Multiple Small Feedings Of The Mind - PowerPoint Presentation

1. Multiple Small Feedings Of The MindEmerging Antibiotic ResistanceRonald W. Flenner, MD, FACPVice Dean for Academic AffairsJames E. Etheridge Jr. Distinguished ProfessorshipEastern Virginia Medical School

2. 64yo femalePMHx significant for HTN, prior CVA, CAD, CHF, and CKD but negative for previous recurrent infectious illnessesPresents to the ED with 3d history of dizziness, hematuria, R flank pain, and n/vVS: T 96.7, HR 85, RR 18, BP 95/50, SpO2 98%WBC 25.1KCT abd/pelvis: (+) evidence of acute pyelonephritisThe patient…

3. IV ceftriaxone begun while awaiting culturesFebrile to 102F after admissionUrine cultures returned E. coli sensitive to only amikacin, meropenem, nitrofurantoin, pip/tazoBlood cultures returned GNBCeftriaxone stopped; meropenem 500mg IVPB Q12h startedThe admission…

4. ID consulted, on detailed history she had two MD appointments the preceding Wednesday—one was to OB/GYN.“[She] noted that it was ‘very hot’ in the exam room and she felt very bad.”That night, she started having fevers, abdominal pain, vomiting which worsened over the next few daysThe consult

5. Blood cultures returned same organism—E. coli with same susceptibilitiesMaintained on Meropenem 500mg IV Q12hTmax peaked at 103F on hospital day 4 (Abx day 3)Defervesced slowlyWBCs peaked day of admission but remained elevated without thrombocytosis (range 14.2-23.4)Cr baseline 1.4-1.6During admission, peaked at 6.4 on hospital day 5 (abx day 4) but has trended down sinceClinical course

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7. Expected risk factors: Immunocompromised statusProlonged hospital/SNF stayChronic indwelling urinary catheterRepeated courses of abxHer risk factors: none of the aboveexposure to healthcare a few hours before symptom onsetSo why is this case clinically important?

8. What are beta-lactams?

9. First penicillinase in 1944Early 1980s: 3rd-gen cephalosporins developed in response to spread of beta-lactamases1983: first report of a beta-lactamase able to hydrolyze new cephalosporins1986: first big outbreak of ESBL-producing bacteria in France (first in Germany & England, but majority of occurrences in France)1988: first reports of ESBL-producing bacteria in USThe rise of the beta-lactamases

10. Extended-spectrum beta-lactamase-producing organismsMost often Escherichia coli and Klebsiella pneumoniae (>75% of studies on ESBL have addressed K. pneumoniae)Produces an enzyme (beta-lactamase) via plasmid that destroys the drug—most ESBLs able to hydrolyze penicillins, broad-spectrum cephalosporins, monobactamsESBL-producing bacteria

11. Serine-based mechanism of action (classed by amino acid sequence—Ambler classes A, C, D)Serine residue near active site of enzyme irreversibly reacts with beta-lactam ringThis inactivates the beta-lactam and regenerates the enzymeCan be inhibited by clavulanic acidAmbler class B use a metalloenzyme as a substrate and can hydrolyze 3rd-gen cephalosporinsE.g., Stenotrophomonas maltophiliaNot inhibited by clavulanic acid, tazobactamInhibited by EDTA (heavy metal chelator)The way they work

12. The rise of the beta-lactamase

13. TEM-1, TEM-2, SHV-1: “classic” beta-lactamasesOft found in EnterobacteriaceaeActive against early penicillins and 1st-gen cephalosporinsSHV-2: G238Sthis mutation single-handedly accounts for ES propertiesTEM-3: extended substrate profile, likely due to overuse of 3rd-gen cephalosporins and aztreonamOver 100 TEM variants; most qualify as ESBLmost are susceptible to suicide inhibitors (clavulanic acid)CMT1-4: able to hydrolyze 3rd-gen cephalosporins but also have inhibitor resistanceTypes of beta-lactamases

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15. MIC of cephalosporins often within susceptible rangeVariations due to:genetic differences in resistance determinantsvarying levels of gene expressionvariations in spectra of enzymatic activityinoculum effectIn vitro: directly proportional rise in MIC of cephalosporins with increase in ESBL-organism inoculumThe problems with cultures

16. Plasmids are transferable from strain to strain and between bacterial speciesOften occur with:plasmids causing aminoglycoside resistanceAmpC beta-lactamaseAssociated with increasing fluoroquinolone resistanceCo-resistance

17. Theoretically beta-lactamase inhibitors should be effective, BUT:Hyperproducing strains may overcome inhibitionPossible presence of AmpC enzyme will make it resistant to inhibitorsDrug of choice: CarbapenemsTreatment

18. Increasing incidence of carbapenem-resistant bacterial species, especially Stenotrophomonas and PseudomonasCRE: carbapenem-resistant EnterobacteriaceaeIMP-1, IMP-7: Beta-lactamases capable of carbapenem hydrolysisPlasmid-mediatedTwo types, both metalloenzymesKPC-1: found in a strain also harboring SHV-29 (ESBL)Possible mechanism: change in affinity of PBPs for carbapenemsConcerns for the future

19. Study by Ahmad, et al: 8 patients with carbapenem-resistant K. pneumoniae following imipenemNo other antibiotic options; six of the eight patients diedSeattle’s Virginia Mason Medical Center32 cases, 11 deathsTransmitted via endoscopesConsider tigecycline, polymixins if treating carbapenem-resistant klebsiellaeNo cross-resistance; mechanisms of resistance are differentCREs in the community

20. Extended-spectrum beta-lactamases pose a significant risk to our ability to combat infections with the antibiotics we haveESBLs come in a variety of types that affect their sensitivities to different drugsCarbapenems are your drug of choice when treating ESBLsIf you’re facing a carbapenem-resistant ESBL, use tigecycline or Colistin (or something that has a different mechanism of resistance)Always promote good antibiotic stewardship! Take-home points

21. MRSA

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24. MRSADescribed in 1961Increase in both Healthcare and Community settingsHA- MRSAInfections occurring > 48 hours following hospitalizationSurgical site infections

25. HA- MRSARoutinely implicated in nearly every type of hospital –acquired infection Biofilm Risk factors:Antibiotic useProlonged hospitalization ICUHemodialysis

26. HA- MRSARisk factors – continuedMRSA colonizationProximity to those with MRSA infection or colonization

27. HA- MRSAHigher mortality, longer hospital stays, higher costs vs. MSSABSI secondary to MRSA – 1.5 – 2.0 fold more likely to die compared with BSI due to MSSAHigher rates of AKI, hemodynamic instability , and prolonged ventilator dependence compared to MSSA

28. CA- MRSAOccurs in the absence of healthcare exposureInitially reported in the 1980’s in IVDA populationNow most common cause of SSTI in U.S.Most carry SCCmec type IV or V genes for cytotoxin Panton- Valentine lukocidin – confers enhanced virulence

29. CA- MRSARisksAnimals – may carry MRSA Many patients have no risk factors

30. HA- MRSA/CA- MRSABlurred epidemiologic distinctionCA- MRSA may be replacing traditional hospital-acquired strains

31. MRSAAntibiotic useCephalosporinsFluoroquinolonesHIV InfectionHemodialysisLTCF

32. MRSATransmissionHC- MRSATransiently contaminated hands of HCWContaminated environmental surfacesCA- MRSADirect contact with colonized or infected individual

33. Staphylococcal ColonizationEcologic niche of S.aureus is the anterior nares.Carriage rates average 20-25% (increased in diabetes, dialysis, IVDA).Carriers have a 2 to 10- fold increased risk of surgical site or IV catheter infections.30-100% of SSI in nasal carriers are caused by the strain carried in the nose.40 different decolonization regimens have been studied over the last 60 years.

34. MRSA ColonizationDecolonization was attempted with rifampin as part of a comprehensive program to control MRSA in a VA Nursing Home Care Unit.For rifampin, 92% of baseline isolates were sensitive; after treatment only 43% were sensitive.Decolonization was “ineffective and potentially hazardous”. Strausbaugh LJ. Infect Control Hosp Epidemiol 1992;13:151-9.

35. Mupirocin Decolonization for MRSAMupirocin applied to the anterior nares for 5 days can reduce colonization by 90-95%.Especially valuable in the treatment of HCW’s linked to nosocomial MRSA infections.Significantly better than bacitracin (94 vs. 44% eradication).May be much lower clearance with multisite carriage (wounds,etc.): 21-44%.

36. MRSA Colonization: MupirocinAll 321 residents of a VA LTCF (Ann Arbor) were cultured; MRSA (+) received mupirocin ointment to nares and wounds.MRSA was rapidly eliminated by the end of 1 week.Even with weekly maintenance mupirocin, 40% recurred and 10.8% became mupirocin resistant.Facility colonization rates did not change. Kauffman CA. Am J Med 1999;94:371-8.

37. Mupirocin for MRSAPrevention of CAPD catheter infections (exit site): decreases GPC exit site infections, increases GNR infections. Ritzau J. Perit Dial Int 2001;21:471-9. Cardiac Surgery: 67% reduction in surgical site infections compared to historic controls; cost $12.47/patient vs. $81,018/deep infection) Ann Thorac Surg 2001;71:1572-8.

38. Take Home: MRSA and MupirocinHighly effective for individuals with nasal colonization, esp. HCW assoc with nosocomial infections.Less successful with colonization other than nares and attempts at decreasing facility wide colonization rates. Resistance most likely with long term use.Areas of interest: preoperative to decrease SSI’s and dialysis (CAPD and HD).

39. Enterococci Normal intestinal flora of almost all animals from cockroaches to humans with typical concentrations of 108/gram of stool.2 predominant species: E. faecalis and E.faecium.E.faecalis causes 80% of human infections, but only 2% are Vancomycin resistant (VRE). E.faecium causes 20% of human infections, but 52% are VRE. Huycke M. Emerg Infect Dis 1998;4:239-49.

40. Enterococci and SynercidE. faecium are almost always sensitive to Synercid (90% of VRE isolates).E.faecalis are almost always resistant to Synercid (10% of all VRE).Mechanism of resistance is unknown but similar observations have been reported for Virginiamycins M and S. Collins L. AAC 1993;37:598-601.

41. Linezolid (Zyvox)First antibiotic from the oxazolidinone class.Inhibits protein synthesis at the bacterial ribosome and is bacteriostatic against Staphylococci and Enterococci.Active against VRE (both E. faecium and E. faecalis), MRSE and MRSA.Cure rates have been comparable to vancomycin. Medical Letter 2000;42:45-6 (issue #1079)

42. Linezolid (Zyvox)Usual dose is 600 mg. Q12H.Available in 600 mg. tablets, oral solution and IV formulation.Each 600 mg. tablet is $53 and a 600mg. IV vial is $72.No dosage adjustment with renal or hepatic failure.

43. Linezolid (Zyvox)Most common adverse events have been nausea, vomiting and diarrhea.Reversible thrombocytopenia has been reported with prolonged use; monitoring of platelet counts has been recommended if treatment is >2 weeks.Weak non-selective reversible inhibitor of monoamine oxidase; patients should avoid foods rich in tyramine which could result in severe hypertension.

44. Linezolid Resistant VRELiver transplant recipient with VRE infection treated with linezolid which became linezolid resistant, but remained synercid sensitive.Strain was transmitted to 6 others, none had overt infection or were treated with linezolid.Associated with a 23S rDNA mutation which has also been described in a linezolid resistant S. aureus. Herrero I.NEJM 2002;346:868-9.

45. Is there ever justification in attempting to eradicate colonization of VRE/MRSA in a patient?

46. Where are patients colonized with VRE?For patients with VRE bacteremia:100% had stool colonization.86% had skin colonization. Beezhold D. Clin Infect Dis 1997;24:704-6

47. VRE Colonization70% of patients colonized with VRE go undetected without active surveillance.VRE colonized and VRE infected have similar amounts of VRE in stool (108/gm of stool).Some remain colonized for > 1 year.

48. Bacitracin for VRE ColonizationNot routinely used to treat systemic infection. Non-absorbable antibiotic first isolated from a Bacillus species.Highly active against gram positives.Acquired resistance unusual..

49. Bacitracin for VRE8 patients treated with bacitracin 25,000u BID x 10d; 5 were repeatedly negative after one course (1 required 2 courses). Chia J. Clin Infect Dis 1995;21:1520.4 LTC facility residents received bacitracin 75,000u QID x 14d; 3 of 4 cleared VRE during therapy, 2 became (+) after 48hrs. Armstrong-Evans M. Infect Control Hosp Epidem 1999;20:312-17.

50. Bacitracin for VREAll colonized inpatients were treated with bacitracin 25k or 50k units QID.VRE was suppressed in stools in 50% and 75% in the low and high dose arms ,respectively. Long term eradication was only 25% and 40%. McGeer A. 35th ICAAC San Fran 1995 Ab# J142.

51. Bacteria are SurvivorsMany beta lactam antibiotics are natural products of microorganisms (Penicillin from Penicillium notatum and Cephalosporins from Cephalosporium acremonium).No slackers, others produced beta-lactamases to inactivate the beta lactams gaining a survival advantage over non-producers. Not to be outdone, other microorganisms counter attacked with beta-lactamase inhibitors (Clavulanic acid was derived from Streptomyces clavuligerus).

52. Resistant Pneumococcus: How Did It Happen?Pneumococci imported and integrated DNA sequences for penicillin resistance from other bacterial species through recombination; the most likely suspects are the viridans streptococci in the mouth. Aminoglycoside resistance gene is the same as the one present in Enterococci and Staphylococci. Erythromycin resistance gene is the same as the one found in Escherichia coli.Resistance traits are perfectly stable and allow normal rates of growth.

53. Pneumococcus Does It All35% of S. pneunoniae are now PCN resistant; 60% are high level resistant (MIC>2 ug/ml).High rates of asymptomatic colonization (5-10% of adults and 20-40% of children) and person to person transmission (esp. day care centers).Driven by the selective pressure of antibiotic use (prior treatment with antibiotics is the #1 risk factor for DRSP infection).

54. Antibiotic Use and ResistanceAntibiotic use creates a competitive advantage for resistant organisms.Forces the acquisition of resistance by sensitive strains in self defense.Selects out resistant subpopulations.

55. Quinolone Resistance in Pneumococcus Resistance occurs by mutations in the parC and gyrA genes which encode topoisomerase enzymes, the target of quinolones.Resistance occurs as a stepwise process with mutation in the primary target followed by a second step mutation (occurs much more easily than first step mutations). Spontaneous mutations occur at a rate of 1 in 106 -109 .Mutants are much more likely to be selected when quinolones are used to treat patients with pneumococcal pneumonia (up to 1010 organisms/ml of sputum) than with simple colonization.

56. Levofloxacin and MPCMutant Prevention Concentration (MPC) is the level of antibiotic at which no mutant can be recovered from >10 billion cells exposed to the drug. For levofloxacin, the MPC for the pneumococcus is near or above the maximal serum concentration.MPC for moxifloxacin is below the serum level for 90% of isolates.Rate of selection of first step mutants is 1000x higher for levofloxacin than moxifloxacin. AAC 2002;46:522-4.Has led some to suggest that levofloxacin may become a “class killer”. Lancet Infect Dis 2001;1:145-6.

57. Beginning of the End or the End of the Beginning4 cases of levofloxacin failure with pneumococcal pneumonia. 2 isolates were sensitive at baseline ( acquired resistance during therapy) and 2 patients had prior courses of quinolones (selection of resistant subpopulation). Davidson R N Engl J Med 2002;346:747-50.

58. Levofloxacin Resistant PneumococcusNational Committee for Clinical Laboratory Standards (NCCLS) does not currently recommend routine quinolone susceptibility testing for pneumococci.Current ATS and IDSA guidelines for treatment of CAP do not mention prior quinolone exposure as a potential problem. “In our opinion,the current data indicate that recent exposure to a fluoroquinolone should be a contraindication to the use of another fluoroquinolone for the empirical treatment of community acquired pneumonia.” Davidson R N Engl J Med 2002;346:747-50.

59. Macrolide Resistant Group A StreptococcusNo macrolide resistance was noted in Group A Streptococci from Oct 1998 to May 2000 in Pittsburgh during a longitudinal study at an elementary school.48% of isolates were resistant to erythromycin from Oct 2000 to May 2001., all were the same strain.Occurred during a time of increased macrolide use.Strep throat often diagnosed with a non-culture technique and even if cultured routine sensitivities are not performed. Martin J. N Engl J Med 2002;346:1200-6.

60. Lessons Learned Bacteria are promiscuous.Bacteria are survivors.Antibiotic use adds to the natural selection pressure giving an advantage to resistant strains.

61. Take Home MessageThe More You Use It, The Faster You Lose It!

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