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. Which of the following resistance patterns is accurate for MRSA (ORSA)?
Drug A B C D E
Penicillin R
Amp-Sulbactam S
Cephalothin
Ceftazidime
Imipenem
Vancomycin
2007 Virginia Board Review Course

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

6. but clinical significance is clear: First-Line β–lactams won’t work!
“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

7. 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
S.aureus
Drug
Interpretation
Oxacillin
RESISTANT
Erythromycin
Clindamycin
SUSCEPTIBLE
Rifampin
TMP/SMX
Vancomycin

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
S.aureus
Drug
Interpretation
Oxacillin
RESISTANT
Erythromycin
Clindamycin
SUSCEPTIBLE
Rifampin
TMP/SMX
Vancomycin

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 MRSA type Community Hospital Chromosomal Cassette IVII
Toxins Produced
Numerous
Few
PVL Toxin
Common
Rare
Common Infections
Skin & Soft Tissue
Lung & Blood
Abx Resistance
Less Resistant
More Resistant

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%
*D-zone test should be done to look for inducible resistance to clindamycin: 7% at HMC and 12% at UWMC

16. Beta-Lactamase Positive
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.
S.Aureus
Beta-Lactamase Positive
Drug
Interpretation
Penicillin
RESISTANT
Oxacillin
SUSCEPTIBLE
Clindamycin
Linezolid
Levofloxacin
TMP/SMX
Vancomycin
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.
> 100K S.aureus
Drug
MIC
Interpretation
Oxacillin 4
RESISTANT
Chloramphenicol
SUSCEPTIBLE
Linezolid 2
Rifampin 1
TMP/SMX
2/38
Vancomycin
No Big Deal
Target Vanco trough 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.
> 100K S.aureus
Drug
MIC
Interpretation
Oxacillin 4
RESISTANT
Chloramphenicol
SUSCEPTIBLE
Linezolid 2
Rifampin 1
TMP/SMX
2/38
Vancomycin

23. IDSA may still call this “GISA” Case: VISA / VRSA?
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. Emergence of Antimicrobial Resistance
Susceptible Bacteria
New Resistant Bacteria
Selective Pressure  Upregulation of resistance factors or novel mutations. XX
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. VRSA
MecA
VanA
VRE
MRSA
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.
LINEZOLID
VANCOMYCIN

32. FYI only… NOT on boards!

33. Newer Treatment Options
Case: VISA / VRSA
Newer Treatment Options
Linezolid
Daptomycin
Tigecycline
Oxazolidinone
Inhibits Ribosomes
> 95% Sensitive
PO & IV: 600 mg Q12 H
Good vol. of distribution
~30%  plts after days…
$$$
Lipopeptide
Depolarizes membrane
IV only: 4mg/kg/day
Will not cover PNA
Renal toxicity & Myositis…
Glycylglycine
~90% Sensitive
IV only: 50mg Q12H
Good distribution
No renal toxicity
30% severe nausea
Watch out for Serotonin Syndrome!

34. Newer Treatment Options
Case: VISA / VRSA
Newer Treatment Options
Linezolid
Daptomycin
Tigecycline
Oxazolidinone
Inhibits Ribosomes
> 95% Sensitive
PO & IV: 600 mg Q12 H
Good vol. of distribution
~30%  plts after days…
$$$
Lipopeptide
Depolarizes membrane
IV only: 4-6 mg/kg/ day
Will not cover PNA
Renal toxicity & Myositis…
Glycylglycine
~90% Sensitive
IV only: 50mg Q12H
Good distribution
No renal toxicity
30% severe nausea

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. Newer Treatment Options
Case: VISA / VRSA
Newer Treatment Options
Linezolid
Daptomycin
Tigecycline
Oxazolidinone
Inhibits Ribosomes
> 95% Sensitive
PO & IV: 600 mg Q12 H
Good vol. of distribution
~30%  plts after days…
$$$
Lipopeptide
Depolarizes membrane
IV only: 4mg/kg/day
Will not cover PNA
Renal toxicity & Myositis…
Glycylglycine
~90% Sensitive
IV only: 50mg Q12H
Poor staying power in blood!
No renal toxicity
30% severe nausea

37. Newer Treatment Options
Case: VISA / VRSA
Newer Treatment Options
Linezolid
Daptomycin
Tigecycline
Oxazolidinone
Inhibits Ribosomes
> 95% Sensitive
PO & IV: 600 mg Q12 H
Good vol. of distribution
~30%  plts after days…
$$$
Lipopeptide
Depolarizes membrane
IV only: 4mg/kg/day
Will not cover PNA
Renal toxicity & Myositis…
Glycylglycine
~90% Sensitive
IV only: 50mg Q12H
Poor staying power in blood!
No renal toxicity
30% severe nausea
Approved in 2011…
Ceftaroline!

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

40. MIC Breakpoints for S.pneumoniae isolated from blood in pts with pneumonia (mcg/mL)
Susceptible
Intermediate
Resistant
Updated 4/08
≤ 2 4
≥ 8
Previous
≤ 0.06
0.12-1
≥ 2

41. 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

42. 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

43. ESBL Variable success: 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)

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

45. New Carbapenem: Doripenem
Case: ESBL
New Carbapenem: Doripenem
Best in-vitro anti-pseudomonal coverage to date.
Just FDA-Approved for complicated UTI & intraabdominal infections.
NOT on Formulary Yet.
NOT approved for VAP

46. GNR Resistance Detection Summary
MOA
ESBL
Location
Plasmid
Bugs
E.coli, Klebsiella
1 gen Ceph R
2 gen Ceph S
3 gen Ceph
4 gen Ceph
R / S
Cefotax + Clav
Carbapenem

47. 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.
S.marcescens
Drug
Prior
Today
Cipro R
Amp
Amp / Sulbactam S
Cefazolin
Cefotixin
Ceftriaxone
Cefepime
Meropenem
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!

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

49. 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”)

50. GNR Resistance Detection Summary
MOA
AmpC
ESBL
Location
Chromosome
Plasmid
Bugs
“SPICEM”
E.coli, Klebsiella
1 gen Ceph R
2 gen Ceph S
3 gen Ceph
4 gen Ceph
R / S
Cefotax + Clav
Carbapenem

51. 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

52. Emerging Resistance: KPC
KPC Carbapenemases
Enzymes hydrolyze carbapenems
All Carbapenems susceptible
Klebsiella pneumoniae strongest association… also seen in enterobacteriaciae & P.aeruginosa
Can be transferred on plasmids
Consider in all infections with K.pneumoniae or other enterobacteriaciae which fail to improve on carbapenem therapy

53. DNA Transfer: Conjugation
bacterconjugation-png-1

54. Emerging Resistance: KPC
Detection Pitfalls
Imipenem, Meropenem, Doripenem may appear susceptible on standard sensi panel (MIC’s relatively low)
Ertapenem has highest MICs, so rule out KPC with erta E-test.

55. Emerging Resistance: KPC
Treatment Options
Beta-lactams are generally ineffective
Plasmids often contain resistance determinants for numerous other drugs
Tigecycline has been used successfully
Test aminoglycosides, FQ’s, tetracyclines, glycylglycines, TMP/SMX, colistin… and pray.

56. GNR Resistance Detection Summary
MOA
AmpC
ESBL
KPC
Location
Chromosome
Plasmid
Bugs
“SPICEM”
E.coli, Klebsiella
Klebsiella, enterobacteriaceae
1 gen Ceph R
2 gen Ceph S
R / S
3 gen Ceph
4 gen Ceph
Cefotax + Clav
Carbapenem

57. “Don’t forget to take a handful of our
complimentary antibiotics on your way out.”

58. Resistance Update: MRSA
Incidence: Huge burden in hospitals and outpatient clinics, and sure to rise!
Vanco MIC Creep: 2 mcg/mL not uncommon… and may lead to clinical failure
Treatment Options:
Vancomycin and TMP/SMX first line or SSTI!
Linezolid vs ceftaroline alternatives
Daptomycin (not in pneumonia)

59. Resistance Update: VISA / VRSA
VISA: Vanco MIC 4-8 mcg/mL
hVISA: Same MIC’s, but harder to detect
VRSA: Vanco MIC ≥ 16 mcg/mL
Incidence: Likely to rise... Beware vanco failures!
Detection: CDC algorithm
Treatment Options:
Linezolid
Daptomycin (not in pneumonia)

60. Resistance Update: PRSP
Apparent disconnect between “resistant” and treatment failures in pneumococcal pneumonia
IDSA Lobby At Work: New breakpoints for pneumonia allow PCN use at higher MICs
No change to more stringent MICs for meningitis

61. Resistance Update: ESBL
Extended-Spectrum ß-Lactamases
Mechanism: Eats PCN’s & Cephalosporins
Location: Plasmid
Risk: Recent cephalosporin use followed by Klebsiella or E.coli infection
Detection: E-test with 3rd Gen Ceph +/- BLI
Empiric Rx: Carbapenem (and await lab confirmation)

62. Resistance Update: AmpC
AmpC ß-Lactamases
Mechanism: Eats PCN’s & 1st-3rd Gen Cephs
Location: Chromosome (SPICEM) or plasmid
Risk: Prolonged treatment with ß-Lactam may induce resistance & cause failure
Detection: Sensitive only to 4th Gen Ceph
Empiric Rx: 4th Gen Ceph or Carbapenem

63. Resistance Update: KPC
KPC Carbapenemases
Mechanism: Eats all beta lactams & carbapenems
Location: Plasmid
Risk: Klebsiella or enterobacteriaciae infection
Detection: E-test with ertapenem
Empiric Rx: Combination with aminoglycoside (and await lab confirmation)

64. Antibiotics Update: What We Didn’t Cover Antifungals Antiretrovirals
Antiparasitics 64

65. Feedback?