Raymond Blum, M.D. Learning Points Antimicrobial resistance among gram-negative pathogens is increasing Infection with antimicrobial-resistant pathogens is associated with increased mortality, length of stay, and costs Few new antimicrobials have been recently approved Practice appropriate initial empiric therapy and de-escalation once culture and susceptibility data become available
Prior to 1980 gram-negatives predominated among nosocomial infections Since 2003 a significant increase Reemergence not a specific organism 60% of nursing home bacteremias are gramnegative In 2003, gram-negative bacilli in the ICU were associated with 1 : 71.1% of urinary tract infections 65.2% of pneumonia episodes 33.2% of surgical site infections 23.8% of bloodstream infections
Arch Int Med 166:1289. Femoral Other Organism Gram Positive 16 (44%) 47 (90%) Gram Negative 14 (39%) 4 (7%) Yeast 6 (16%) 1 (2%)
ICU Infections Associated With Gram-negative Bacilli in 2003 (%) 1 80 70 60 50 40 30 20 10 0 NNIS epidemiologic data of ICU infections in 2003 65.2 Pneumonia episodes (n = 4365) 23.8 Bloodstream infections (n = 2351) 71.1 Urinary tract infections (n = 4109) 33.8 Surgical site infections (n = 2984) NNIS = National Nosocomial Infections Surveillance System; ICU = Intensive Care Unit Gaynes R, et al. Clin Infect Dis. 2005;41:848-854. Type of Infection Pneumonia (n=4365) Bloodstream infection (n=2351) Urinary tract infection (n=4109) Surgical site infection (n=2984) E coli, Enterobacter Acinetobacter spp, % spp, % P aeruginosa, % K pneumoniae, % % 5.0 10.0 18.1 7.2 6.9 3.3 4.4 3.4 4.2 2.4 26.0 6.9 16.3 9.8 1.6 6.5 9.0 9.5 3.0 2.1 Boxes indicate most prevalent gram-negative species isolated for type of infection Data from the National Nosocomial Infections Surveillance (NNIS) System, 2003. Percentages of bacterial ICU isolates are shown. Gaynes R, Edwards JR. Clin Infect Dis. 2005;41:848-854. Differs from gram positive LPS activates immune system Ability to bind to receptors Production of exotoxins pseudomonas e.g.
Diplococci Neisseria Meningitidis Neisseria Gonorrhea Capnocytophaga dog bites, asplenia Paturella cat bites Non-lactose Fermenters Pseudomonas Proteus Serratia Acinetobacter Citrobacter (some) Enterobacter (some) Enteric pathogens Salmonella Shigella Camplobacter Vibrio E.Coli
Gram Negative Bugs Lactose Fermenting Rods E. coli 90% of UTIs Klebsiella Citrobacter (some) Enterobacter (some) HACEK Haemophilus Actinobacillus Cardiobacterium Eikenella Kingella Cause of endocarditis, bone and joint infections Resistance is increasing among many gramnegative pathogens 1 Infection with resistant pathogens is associated with negative health outcomes 3,4 Mortality/morbidity Length of ICU and hospital stay Healthcare costs No new antibiotic classes under development 2 Highlights the need to optimize existing classes of antimicrobials 1. Gaynes R, et al. Clin Infect Dis. 2005;41:848-854. 2. Spellberg B, et al. Clin Infect Dis. 2004;38:1279-1286. 3. Lautenbach E, et al. Infect Control Hosp Epidemiol. 2006;27:893-900. 4. Cosgrove, S et al. Clin Infect Dis. 2006;42:S82-S89..
Over 100 have been described Chromosomal and plasmid Confer resistance to all cephalosporins, monobactams and penicillins Often resistant to aminoclycosides, quinolones Carbapenems drugs of choice Some sensitive to tigecycline 30% Enterobacter resistant to 3 rd generation cephalosporin in 2003 20% Klebsiella 60% of surveyed ICUs had ESBLs Hidden resistance ESBLs are difficult to detect Adverse outcomes associated with failure to detect ESBLs Only 70% of labs screen for ESBLs Also known as MDR (multi-drug resistant) PDR (pan-drug resistant) Klebsiella, Acinetobacter and Pseudomonas Resistant to all cephalosporins, penicillins, carbapenems Aminoglycosides amikacin Colisitin
Bloodstream Isolates Within 48 hours
Pathogen Prevalence n (%) Mortality a n (%) P aeruginosa 57 (14.3) 16 (28.6) K pneumoniae 13 (3.3) 3 (23.1) Enterobacter spp 13 (3.3) 1 (7.7) VAP is often associated with gram-negative pathogens and high mortality 1-3 E coli 12 (3.0) 3 (25.0) Acinetobacter spp 8 (2.0) 4 (50.0) Adapted fromkollef MH, et al. Chest. 2006;129:1210-1218. 1. Kollef MH, et al. Chest. 2006;129:1210-1218. 2. Luna CM, et al. Eur Respir J. 2006;27:158-164. 3. Chastre J, Fagon J-Y. Am J Respir Crit Care Med. 2002;165:867-903. Resistance is a complex problem 1,2 Multiple/concurrent mechanisms Expanding mechanisms >500 discrete β-lactamases Evolution of carbapenemases Efflux pumps Permeability changes Selective antimicrobial pressure favors amplification of resistant bacteria Adverse impact on patient outcomes 3 Mortality, length of stay, healthcare costs 1. Talbot GH, et al. Clin Infect Dis. 2006;42:657-68. 2. Bush K. Clin Infect Dis. 2001;32:1085-1089. 3. Cosgrove SE. Clin Infect Dis. 2006;42(S2):S82-S89.
Imipenem Ceftazidime 25 Proportion of resistant isolates (%) 20 15 10 5 0 1986 1988 1990 1992 1994 1996 1998 2000 2002 2004 Independent study of 8,244 P aeruginosa ICU isolates collected from 1994 to 2000 reported the following average susceptibilities 2 : tobramycin, 87% imipenem, 83% amikacin, 90% piperacillin-tazobactam, 78% cefepime, 71% Year Data from the National Nosocomial Infections Surveillance System, ICU isolates. Adapted with permission from: Gaynes R, et al. Clin Infect Dis. 2005;41:848-54 1. Gaynes R, et al. Clin Infect Dis. 2005;41:848-854. 2. Neuhauser M, et al. JAMA. 2003;289:885-888. Resistance to imipenem Resistance to ceftazidime No n = 114 Imipenem No. (%) of patients, by previous antibiotic received Yes n = 21 Third-generation Cephalosporin No n = 73 Yes n = 62 Fluoroquinolone No n = 100 Yes n = 35 19 (16.7) 11 (52.4) a 12 (16.4) 18 (29.0) 18 (18.0) 12 (34.3) d 17 (14.9) 7 (33.3) 6 (8.2) 18 (29.0) b 14 (14.0) 10 (28.6) Resistance to 35 (30.7) 11 (52.4) 25 (34.2) 21 (33.9) 26 (26.0) 20 (57.1) ciprofloxacin c a P =.0009; b P =.003; c P =.001; d P =.05. All P values are for comparisons between the No and Yes groups. Data from a prospective single-icu study including 135 patients with VAP admitted between January 1994 and August 1999. 125 (93%) of patients had received antibiotics within 15 days prior to receiving the diagnosis of VAP. Trouillet JL, et al. Clin Infect Dis. 2002;34:1047-1054. 80 Imipenem Amikacin Ceftazidime 70 Proportion of resistant isolates (%) 60 50 40 30 20 10 0 1986 1988 1990 1992 1994 1996 1998 2000 2002 2004 Year Data from the National Nosocomial Infections Surveillance System, ICU isolates. Adapted with permission from: Gaynes R, et al. Clin Infect Dis. 2005;41:848-54 Recent reports of rapid emergence of resistance to tigecycline among Acinetobacter spp worrisome 2-4 Efflux-based mechanism may play a role 4 1. Gaynes R, et al. Clin Infect Dis. 2005;41:848-54. 2. Peleg AY, et al. J Antimicrob Chemother. 2007;59:128-131. 3. Navon-Venezia S, et al. J Antimicrob Chemother. 2007;59:772-774. 4. Peleg AY, et al. Antimicrob Agents Chemother. 2007. In press.
Differs from gram positive LPS activates immune system Ability to bind to receptors Production of exotoxins pseudomonas e.g. E coli K pneumoniae 25 Proportion of resistant isolates a 20 15 10 5 0 1986 1988 1990 1992 1994 1996 1998 2000 2002 2004 Year Data from the National Nosocomial Infections Surveillance System, ICU isolates. a Includes intermediately susceptible or resistant isolates. Adapted with permission from: Gaynes R, et al. Clin Infect Dis. 2005;41:848-54 Gaynes R, Edwards JR. Clin Infect Dis. 2005;41:848-854. Association of MDR P aeruginosa With Mortality, LOS, and Cost 1,2 2 2 Mortality LOS (21%) (12%) (20 d) (10 d) P =.04 P =.001 1 Cost ($22,116) ($54,081) Multiresistant Nonresistant 0 20 40 60 80 100 Percent, Dollars (000), Days MDR = multidrug-resistant; LOS = length of stay 1. Harris A, et al. Clin Infect Dis. 1999;28:1128-1133. 2. Aloush V, et al. Antimicrob Agents Chemother. 2006;50:43-48.
Negative Outcomes Associated With Resistant Gram-Negative Infections Infection with imipenem-resistant P aeruginosa associated with higher mortality, LOS, and hospital costs Outcome Imipenemsusceptible Imipenem -resistant P value Mortality 16.7% 31.1% <.001 a LOS (days) Hospital costs 9 15.5.02 $48 381 $81 330 <.001 a Relative risk, 1.86; 95% CI, 1.38-2.51; LOS = length of stay Adapted from: Lautenbach E, et al. Infect Cont Hosp Epid. 2006;27:893-900. Number of New Antimicrobial Agents Approved 18 16 14 12 10 8 6 4 2 0 1983-1987 1988-1992 1993-1997 1998-2002 Period Spellberg B, et al. Clin Infect Dis. 2004;38:1279-1286. Of 89 drugs approved in 2002, none was an antimicrobial 1 1. Infectious Diseases Society of America. Bad Bugs, No Drugs: As Antibiotic Discovery Stagnates, A Public Health Crisis Brews. http://www.idsociety.org/pa/idsa_paper4_final_web.pdf. July, 2004. Accessed March 17, 2007. 2. Spellberg B, et al. Clin Infect Dis. 2004;38:1279-1286. The use of an antimicrobial agent that is correct on the basis of all available clinical, pharmacologic, and microbiologic evidence 1 Includes the following practices 1-4 : Initiate broad-spectrum empiric treatment Use optimal dosing regimens (dose, dosing interval, infusion time) De-escalate therapy to narrower spectrum agents when culture and susceptibility data and patient response assessments are available Utilize adequate treatment duration to reduce or eradicate bacterial burden while minimizing risk of superinfection Avoid duplicative combination regimens 1. Harbarth S, et al. Clin Infect Dis. 2007;44:87-93. 2. Rodloff AC, et al. J Antimicrob Chemother. 2006;58:916-929. 3. Dellit TH, et al. Clin Infect Dis. 2007;44:159-177. 4. American Thoracic Society/Infectious Diseases Society of America. Am J Respir Crit Care Med. 2005;171:388-416
Empiric therapy options when potentially drugresistant gram-negative pathogens are suspected in late onset HAP, VAP, and HCAP 1 Potential Pathogen Pseudomonas aeruginosa Klebsiella pneumoniae (ESBL-producing) Acinetobacter spp Antimicrobial Therapy Antipseudomonal cephalosporin Or Antipseudomonal carbapenem Or β-lactam/β-lactamase inhibitor Plus Antipseudomonal fluoroquinolone Or Aminoglycoside HAP = Hospital-acquired pneumonia; VAP = Ventilator-associated pneumonia; HCAP = Healthcare-associated pneumonia (as per American Thoracic Society Guidelines) Adapted with permission from: American Thoracic Society/Infectious Diseases Society of America. Am J Respir Crit Care Med. 2005;171:388-416. Selected recommendations from the guidelines: Collect cultures from all patients prior to initiating therapy; however, do NOT delay treatment of critically ill patients Early, appropriate, broad-spectrum, empiric antibiotic therapy and adequate doses Consider de-escalation once culture and susceptibility data are available Consider duration of therapy American Thoracic Society/Infectious Diseases Society of America. Am J Respir Crit Care Med. 2005;171:388-416. Initial broad-spectrum therapy followed by narrowing or discontinuation of antimicrobials after obtaining susceptibility results and observing the patient s clinical course 1 Balances the need to provide broad-spectrum treatment with the need to limit antimicrobial exposure, in order to minimize the emergence of resistance 2 Endorsed recently in the IDSA/SHEA antimicrobial stewardship guidelines 3 1. Park DR, et al. Respir Care. 2005;50:932-952. 2. Kollef MH. Drugs. 2003;63:2157-2168. 3. Dellit TH, et al. Clin Infect Dis. 2007;44:159-177.
Obtain culture specimens prior to initiating therapy Use updated, accurate institutional and unit-specific antibiograms Awareness of the pathogens and their susceptibilities most likely to be associated with infection Include in empiric regimen treatment for potentially resistant pathogens associated with infection type For example: P aeruginosa, Acinetobacter spp, Klebsiella pneumoniae, Enterobacter spp, and Staphylococcus aureus Modify therapy once culture and susceptibility results become available Switch to narrower-spectrum agents as appropriate Kollef MH. Drugs. 2003;63:2157-2168. Initial therapy should be broad to avoid inadequate treatment Determined by local data Use guidelines and know the risk factors for resistance Don t treat longer than necessary to eradicate the pathogen Based on clinical data and follow-up cultures, as available Serious hospital-acquired acquired infection suspected Obtain appropriate microbiological samples for culture and special stains Begin empiric antibacterial treatment with a combination of agents targeting the most common pathogens based on local data Follow clinical parameters: temperature, white blood cell count, chest radiograph, P a O 2 /F i O 2 hemodynamic parameters, organ function De-escalate antibacterials based on results of clinical microbiology data Continue to follow clinical parameters Search for superinfection, No Significant clinical abscess formation, improvement after 48-96 hours noninfectious of antibacterial treatment? causes of fever/inflammation, Yes inadequate tissue Discontinue penetration of antibacterial after a 7- antibacterials 7-14- to day course based on site of infection and clinical response Adapted from: Kollef MH. Drugs. 2003;63:2157-2168. Sepsis costs up to $50000 per patient $17 Billion annually in the US Mortality of 25-50% 2 nd leading cause of death in ICUs 10 th leading cause of death overall Survivors has significant disabilities
Organ and stem cell transplants Liver Failure Albumin <3mg/dl Diabetes Pulmonary Disease ESRD HIV Steroids Elderly Fever +/- Chills SIRS Confusion Respiratory Failure Septic Shock GI sxs Petichiae, purpura
Binding of ligands to Toll-like receptors LPS Flagellin Lipoproteins Know local resistance patterns Antibiograms are helpful Note differences between community, hospital and special units Inappropriate empiric treatment higher mortality Aid to appropriate empiric treatment Need to be interpreted They must be unit specific ICU, OPD, Bone Marrow etc Should include source Minimum of 30 unique isolates
Kang CI, et al Anti Agent Chemo 49:760
Kang CI, et al Anti Agent Chemo 49:760
Derivative of minocycline Activity against MRSA, VRE, ESBL acinetibacter Approved SSTI, GI infections Role in VAP not clear Polymixin E Activity against MDR- GNR including pseudomonas Nephrotoxicity and CNS toxicity
Treatment depends on severity Complicated Chronic catheter Epidemiology Prior treatment Local resistance patterns Quinolones no longer initial drug of choice Neutropenic patients Potential for resistance
One of the more challenging infections to diagnose and treat 30% mortality rate Peritonitis Spontaneous Secondary Tertiary Cholangitis Diverticulitis
Use only if necessary not for incontinence Use only as long as necessary Remove post-op Consider other options Intermittent, suprapubic, condom Keep system closed Unobstructed flow Need to consider host Immune compromised- neutropenic Catheters IV, urinary Prior antimicrobials Source of infection urine, biliary, pneumonia Severity of illness Hospital ecology Resistance patterns Learning Points Antimicrobial resistance among gram-negative pathogens is increasing Infection with antimicrobial-resistant pathogens is associated with increased mortality, length of stay, and costs Few new antimicrobials have been recently approved Practice appropriate initial empiric therapy and de-escalation once culture and susceptibility data become available