Impact on Patient Care

Update on Antibacterial Resistance<strong>Impact</strong> on Patient CareJohn G. Gums, Pharm. D., FCCPProfessor of Pharmacy and MedicineAssociate Chair, Department of Pharmacotherapyand Translational ResearchDirector of the Antimicrobial Resistance Management (A.R.M.) ProgramUniversity of FloridaHealth Care Improvement FoundationPhiladelphia, PANovember 12, 20091

Bugs vs. DrugsNew Yorker 20082

Bad Bugs—No Drugs!2 M people will acquire bacterial infections in the hospital 90 k will die (4.5%)70% of bacteria will be resistant to at least one drug30% resistant to at least 3 antibiotics!!Review of 15 pharmaceutical companies and 7 major biotechcompanies revealed: 506 drugs in development (phase II/III)5 antibiotics67 cancer-related33 inflammation/pain34 endocrine32 pulmonary diseaseIDSA 20043

Clin Infect Dis 2009;48:1-12E: E.faeciumS: S. aureusK: K. pneumoniaA: A. baumaniiP: P. aeruginosaE: E. species4

Major Factors Contributing to theEmergence of Infectious Diseases International travel and commerce Human demographics and behavior Breakdown of public health measuresInstitute of Medicine Report, 1992 CDC5

Antibiotic Production 15.5 million kg (17,000 tons) PCN– 3.85 gms/persons on earth– 4.5 million kg (5,000 tons) TCN 40% used in livestock “Farm-to-Fork” modelWebster P. Lancet 2009;374:772-774JAC 2003; 52:5-76

Historical Perspective Until 1989 vancomycin resistance had not beenreported; Antibacterial-containing In 1994 14% of hospital-acquiredsoapsenterococci -Meta-analysis were of 27 resistant studies between to vancomycin1980-2006(32% as of 2003) - MMWR 1993;42:597-99-soaps containing triclosan(0.1%-0.45%) were no more effectivethan plain soap in preventing illness and reducing bacterial levels Not on the confined hands to bacteria - Candida sp.-several J Clin Microbiol studies showed 1994;32:1092-98 evidence of triclosan-adapted crossresistance to antibioticsCID 2007 (September) :45:S137-147 Also seen with mupirocin - JAC 2003; 51:613-17 Vancomycin-dependent Enterococci (VDE) – EID 2004;10(7):1277-817

The Rules of Antibiotic Resistance1. Given enough antibiotic and time, resistance will appear2. Resistance is progressive, moving from low tointermediate to high levels3. Organisms that are resistant to one antibiotic will likelybecome resistant to others ( “cross-resistance”)4. Once selected, drug resistance will not disappear,although it may decline5. Select antibiotics to treat “both” patients!Levy SB NEJM 1998; 338:1376-8.8

400 + Hospitals21% Teaching79% Community15% North Central30% Northeast2% Northwest16% South Central29% SoutheastGums, JG. University of Floridawww.armprogram.com8% Southwest9

Gums, JG. University of Floridawww.armprogram.comTotal Isolates Compared Nationally (1990-2009): 30,027,284‣ 2,836,156 Pseudomonas aeruginosa isolates‣ 5,558,999 Staphylococcus aureus isolates (incl. MRSA)‣ 220,040 Streptococcus pneumoniae isolates‣12,176,916 E. coli isolates‣ 2,907,015 Klebsiella pneumoniae isolates10

Escherichia coli Leading nosocomial pathogen (16%) Resistance to amoxicillin 30% in community Hyperproduction of TEM-1 -lactamase.Large quantities of enzyme not suppressedby inhibitors Resistance to:– AMP/SULB = 35%– TIC/CLAV = 14%– PIP/TAZ = 12%11

A.R.M. Program: Escherichia coli(2000-2008)1009080706050403020100AmpicillinAmp/SulbNationalNENJPA12

A.R.M. Program: Escherichia coli(2000-2008)1009080706050403020100Cefazolin Cefuroxime CeftazidimeNationalNENJPA13

A.R.M. Program: Escherichia coli(2000-2008)1009080706050403020100CirprofloxacinLevofloxacinNationalNENJPA14

Klebsiella pneumoniae Resistance caused by extended-spectrumcephalosporinases Related to -lactamases (TEM-1, TEM-2, SHV-1)but target 3rd generation cephalosporins National incidence: 14% (variable) Brooklyn,NY-15 hospitals. MDR incidence = 2.5%(2005)vs. 22% (2006) JAC 2007 (May 9)15

A.R.M. Program: Klebsiella Pneumoniae(2000-2008)1009080706050403020100Cefazolin Cefuroxime Ceftriaxone CefepimeNationalNENJPA16

Pseudomonas aeruginosa Inducible, chromosomally-mediated -lactamase Plasmid-mediated -lactamase Loss of an outer membrane protein and plasmidencodedimipenemase confers resistance toimipenem17

A.R.M. Program: Pseudomonas aeruginosa(2000-2008)1009080706050403020100Selective Use PressureAmikacin Gentamicin TobramycinNationalNENJPA18

Gram-Positive OrganismsIf We Only Knew….. August 20, 1999TABLE 1. Cases of community-acquired methicillin-resistant Staphylococcus aureus,byselected characteristics -- Minnesota and North Dakota, 1997-1999 4 Characteristic pediatric Case cases: 1 Case 12months-2 Case 3 13 years Case 4 RuralAgeareas7 yearsof Minnesota16 monthsand13 yearsNorth12DakotamonthsSyndrome septic arthritis, severe sepsis necrotizing necrotizingsepsis, pneumonia, pneumonia, pneumonia/ All received β-lactam antibiotics severe sepsis which severe sepsis delayed IDempyemaof MRSAAntimicrobial t/s, tet, cip, gent, t/s, tet, cip, gent, t/s, cep, cip, gent, t/s, tet, cip,susceptibility* ery, clind, vanc ery, clind, vanc ery, clind, vanc gent, ery,clind, vanc All died of systemic MRSA infectionToxin test+ SEC positive SEC positive SEB positive SEB positive MIC’s to Vanc ≤ 2 mcg/ml and sensitive to multiple* t/s=trimethoprim-sulfamethoxazole, tet=tetracycline, cip=ciprofloxacin, gent=gentamicin,antibioticsery=erythromicin, clind=clindamycin, and vanc=vancomycin.+ SEB=staphylococcal enterotoxin B;SEC=staphylococcal enterotoxinMMWR MMWR 1999;48(32):707-1019

August 1999CA-MRSASCCmec IV or V (rather than I-III)Smaller genome, more mobile, replicates quickerMay displace HA-MRSAVirulence genesPotent toxin PVL (Panton-Valentine leukocidin)20

A.R.M. Program: Staph aureus(2000-2008)1009080706050403020100Nafcillin/OxacillinNationalNENJPA21

Vancomycin IntermediateStaphylococcus aureus (VISA) VISA (MIC = 8 g/cc) May 1996: First reported in Japan July 1997: Peritonitis in a long-term peritoneal dialysispatient (Michigan) August 1997: Bloodstream infection with long-termMRSA colonization (New Jersey) Report immediately to State Health Department Isolation mandatory Contact FDA for drug therapy optionsState of FloridaMMWR Sept. 5, 1997:46(35)22

Vancomycin ResistantStaphylococcus aureus (VRSA)June 2002--catheter exit site in a 40 y.o. dialysis patient with DM,PVD, & CRF (oxacillin >16 g/cc, vancomycin > 128 g/cc).(MMWR July 5, 2002;51(26):565-67)April 2002--MRSA bacteremia treated with vancomycin and rifampin.Also infected with VRE and K. oxytoca.Resistant isolate contained the vanA gene from enterococci.September 20, 2002--Pennsylvania: possible osteomyelitis(vancomycin=64 g/cc), contained mecA and vanA genes.(MMWR Oct. 11, 2002;51(40):902-3) April 23, 2004 – New York: LTCF, urine culture – microscan MIC =4 g/cc, E test = MIC = >256 g/cc; mecA (oxacillin) and vanA(vancomycin) genes present. (MMWR 2004;53(15):322-2323

A.R.M. Program: Staphylococcus aureus(2000-2008)1009080706050403020100ClindamycinErythromycinNationalNENJPA24

% macrolide resistanceRelationship of Efflux vs.Methylation-Induced Resistance in S. Aureus2000 - 200810080604056% erm58% erm65% erm53% erm36.8 2029.7 35.6effluxmethylation2026.6 25.3 2938.30National NE NJ PA25

CA-MRSA and Clindamycin:Is there inducible resistance?S. aureus soft tissue infection• Penicillin• Erythromycin• Clindamycin• Levofloxacin• Oxacillin• VancomycinRRSRRSIs this phenotypeauthorization to prescribeclindamycin?(+) D-test ~ (+erm)(Good chance clindamycin will fail)Frank AL, et al. Pediatr Infect Dis J 2002;21:530-4. Lewis JS, et al. Clin Infect Dis. 2005 Jan 15;40(2):280-5Levin TP, et al. Antimicrob Agents Chemother 2005;49:1222-4. 26

A.R.M. Program: Enterococcus faecium:(2000-2008)1009080706050403020100VancomycinNationalNENJPA27

Penicillin-Resistant Pneumococcus Model of evolution indicates a slow emergencephase followed by an exponential growth phase of10 years reaching a stationary phase when PRP =50% Primary mechanism of resistance is alteredPBP’s, not by production of -lactamase-lactamase inhibitors do not affect thesusceptibility of these strainsJ Antimicrob Chem 1997;40 (Suppl A):11-1828

A.R.M. Program: Streptococcus pneumoniae(2000-2008)1009080706050403020100PenicillinNationalNENJPA29

Campaign to Prevent Antimicrobial Resistance in Healthcare SettingsKey Prevention Strategies• Prevent infection• Diagnose and treat infectioneffectively• Use antimicrobials wisely• Prevent transmissionClinicians hold the solution!

Preventing ResistanceUnrealistic patient expectationsNOW ® - Streptococcus pneumoniae urinaryantigen test 15 min. for presumptive Dx of Pneumococcalpneumonia (sensitivity = 86%, specificity = 94%, accuracy= 93%) (J Clin Microbiol. 2003;41:2810-13)Snort. Sniffle. Sneeze.No Antibiotics, Please. (FDA/CDC; January 2004)POC CRP testing - CRP>60mg/l - QuikRead31

Strategies for Overcoming ResistanceAvoid exclusive use patterns Use broad-spectrum agents appropriately– Induces resistance– Facilitates cross-resistance– Sustains organism in genesis environment New Drug Development– Do they contribute to the problem?32

Strategies for Overcoming Resistance Rotate agents Alternate between classes rather thanbetween agents within the class Shorten courses rather than lengthen Use targeted regimens as soon assusceptibility tests are available(bb guns, not shotguns)NEJM 1994;330:1240-4133

Is the Antibiotic Steward “Ship”Sinking??Junk in, Junk outAntibiograms are old dataData is often not differentiated between urine,systemic, ICU, non-ICU, hospital to hospital, outpatientvs. in-patient, and even duplicate isolates.Data reflects the aggregate not the patient34

Changing the Paradigm: What does thefuture of Antibiotic Stewardship Look Like?35

Hunterdon HospitalE. Coli60% antibiotics >5% increase in susceptibility20% antibiotics >5% decrease in susceptibilityKlebsiella pneumonia87% antibiotics >5% increase in susceptibilityPseudomonas aeruginosa78% antibiotics >5% increase in susceptibility11% antibiotics >5% decrease in susceptibilityStaphylococcus aureusMRSA rates declined by 23%FinancialTotal cost savings year 1: ~$139,000Total cost savings year 2:~$70,00040

Program InformationA.R.M. ProgramParticipating institutions receive a customized report profiling trendanalysis within the hospital/system and benchmarking to national, regionalor state comparatorsBugs and Drugs ProgramVHA collaborative program that works with individual hospital/systemsproviding a customized analysis of relationship between antibiotic use andresistance trends, including predictive models.iDOP ProjectInnovative data-mining pilot project evaluating patient-specific variableslinked to antibiotic utilization and outcomes. Participating institutionsreceive a customized comprehensive and executive report. Need 5 pilotinstitutions.45

Strategies for Overcoming Resistance Increase handwashing 175 individuals (95 women and 80 men) usingpublic restrooms…with and w/o signs 61% of the and 37% of the washed theirhands with soap, in the absence of the sign 97% of the and 35% of the washed theirhands in the presence of the sign.Percept Mot Skills. 2003 Dec;97(3 Pt 1):805-10.46