm Hg for more than 2 h, need for inotropic support despite adequate volume replacement) Renal failure with hyperkalemia/ hypercalcemia leading to cardiac arrest Rupture or necrosis of abdominal organ not manageable by surgery or pancreatitis with irreversible shock Definition of abbreviations: CNS = central nervous system; GCS = Glasgow Coma Scale; SVR = systemic vascular resistance. * Presence of irreversible organ failure was counted as primary cause of death. E2
TABLE E2. DEMOGRAFIC AND DIAGNOSTIC INFORMATION ON THE STUDY PATIENTS ON ADMISSION Characteristic Prophylaxis Placebo (n = 262) (n = 265) Age, y 52.7 ± 18.8 53.7 ± 19.0 Age > 70 y 52 (20) 55 (21) Males/females 167/98 160/102 Body weight, kg 73.9 ± 13.4 75.5 ± 15.0 Body height, cm 171.0 ± 8.6 171.1 ± 8.5 Severity of diseases APACHE-II scores 20.4 ± 6.7 20.2 ± 6.8 Expected mortality (MPM 0 )* 0.26 ± 0.24 0.25 ± 0.24 Expected mortality (APACHE-II) 0.29 ± 0.20 0.30 ± 0.21 TISS points 44.9 ± 9.5 44.3 ± 8.0 APACHE-II scores 19 (stratum I) 120 (45.3) 121 (46.2) APACHE-II scores 20 29 (stratum II) 122 (46.0) 115 (43.9) APACHE-II scores 30 (stratum III) 23 (8.7) 26 (9.9) Type of admission Admission after surgery 172 (64.9) 179 (68.3) Admission from other ICU 41 (15.5) 47 (17.9) Admission from general ward 33 (12.5) 29 (11.1) Diagnoses CPR within preceding 24 h 17 (6.4) 13 (5.0) Respiratory failure 164 (61.9) 165 (63.0) COPD 21 (7.9) 26 (9.9) Thoracic or abdominal surgery 75 (28.3) 78 (29.8) Surgery for polytrauma 33 (12.5) 30 (11.5) Impaired consciousness 76 (28.7) 73 (27.8) Cranial injury 34 (12.8) 37 (14.1) Status post craniotomy 20 (7.5) 25 (9.5) Organ system dysfunction (any) 169 (63.8) 170 (64.9) Circulation 124 (46.8) 136 (51.9) Heart 23 (8.7) 18 (6.9) Lung 43 (16.2) 56 (21.4) Central nervous system 35 (13.2) 34 (13.0) Coagulation 12 (4.5) 18 (6.9) Hematological system 19 (7.2) 23 (8.8) Liver 35 (13.2) 38 (14.5) Kidney 59 (22.3) 77 (29.4) Gastro-intestinal tract 20 (7.5) 26 (9.9) Infection (any) 101 (38.1) 110 (42.0) Pneumonia 16 (6.0) 17 (6.5) Lower respiratory tract (excluding pneumonia) 57 (21.5) 63 (24.0) Bloodstream 9 (3.4) 8 (3.1) Urinary tract 11 (4.2) 15 (5.7) Intra-abdominal 10 (3.8) 14 (5.3) Wound 2 (0.8) 2 (0.8) Other 16 (6.0) 11 (4.2) Treatment Tracheal intubation 247 (93) 241 (92) Systemic antibiotic treatment 56 (21.1) 64 (24.4) Perioperative antibiotic prophylaxis 114 (43.0) 105 (40.1) Immunosuppressive therapy 15 (5.7) 15 (5.7) Parenteral nutrition 41 (15.5) 43 (16.4) Definition of abbreviations: CPR = cardiopulmonary resuscitation; COPD = chronic obstructive pulmonary disease. * Mortality calculated according to mortality prediction model (MPM 0 ). Mortality calculated according to APACHE II. Plus-minus values are means ± SD. Values in parentheses are percentages. E3
TABLE E3. NUMBERS OF PATIENTS COLONIZED BY RESISTANT BACTERIA Prophylaxis Group On Admission During Study End of Study No. of Patients Examined 207 175 144 Ci Ge Po Ci Ge Po Ci Ge Po Escherichia coli 1 1 1 Klebsiella spp. 1 1 1 1 Proteus spp. 10 9 6 Other Enterobacteriaceae 2 1 1 2 Pseudomonas spp. 3 2 1 3 5 4 Acinetobacter spp. 1 2 Ci Ge Ox Ci Ge Ox Ci Ge Ox Staphylococcus aureus 2 1 3 6 2 2 2 1 Coagulase-negative staph. 11 19 16 53 62 58 20 24 22 Enterococcus spp. 4 33 13 53 5 14 Placebo Group On Admission During Study End of Study No. of Patients Examined 203 171 138 Ci Ge Po Ci Ge Po Ci Ge Po Escherichia coli 2 2 2 Klebsiella spp. 1 1 2 Proteus spp. 15 1 29 10 Other Enterobacteriaceae 3 1 3 2 Pseudomonas spp. 2 2 2 10 1 3 Acinetobacter spp. 2 Ci Ge Ox Ci Ge Ox Ci Ge Ox Staphylococcus aureus 2 2 1 9 11 7 4 4 1 Coagulase-negative staph. 8 17 18 48 66 63 17 20 18 Enterococcus spp. 5 39 18 88 3 30 Definition of abbreviations: Ci = ciprofloxacin; Ge = gentamicin; Po = polymyxin B; Ox = oxacillin. Summary data from surveillance cultures, which were regularly performed from tracheobronchial, oropharyngeal, and gastric secretions, and from rectal swabs. Patients were considered to be colonized if resistant bacteria were recovered at least once from any of these sources. Polymyxin resistance was tested for Gram-negative bacteria only and oxacillin resistance only for staphylococci. E4
References E1. Goris RJA, te Boekhorst A, Nuytinck JKS, Gimbrère JSF. Multiple-Organ-Failure. Generalized autodestructive inflammation? Arch Surg 1985;120:1109-1115. E2. Knaus WA, Draper EA, Wagner DP, Zimmerman JE. Prognosis in acute organ-system failure. Ann Surg 1985;202:685-693. E3. Montgomery AB, Stager MA, Carrico CJ, Hudson LD. Causes of mortality in patients with the adult respiratory distress syndrome. Am Rev Respir Dis 1985;132:485-489. E5