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ID Board Review: Antimicrobial Resistance

ID Board Review: Antimicrobial Resistance. Paul Pottinger, MD, DTM&H Director, UWMC Antimicrobial Stewardship Program July 8 , 2011. Objectives. Review mechanisms of abx resistance among gram-positive & gram-negative bacteria. Best guess as to Boards content.

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ID Board Review: Antimicrobial Resistance

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  1. ID Board Review:Antimicrobial Resistance Paul Pottinger, MD, DTM&H Director, UWMC Antimicrobial Stewardship Program July 8, 2011

  2. Objectives • Review mechanisms of abx resistance among gram-positive & gram-negative bacteria. • Best guess as to Boards content. • Suggested approaches for real-life clinical ID.

  3. What will be on the Boards? • Handful of flat-out resistance questions (e.g. “The mechanism of vancomycin resistance in VRSA is…”) • Likely clinical stem: pt with proven bacterial infection is failing therapy, and you need to decide why... And what to do next. • Probably not much related to abx stewardship 

  4. 2007 Virginia Board Review Course

  5. 1981 Community-Acquired MRSA Reported Told you so 1961 Methicillin-resistant S.aureus (MRSA) Described in Europe 1928 Penicillin Discovered (on S.aureus plate) 1968 MRSA found in Boston Hospitals 1950’s S.Aureus shows PCN-resistance 1942 Penicillin Cures S.aureus wound 1959 Methicillin Introduced to kill PRSA 1974 MRSA: 2% of US nosocomial staph infections MRSA in 2007: 94,000 severely ill 19,000 die 1997 MRSA: 50% US nosocomial staph infxns 1999 CDC: 4 healthy kids die of CA-MRSA Charles Darwin(1809-1882)

  6. “MRSA” a misnomer… but clinical significance is clear: First-Line β–lactams won’t work! • Therapy may require: • Expensive and Toxic Abx • IV administration • Longer Courses of Therapy http://www.lg1.ch/cpg/thumbnails.php

  7. MRSA • MRSA: Resistant to all beta-lactams, monobactams, carbapenems • MOR: • Target Modification: MecA gene encodes altered PCN-binding protein PBP2A • Dx by KB-diffusion (Fox best inducer!), robotic microtiter, PBP2A latex agglutination, or MecA PCR • Other resistance genes common!

  8. Case • A 20 y/o woman with painful, red rash on buttock for last 4 days • Recently joined college rowing team

  9. Clindamycin is started pending susceptibility results. • No culture is necessary; Rx Keflex • Specimen should be sent for culture, and empiric Clav-Amox should be Rx’d • Specimen should be sent for culture, and empiric Trimethoprim / Sulfa should be Rx’d • Culture is not necessary; empiric Levofloxacin should be Rx’d, as no resistance to gram positives is reported • No culture is necessary; Rx Keflex • Specimen should be sent for culture, and empiric Clav-Amox should be Rx’d • Specimen should be sent for culture, and empiric Trimethoprim / Sulfa should be Rx’d • Culture is not necessary; empiric Levofloxacin should be Rx’d, as no resistance to gram positives is reported

  10. Clindamycin is started pending susceptibility results. • Check on the patient and request a D test to rule out inducible resistance • Continue clinda. No further testing. • Change to Trimethoprim / Sulfa • Add rifampin • Change to linezolid • Check on the patient and request a D test to rule out inducible resistance • Continue clinda. No further testing. • Change to Trimethoprim / Sulfa • Add rifampin • Change to linezolid

  11. MRSA • Clinda Resistance • MOR: • Target Modification: erm gene encodes methylated 50S ribosome subunit, inactivating erythro and clinda. • Constitutive or Inducible. • Erythro a more potent inducer than clinda in vitro.

  12. MRSA • Clinda Resistance • Detection: • Put clinda disk next to erythro, look for “D-zone.” • Clinical Significance: • Uncertain, but Rx failures reported with clinda… for boards & your practice, take D-zone seriously, and consider changing therapy if this is detected.

  13. MRSA: Two Flavors Spectrum of Disease CA-MRSA HA-MRSA

  14. MRSA: Two Flavors

  15. MRSA Susceptibilities: Seattle 2009 Clindamycin* Levofloxacin Doxycycline TMP/SMX Vancomycin Linezolid Daptomycin Harborview UWMC 63% 41% 20% 12% 94% 94% 95% 95% 100% 100% 100% 100% 100% 100% *D-zone test should be done to look for inducible resistance to clindamycin: 7% at HMC and 12% at UWMC

  16. Case • A PCP calls MEDCON wanting to know how to interpret a sensi pattern. • Otherwise healthy young man with infected wound of his ankle… already on empiric cephalexin… no major change in wound appearance since cx drawn 48 hours ago. • This is MRSA, change to TMP/SMX. • This is MRSA, change to IV Vanco. • This is MSSA, continue cephalexin. • Something is wrong with your lab…. • This is MRSA, change to TMP/SMX. • This is MRSA, change to IV Vanco. • This is MSSA, continue cephalexin. • Something is wrong with your lab….

  17. MSSA: Beta Lactamases • Original form of PCN resistance: PRSA. • Still the rule (~5% of MSSA has no beta-lactamase activity, thus is PSSA). • For most situations, what you see is what you get for MSSA sensitivities.

  18. MSSA: Beta Lactamases • Caveat: Not all beta-lactamases are the same! • Type A beta-lactamase may hydrolyze cefazolin specifically at high inocula (eg: IE)… this is the “inoculum effect” • If pt with MSSA IE fails cefazolin, recognize inoculum effect and recommend change to naf or ox. Nannini et al, CID 2009

  19. Case • A 70 y/o woman with dementia & DM-nephropathy admitted from SNF for sepsis. • Long h/o foot ulcers with VRE & MRSA. • Urine grows MRSA → Vanco begun. • Remains febrile after 6 days. • No Big Deal • Target Vanco trough 15-20 mcg/mL • Consider Daptomycin • Consider Linezolid • Wish I had dedicated my career to combating antimicrobial resistance….

  20. MRSA: Vancomycin MIC Creep? • Not all VSSA created alike. • Published reports of rising vanco MIC’s in last 5 years. • Presumed MOR: increased cell wall thickness. • Retrospective case series: higher MIC’s associated with higher liklihood of clinical failure on vanco (Soriano et al, CID 2008).

  21. MRSA: Vancomycin MIC Creep? • MIC ≤ 2 still considered susceptible (VSSA)… Concern: clinical failures with vanco, and theoretically with dapto. • Recommend you check vanco MIC when pt fails to clear bacteremia or clinically improve after 7 days of therapy. • “Consider” switch to alternative agent if MIC = 2, and if pt is failing vanco.

  22. Case • A 70 y/o woman with dementia & DM-nephropathy admitted from SNF for sepsis. • Long h/o foot ulcers with VRE & MRSA. • Urine grows MRSA → Vanco begun. • Remains febrile after 6 days.

  23. Case: VISA / VRSA? IDSA may still call this “GISA” • VISA: MIC 4 – 8 mcg/mL • Increasing # of case reports: MSSA & MRSA • MOR: Increased Target Density Prolonged Vanco exposure Selection of Thicker Cell Walls Vanco exposure to D-Ala-D-Ala residues

  24. Selective Pressure Upregulation of resistance factors or novel mutations. XX New Resistant Bacteria Emergence of Antimicrobial Resistance Susceptible Bacteria Told you so CDC

  25. Case: VISA? • VISA: MIC 4 – 8 mcg/mL • Clinical Significance • Treatment failures reported with standard-dose vancomycin • In theory, can overwhelm resistance mechanism by pushing dose to “saturate” thicker wall… but not recommended (higher toxicity, risk of failure, alternatives available)

  26. Case: VISA? • hVISA: MIC 4 – 8 mcg/mL • Heteroresistant VISA • MOR: Mixed population of thickened cell wall bugs • hVISA well described, but of unclear clinical significance • Reports of vanco treatment failure reported… but detection bias is almost certainly taking place

  27. Case: VISA? • hVISA: MIC 4 – 8 mcg/mL • Detection Issues • Standard disk diffusion (zone ≤15 mm) and automated systems (Vitek) will miss hVISA • Suspect hVISA if pt persistently culture + after 7 days on vanco • Consider 0.5 McFarland starting culture for E-test • Consider sending isolate to state lab No CLSI-approved detection methods for hVISA!

  28. Case: VISA? • hVISA: MIC 4 – 8 mcg/mL • Robin Howe (ICAAC 2007) • Reasonable balance of sensitivity & specificity: plate on MHA with teicoplanin at 4 mcg/ml x 48 hours to pick up most VISA & hVISA. • Consider sending isolate to state lab if any question of hVISA! • Unlikely to appear on boards.

  29. VRE MRSA VanA MecA VRSA integration

  30. Armageddon: VRSA • VRSA: MIC  16 mcg/mL • Few case reports… Under-detected? • MOR: • Altered target. • VRE implicated as source of VanA gene encoding altered cell wall (D-ala-D-ala → D-ala-D-lac) • Treatment Option: Linezolid first-line 11th US case reported 5/6/10!

  31. Case: VISA / VRSA? • DIAGNOSIS • Robots have missed VISA & VRSA!! • CDC: Vanco plate (6mg/mL) should accompany all S.aureus isolates… but this alone is not enough. • Formal rule-out • not done routinely. VANCOMYCIN LINEZOLID

  32. FYI only… NOT on boards!

  33. Case: VISA / VRSA Watch out for Serotonin Syndrome!

  34. Case: VISA / VRSA

  35. VISA / VRSA Rx Options • Massive, Cyclic Lipopeptide • Excellent MIC’s vs. MRSA, but… • Dissolves in Alveolar Surfactant! • Failure risk in thick-walled VISA!

  36. Case: VISA / VRSA

  37. Approved in 2011… Ceftaroline! Case: VISA / VRSA

  38. Odds of PCN Resistance in S.pneumoniae as Function of PCN Consumption PRSP: What’s New?

  39. Case • A 68 y/o woman with type-2 DM & HTN recently Rx’d for CAP with cefotaxime. • Now admitted for major CVA. • Febrile → BCx & foley cath urine grew K.pneumoniae → Ceftazidime started. • Two days later: Fever breaks, but she becomes less responsive…. • Switch to Levo or Cipro • Switch to Ceftriaxone • Switch to Cefepime • Switch to Meropenem • Everything’s groovy, make no change • Switch to Levo or Cipro • Switch to Ceftriaxone • Switch to Cefepime • Switch to Meropenem • Everything’s groovy, make no change

  40. Emerging Resistance: ESBL • Extended Spectrum ß-Lactamases • Mutant TEM-1, SHV-1, CTX-M, or OXA ß-lactamase • MOR: Drug Inactivation (Enzymes hydrolyze all ß-lactams, not inhibited by BLI’s) • Usually in Klebsiella spp. and E.coli… but plasmid-encoded! • Consider in all nosocomial infections with these organisms • Risk Factor = Previous ß-lactam use

  41. ESBL • Worry if resistance “skips a generation” • Confirm with  3-fold decrease in MIC with ß–lacatmase inhibitor • Rx of choice: • Carbapenem • Variable success: • FQ • Aminoglycoside • Cefoxitin (we do NOT report as sensitive)

  42. New Resistant Bacteria Emergence of Antimicrobial Resistance Susceptible Bacteria Resistant Bacteria Resistance Gene Transfer CDC

  43. GNR Resistance Detection Summary

  44. Case • A 58 y/o man with Serratia marcescens hardware-associated osteomyelitis of the tibia. • Treated for last 4 weeks with IV ampicillin / sulbactam, doing well. • Unexpected fever develops → BCx grows Serratia. • Switch to Levo or Cipro • Switch to Ceftriaxone • Switch to Cefepime • Switch to Meropenem • I should have talked to the Micro Lab! • Switch to Levo or Cipro • Switch to Ceftriaxone • Switch to Cefepime • Switch to Meropenem • I should have talked to the Micro Lab!

  45. AmpC: What’s in a Name? Serratia Pseudomonas, Providencia Indole + Proteus (vulgaris) Citrobacter Enterobacter Morganella S P I C E M Paul Pottinger, MD

  46. Emerging Resistance: AmpC • AmpC ß-Lactamases • Enzymes hydrolyze penicillins & Gen 1-3 cephalosporins • Chromosome of “SPICEM” organisms, but often not expressed until drug pressure applied • Can be transferred on plasmids also • Consider in all infections with SPICEM bugs when initial improvement fails (“induction of AmpC”)

  47. GNR Resistance Detection Summary

  48. Case • A 75 y/o woman is admitted with massive myocardial infarction. • After five days on the ventilator, she develops hypoxemia, fever, leukocytosis, and infiltrates. She is treated empirically for VAP using meropenem. • Sputum gram stain shows 3+ GNR’s. • Clinical illness worsens on therapy…. • Switch to Levo or Cipro • Switch to Ceftriaxone • Switch to Cefepime • Switch to Imipenem • Switch to tobramycin • Switch to Levo or Cipro • Switch to Ceftriaxone • Switch to Cefepime • Switch to Imipenem • Switch to tobramycin

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