Strategies in the Selection of Antibiotic Therapy in the ICU Mazen Kherallah, MD, FCCP King Faisal Specialist Hospital & Research Center

Scope of the Problem Inadequate Initial Antibiotic TherapyBacterial Resistance

Infection Distribution in Adult ICU’s Major Types of Infection (NNIS data, )

Nosocomial Infection Richards MJ et al, CCM. 1999;27:

NNIS

Pathogens Most Frequently associated with Nosocomial Pneumonia in the ICU

Inadequate Initial Antibiotic Therapy Inadequate Initial Antibiotic Therapy

Initial Inadequate Therapy

Mortality Associated with Initial Inadequate Therapy

Resistant Pathogens, Inadequate Treatment and Mortality (BSI) Ibrahim EH, et al. Chest 2000;118:

Inadequate Antimicrobial Therapy ► 2000 consecutive MICU/SICU patients ► 655 (25.8%) with infections ► 169 (8.5%) with inadequate therapy Kollef MH, et al chest. February 1999;115(2):

Infection Classification Kollef MH, et al chest. February 1999;115(2):

Cohort of Infected Patients and Inadequate Therapy Kollef MH, et al chest. February 1999;115(2):

Most Common Pathogens ► Inadequate therapy (n=169)  P. aeruginosa: 53  MRSA: 45  VRE: 13 ► Adequate therapy (n=486)  Escherchia coli: 76  MSSA: 88 Kollef MH, et al chest. February 1999;115(2):

Clinical Outcomes Kollef MH, et al chest. February 1999;115(2):

Hospital Mortality of Infected Patients Kollef MH, et al chest. February 1999;115(2): P<0.001

Reduce Inappropriate Initial Antimicrobial Therapy ► Guidelines ► Broad spectrum and combination antibiotics ► ID consultation ► Automated antibiotic consultant ► More selective and sensitive diagnostic methods

Clinical Guidelines for the Treatment of Ventilator Associated Pneumonia ► Prospective study: 50 patients were evaluated in the before group and 52 in the after group ► Administration of vancomycin/imipenem/ciprofloxacin within 12 hours of clinical diagnosis ► Antibiotic modification after24-48 hrs ► Seven-day course of therapy (>7 days if symptoms and signs are persisted) Ibrahim EH et al. Crit Care Med, 2001;29:

Clinical Guidelines for the Treatment of Ventilator Associated Pneumonia Ibrahim EH et al. Crit Care Med, 2001;29:

Automated Antibiotic Consultant Evans Arch Int Med 1994

Broad-Spectrum and Combination Antibiotics Trouillet et al. Am J Res Crit Care Med. 1998;157:

ID Consultation Byl B. Clin Inf Dis; 1989

Emergent Bacterial Resistance Bacterial Resistance

Impact of Antibiotic Restriction on Resistance Neurosurgical Intensive Care Unit in London All antibiotics stopped Price. Lancet. 1970

Decrease in Hospital-acquired ICU Infection Rates, NNIS,

Possible Explanation for Decrease in Infection Rate ► Efforts to prevent infections: new research findings, prevention guidelines ► Shift of health care from hospital-based care ► True decrease secondary to adhesion to infection control policies

Rates of Resistance Among Nosocomial Infections Reported in Intensive Care Patients, Comparison of 1999 (January-July) with Historical Data January-July

Emerging Pathogens ► Methicillin-resistant Staphylococcus aureus (MRSA) ► Methicillin-resistant Staphylococcus epidermitis (MRSE) ► Vancomycin-resistant enterococci (VRE) ► Vancomycin-intermediate Staphylococcus aureus (VISA) ► Extended-spectrum beta-lactamase (ESBL)-producing gram-negative organisms ► Multidrug-resistant Acinetobacter spp.

Antibacterial Resistance in Nosocomial Infections Gram-Negative Pathogens Fridkin and Gaynes. Clin Chest Med. 1999:20:

Antibacterial Resistance in Nosocomial Infections Gram-Positive Pathogens Fridkin and Gaynes. Clin Chest Med. 1999:20:

Methicillin Resistant Staphylococci by setting Fridkin. Clin Infect Dis.1999

Vancomycin-resistant Staphylococcus aureus ► June First case of VRSA isolated from a swab obtained from a catheter exit site ► The isolate was resistant to:  Oxacillin (MIC >16 µg/ml)  Vancomycin (MIC >128 µg/ml) ► The isolate contained:  The oxacillin-resistant gene mecA  The vanA vancomycin resistant gene from enterococci CDC MMWR. 2002;51:

Epidemiology of VRE ► Present in all 50 states in the United States ► Number of isolated continues to grow ► Recognized in Europe, Japan, Central and South America ► Resistance to alternate antibiotic therapy continues to be a problem

Risk Factors for VRE ► Prior broad spectrum antibiotics (especially cephalosporins and vancomycin) ► Prolonged hospitalization ► Immunocompromised host ► Neutropenia ► Admission to an intensive care unit ► Renal failure requiring dialysis Noskin. J Lab Clin Med. 1997

Antibiotics and Colonization with VRE Ostrowsky. Arch Intern Med. 1999

Use of Vancomycin in US and Rate of VRE Kirsl et al. Historical usage of vancomycin. Antimicrob Agent Chemo 1998 National Nosocomial Infection Surveillance System (CDC)

Independent Predictors of Vancomycin- Resistant Enterococci in Adult Intensive Care Units NNIS

Enterococcal Resistance by Species Jones. Diagn. Microbiol Infect Dis. 1998

Outcome of Enterococcus faecium Bacteremia Stosor. Arch Intern Med. 1998

Extended Spectrum  - lactamases ESBLs ► ESBL inactivates oxyamino beta-lactams and fourth-generation cephalosporins (to some extent) and aztreonam ► Large plasmids encoding multiple antibiotic resistance determinants including aminoglycoside modifying enzymes ► Strains producing ESBL are typically sensitive to cephamycins and carbapenems ► Common ESBL-producers: K. pneumoniae, and less common other Enterobactericae

K. pneumoniae Resistant to Extended- Spectrum  -lactam (ESBL) at NNIS Evidence of Inter-hospital Transmission Infect Control Hosp Epidemiolo Mannel DL, et al. Infect Control Hosp Epidemiolo 1997

Emergence of Carbapenem- resistant Acinetobacter spp. ► Frequent use of aminoglycosides, fluroquinolones, ureidopenicillins and third generation cephalosporins ► Reported from South America, Europe, Far East, Middle East, and United States ► Numerous outbreaks (some strains susceptible only to polymyxin B) ► High mortality rates ► Endemic in some hospitals

Endemic Carbapenem-Resistant Acinetobacter spp. In Brooklyn, New York ► 15 hospitals ► November 1997, all aerobic bacteria collected ► Acinetobacter spp. (233) accounted for 10% of the gram negative bacilli ► Carbapenem resistance ranged from 0-100% ► 10% of isolated were susceptible only to polymyxin ► Risk factors  Use of third generation cephalosporins plus aztreonam  Environment and healthcare worker hands contamination documented  PFGE documented inter- and intra-hospital spread VM Manikal et al. CID. 2000

Antimicrobial Susceptibility of 233 Acinetobacter spp., 15 Hospital, Brooklyn, New York VM Manikal et al. CID. 2000

Efforts to Decrease the Rate of Emergent Antimicrobial Resistance ► CDC guidelines and barrier precautions ► Antibiotic restriction ► Selective bowel decontamination ► Rotation antibiotics ► Short course antibiotic course

Impact of CDC Guidelines on Endemic VRE M. Montecalvo et al. Ann Int Med J Morris et al. Ann Int Med E Jochimsen et al. ICHE 1999

Impact of Formulary Change on VRE Empiric therapy for febrile neutropenia Lisgaris. IDSA (abstract). 2000

Bradley. JAC Prevention of GRE Therapy for Febrile Neutropenia ► Purpose: reduce glycopeptide resistant enterococci (GRE) ► Situation: 50% colonization rate in oncology units ► Methods:  Phase 1: no intervention (ceftazidime)  Phase 2a and 2b: replace ceftazidime with piperacillin/tazobactam  Phase 3: return to ceftazidime

Results Phase 1 vs 2b (P<0.001) Bradley. JAC. 1999

Antimicrobial Utilization and Resistance ► Interdisciplinary team in Indianapolis to control resistant organisms ► Interventions:  Reduce third generation cephalosporin use  Reduce imipenem use  Encourage use of ampicillin/sulbactam and piperacillin/tazobactam  Enhance compliance with infection control  Education regarding antimicrobial resistance

Antimicrobial Utilization and Resistance  Piperacillin/tazobactam resistant Smith. Pharmacotherapy 1999

Impact of Formulary Changes on MRSA and Ceftazidime Resistant K. Pneumoniae ► Reduce usage of cephalosporins, imipenem, clindamycin and vancomycin ► Increased use of  - lactam/  -lactamase inhibitors Landman. Clin. Infect Dis. 1999

Ceftazidime Resistant K. pneumoniae Cleveland VA Medical Center

Impact of a Rotating Empiric Antibiotic Schedule on Infectious Mortality in an Intensive Care Unit Raymond DP. Crit Care Med 01-Jun-2001, 29(6);1101-8

Impact of a Rotating Empiric Antibiotic Schedule on Infectious Mortality in an Intensive Care Unit Raymond DP. Crit Care Med 01-Jun-2001, 29(6);1101-8

Short Course Antibiotic Therapy Hospital Acquired Pneumonia Clinical Pulmonary Infection Score (CPIS) <6 >6 Antibiotics days Ciprofloxacin 3 days Antibiotics days <6 D/C >6 treat as pneumonia Reevaluate CPIS at 3 days Singh N, et al. Am J Resp Crit Care Med. 2000;162:

Short Course Antibiotic Therapy Hospital Acquired Pneumonia Singh N, et al. Am J Resp Crit Care Med. 2000;162:

In Conclusion:

Reduce Inappropriate Initial Antimicrobial Therapy ► Guidelines and goal directed protocols ► Broad spectrum and combination antibiotics ► ID consultation ► Automated antibiotic consultant! ► More selective and sensitive diagnostic methods

Efforts to Decrease the Rate of Emergent Antimicrobial Resistance ► CDC guidelines and barrier precautions ► Antibiotic restriction and appropriate utilization:  Decrease cephalosporin use  Increase extended-spectrum penicillin/beta- lactamase inhibitor use  Limit carbapenem and vancomycin use to desired therapy ► Selective bowel decontamination ► Rotation antibiotics ► Short course antibiotic course: HAP

Conclusion Judicious Use of Antimicrobial ► Decrease cephalosporin use ► Increase extended-spectrum penicillin/beta-lactamase inhibitor use ► Limit carbapenem and vancomycin use to desired therapy

Handwashing compared to Alcohol Hand