1/28/021Implications of Bacterial Resistance on Antibiotic SelectionJohn C. Rotschafer, Pharm. D., FCCPProfessorCollege of PharmacyUniversity of MinnesotaOverview! Bacterial resistance"Gram positive & Gram negative bacterial resistance is increasing"Pathogens often resistant to multiple antibiotics#Reduced susceptibility to conventional antibiotics#New gram positive agents are limited & expensive#Virtually nothing on the horizon for resistant gram negatives"Complicates medical management & clinical outcome#Morbidity & Mortality"Increases the cost of care#LOS, supportive measures & antibiotics/drugs"Function of antibiotic pressure"Wide based societal problem******************What would “the mind” do in regards to ???•Antibiotic Resistance•Appropriate antibiotic use•Appropriate use of infectioncontrol practicesMinnesota’s Mr. Right1/28/024Bacterial ResistanceAntibiotic BacteriaPharmacokinetic transport to site N/ADrug must be taken into cell Influx/EffluxDrug must remain viable Enzyme/EnvironmentDrug binds to target Target alterationDrug attack metabolic process Bypasses effect using antidote ! Bacteria can rapidly replace the former generation! Bacteria naturally mutate or acquire resistance (plasmids)! Mechanisms of resistance are not mutually exclusive1/28/025The Antibiotics We Use! Overt and Covert Use of Antibiotics"Hospital vs. Nursing Home vs. Day Care vs. Community#Prophylaxis#Therapeutic#Inappropriate"Passed Down the Food Chain (Animal Feed)"Antibiotics are part of our daily living (Triclosan)! Overuse, misuse, and/or underdosing of antibiotic can precipitate bacterial resistance! Direct and Collateral Damage"Ceftazidime – ESBL"Cephalosporins, Vancomycin, Anaerobic Agents - VRE1/28/026Antibiotic Selection & DosingRight drug, dose, interval, and duration! Level of prescribing sophistication:"Known or suspected site of infection"Known or suspected bacteria"Known or likely antibiotic susceptibility"Level of understanding regarding antibiotic mechanism of action &/or resistance"Knowledge of antibiotic pharmacokinetic & pharmacodynamic principles"Understanding of evidenced based disease state literature! Bacterial resistance drives antibiotic selection but antibiotic selection also drives bacterial resistanceInfluences that Increase Antibiotic PrescribingJuly 1998 Survey of all primary care MD’s in MassachusettsAPUA Newsletter Vol 19 2001! 499 usable responses out of ~6,000 questionnaires (8%)#93% agreed that physicians over prescribe antibioticsFactor % MD’s Factor influenced RxPurulent Discharge 64%Dx Uncertainty 62%Patient request 59%Patient satisfaction 48%Fever 47%Tx Uncertainty 36%Payer Policy-formulary 28%Time Pressure 26%?Return visit cost 20%Litigation concern 19%Payer policy-QA 13%Drug promotion 7%Resistance concern 5%Cost 2%1/28/028Ceftazidime Induced ESBL with Gram Negative BacteriaRice, LB Pharmacother 19: 120S-128S, 1999! Overuse &/or underdosing of ceftazidime may precipitate an ESBL (TEM or SHV) problem with Klebsiella or Enterobacter ! Piperacillin/tazobactam substituted for ceftazidime but Amp-C like enzymes or overproduction of ESBL can inactivate tazobactam ! Treatment of these organisms with imipenem or fluoroquinolones may precipitate multi-resistant A. baumanniAntibiotic Use and Resistance0510152025301st Qtr 2nd Qtr 3rd Qtr 4th Qtr 1st Qtr 2nd Qtr 3rd Qtr 4th Qtr0100200300400500600700800Ceftazidime Pip/TazoCeftazidimePip/TazoRice et al. CID 1996% resistanceGrams of antibiotic use1/28/0210Resistant A. baumanni in ICUWeingarten, CM Pharmacother 19:1080-1085, 1999Infected Match p valueAge 51 yrs 50 yrs NSApache II 16 11 <0.001Mortality 34% 18% <0.01LOS 51 days 19 days <0.001Phar cost $19K $3K <0.001Hosp cost $128K $31K <0.0011/28/0211Vancomycin Prescribing PatternsJohnson SV et al. Pharmacotherapy 1995Johnson SV et al. Pharmacotherapy 1995! Retrospective study May 1993-April 1994!Preliminary guidelines published Federal Regis May 1994! N = 135 patients ! Appropriate or inappropriate usage defined using CDC criteria ! 83/135 (61%) of vancomycin usage was inappropriate! Question whether U.S. hospitals doing an adequate job controlling usage1/28/0212Wide Overuse of Antibiotic Cited in StudyWSJ (September 4, 1997)■7,147 medicare patients in 131 hospitals studied in 1995■63% of vancomycin orders did not follow CDC guidelines■No difference in comparing large urban teaching centers to small rural hospitals■Beth Israel-Deaconess - fliers & lectures did not alter prescribing behavior1/28/0213Is Vancomycin Bigger, Better, & More Powerful?■ Karchmer Editorial ✦Ann Intern Med 115: 739, 1991■ Data suggests✦Vancomycin kills bacteria at a slower rate– Levine: Ann. Intern. Med. 115:574, 1991✦Higher mortality with vancomycin treated patients– Gonzalez: CID 29:1171, 1999✦Clox/gent significantly better than Vanco or Teico/gent in short course therapy of right side endocarditis– Fortun: CID 33:120-125, 2001✦Vancomycin is an independent risk factor for the development of gram negative bacteremia– Van Houten: Pediatr Infect Dis J 20:171, 2001✦Independent risk factor for VREResistance in Respiratory PathogensKorea 88%Korea 88%Germany 5.3%Germany 5.3%Staples, A., Thornsberry, C. et al ICAAC Abst 1221, 2000H. influenzae 17% AMP-RM. catarrhalis 94% AMP-RS. pneumoniae 35% PCN-NS/R USA~35%Tmp/Smx 32 / 87% Clari 31 / 76%Azithro 29 / 66% Cefur 99.9/ 99.9%Ceftriax 4 / 22% Levo 1.3 / 2.6%PCN- NS / PCN-R %1/28/0215PCN-R S. pneumoniaeFeiken DR. Am J Public Health. 90:223-229, 2000! Retrospective 1995-1997 study of US 5,837 adults pneumococcal pneumonia or bacteremia "3,452 Pen-S, 377 Pen-NS, and 364 Pen-R! Pen-R (MIC ≥≥≥≥ 4) 5.5 x RR death after day 2, 7.1 x RR death after day 4.! Cefotaxime-R (MIC ≥≥≥≥ 2) 4.3 x RR death after day 2, 5.9 x RR death after day 4.PCN-R S. pneumoniae Therapeutic Options! The 20% resistance threshold for change! New quinolones (URTI & LRTI agents) "Levofloxacin—Levaquin®(OMP) 500/750 mg PO QD"Moxifloxacin—Avelox®(Bayer) 400 mg PO/IV QD"Gatifloxacin—Tequin®(BMS) 400 mg PO/IV QD "Gemifloxacin—Factive®(SKB) 320 mg PO QD—?! Other possible antibiotic options! Vancomycin, linezolid, & ketolides! Pneumovax®! Heptavalent S pneumoniae (Prevnar®) vaccineIncreased Efficacy for Advanced Generation Fluoroquinolones in Community Acquired PneumoniaMetge et al ICAAC 2000•Inpatient: FQ vs. Ceftriaxone and Macrolide–5 additional clinical