1. Community Associated Resistant Bacteria:What Bugs and What Drugs Work Against Them?
Lilly Immergluck, MD
Associate Professor of Pediatrics
Divisions of General Pediatrics and Pediatric Infectious Diseases
Morehouse School of Medicine
March 1, 2006

2. Background Information

3. Emergence of Antimicrobial Resistance
Campaign to Prevent Antimicrobial Resistance in Healthcare Settings
Emergence of Antimicrobial Resistance
Susceptible Bacteria
New Resistant Bacteria
Mutations XX
Resistant Bacteria
Resistance Gene Transfer
Bacteria have evolved numerous mechanisms to evade antimicrobial drugs.
Chromosomal mutations are an important source of resistance to some antimicrobials.
Acquisition of resistance genes or gene clusters, via conjugation, transposition, or transformation, accounts for most antimicrobial resistance among bacterial pathogens.
These mechanisms also enhance the possibility of multi-drug resistance.

4. Selection for antimicrobial-resistant Strains
Campaign to Prevent Antimicrobial Resistance in Healthcare Settings
Selection for antimicrobial-resistant Strains
Resistant Strains
Dominant
Antimicrobial
Exposure x
Resistant Strains Rare x
I am giving the punchline for my talk at the beginning….before I lose some attention..
And hopefully, you all will be thinking that I am preaching to the choir
Once resistant strains of bacteria are present in a population, exposure to antimicrobial drugs favors their survival.
Reducing antimicrobial selection pressure is one key to preventing antimicrobial resistance and preserving the utility of available drugs for as long as possible.
My focus today is:
Bugs that have developed in our community in children
Hopefully, I will convince you that we need to understand the epidemiology (including risk factors) and take measures to try and prevent their spread…

5. What “Bugs” are we talking about…in Pediatrics?
Community-associated Methicillin Resistant Staphylococcus aureus
Drug Resistant Streptococcus pneumoniae
There are many resistant bacteria
Focus on 2 that are emerging specifically among children in the last 5-10 years
Although I worry about Vancomycin resistant enterococci….my focus today is on bugs that are prevalent in an otherwise healthy community or population of children

6. Methicillin Resistant Staphylococcus aureus
Although not new, Methicillin –resistant Staph has taken on a new twist
These gram positive cocci in clusters…
It is emerging among children without risk factors

7. Cartoon of SA
Shows surface and secreted proteins
Cross panel B shows enzymes produced by staph:
beta lactamase (red circles) (penicillinase) that inactivates the beta lactam ring of penicillin
PBPs(aqua capsules) (penicillin binding proteins)-enzymes located in cytoplasmic membrane that are involved in cell-wall assembly
MEC A gene encodes PBP 2A
Probably originated from a different staph species
Excision/integration of mec catalyzed by “cassette chromosome recombinases A and B that is conded by mec associated genes (ccrA and B)
Lowy, Frank,Staphylococcus Infections. NEJM. August, 1998

8. Types of MRSA BRSA- Borderline MRSA MRSA- related to mecA gene=ORSA
Hospital associated MRSA
Community associated MRSA
Start off by making sure we all understand some of the terminology in discussion this bacteria:
Borderline MRSA- S. aureus isolates with MICs of 2-4 mcg oxacillin/ml, values close to the limit of susceptibility
·Isolates are uniformly susceptible to amoxicillin/clavulanate
·Increased production of beta-lactamase
·Not mediated by presence of mecA gene
MRSA conferred by presence of mecA gene
Hospital associated
Community-associated

9. Mechanism of Resistance for MRSA
Mec A gene
Staph
Staph
Cartoon to depict the mechanism of resistance
Traditionally,
With repeated exposure to antibiotics, SA pick up DNA (MecA)
Alters the PBP’s (red,orange, pink,yellow) especially a PBP2A
Does not allow beta lactam antibiotics to attach to cell wall
Resistance is related to DNA flanking the mecA gene which has many potential sites for integration of transposons (genetic elements that mediate antibiotic resistance)
·MRSA have developed at multiple independent times via lateral transfer of mec A gene into methicillin-susceptible precursors
·MecA gene encodes an altered penicillin binding protein (PBP)2A with very low affinity for beta-lactam antibiotics
·PBP2A is transpeptidase that restores cell wall biosynthesis along with PBP2, reduced affinity for beta lactam antibiotics
antibiotic

10. Staphylococcal chromosomal cassette mec IV, type 4 (SCC mec type IV)
Mec A gene is encoded within the Staphylococcal chromosomal cassette
SCC mec type IV lacks antibiotic resistance elements directed at non- beta lactam antibiotics
ccrA2 and ccrB2 designate cassette chromosome recombinases
mecA encodes PBP2a
Delta ec R1 is a signal transducer gene, when activated by beta lactam antibiotics inactivates mec I repressor gene product, allowing expression of mec A
Tn554, genetic element, that can be found in some SCC, encodes resistance to macrolides, clindamycin and streptogramin B
pT181, encodes resistance to tetracyclines
Derensinski S. Clin Infect Dis 2005:562-73

11. Emergence of USA 300 clone Result of insertion of SCCmecA type IV
Donor staph isolate is MSSA
Differences from HA-MRSA:
Gene cassette coding for methicillin resistance
Carriage of plasmids encoding resistance to antibiotics of other classes
Associated virulence factor

12. SCCmec types I-V I II III IV V
Size of SCCmec
Other Antibiotic Resistance elements on SCCmec
Origin of S. aureus isolates
Presence of Panton Valentine leukocidin I 34
...
Hospital
Infrequent II 53
PUB110 (aadD)b, Tn554 (ermA)c
III 67
PUB110 (aadD)b, PT181 (tetK)d IV
21–24
Community
Frequent V 28
Unknown
PVL- first described in 1932
Bicomponent synergohymenotropic (synergistic membrane-tropic) toxin
Was present in <5% of unselected S. aureus isolates but is present in majority of CA-MRSA isolates studied
Ca-MRSA isolates from Australia infrequently carry genes encoding PVL
Encoded by contiguously located cotranscribed genes, luk S-PV and lukF-PV, inserted near att site
Function: exert cytolytic pore-forming activity specifically directed at cell membranes of polymorphonuclear neutrophils and monocytes and/or macrophages
Injection of PVL into skin of rabbits causes dermal necrosis
Derensinski S. Clin Infect Dis 2005:562-73

13. Staphylococcus sp.
“Isolates of staphylococci that are shown to carry the mecA gene, or that produce PBP2a, the gene product, should be reported as oxacillin resistant”
SA if oxacillin MIC < 2mcg/ml=Susceptible
If > 4 mcg/ml=resistant

14. Epidemiology of MRSA First described in 1961
Approximately 50% of Staphylococcus aureus infections in ICU in US due to MRSA
Approximately one third of general population is colonized with SA
First described in 1961
Hospital acquired
-common nosocomial pathogen since 1960s
Approx. 50% of SA infections in intensive care units in US health care facilities is due to MRSA (1999 National Nosocomial Infection Surveillance (NNIS) System report

15. Risk Factors for Hospital acquired MRSA in Adults
Prolonged/recurrent antibiotic exposure
Prolonged hospitalization or ICU
Chronically ill
Nursing home residence
Dialysis or Malignancy
-In adult medical literature, the acquisition of MRSA in a hospital or long-term care facility is well documented
Also, prolonged/recurrent antibiotic exposure, surgical procedures, chronic illness, IV drug use, close proximity to patient in hospital who are infected/colonized, recent outpatient visit
-Fewer descriptive data for pediatric population but presumably includes above list and : invasive or surgical procedures, indwelling catheters, endotracheal tubes.
Also, includes day-care center attendance (implicated from CA-MRSA hospitalized children in Texas and Canada)

16. HA-MRSA Prevalence
Lowy, Frank,Staphylococcus Infections. NEJM. August, 1998
Data from summarizing % of infections resistant to Methicillin and MRSA sensitive to only vanco
Increasing trend of all infections resistant to methicillin (squares)
Increasing trend of all MRSA infections sensitive only to vancomycin(filled circles)
Lowy, Frank,Staphylococcus Infections. NEJM. August, 1998

17. Definition of Community-associated MRSA
Hospital-acquired or nocomially acquired
Community-acquired-
1.Defined by time line, within hours of admission to hospital
a.With risk factors-
Most of data reported prior to 1990s are in adult individuals with a recognized risk factor: contact with health care providing environment or parenteral substance abuse.
2.Without usual risk factors- (focus of today’s discussion)
Unusual in children and adults prior to1995
-First described:
Moreno, et al Clin InfectDis, in 1995
Herold, et al , in first series looking at children
Salgado, Farr, Calfee Clin Infect Dis, 2003

18. Epidemiology of Community acquired MRSA
Case Report in Chicago
Outbreak among high school wrestling team in Vermont
Reports have occurred in Chicago, Minnesota, North Dakota, Dallas, Winnipeg, Toronta, and in Australia
Community acquired
-First case of CA-MRSA-1980 occurred in MI
-Case report, Immergluck et al (describe)
-Outbreak among highschool wrestling team in Vermont
-Outbreak in a rugby team in UK
Now reports have occurred in Chicago, Minnesota and North Dakota, Dallas, Winnipeg and Toronto and Australia

19. Headlines to catch our attention…
Methicillin-Resistant Staphylococcus aureus Infections Among Competitive Sports Participants --- Colorado, Indiana, Pennsylvania, and Los Angeles County, 2000—2003
Four Pediatric Deaths from Community-Acquired Methicillin-Resistant Staphylococcus aureus -- Minnesota and North Dakota,

20. “Study Finds Spread of Resistant Staph”
By THE ASSOCIATED PRESS Published: April 7, 2005
Study Finds Spread of Resistant Staph
By THE ASSOCIATED PRESS Published: April 7, 2005
“Study Finds Spread of Resistant Staph”
By THE ASSOCIATED PRESS Published: April 7, 2005, NY Times

21. “PRO FOOTBALL; After Medical Scare, Giants' Center Improves”
November 4, 2004, Thursday
By LYNN ZINSER (NYT); Sports Desk
Late Edition - Final, Section D, Page 4,
“At first, Giants center Shaun O'Hara said he had no idea why his swollen calf was causing so much alarm among team trainers last week. He knew nothing about the staph infections that had struck seven Miami Dolphins last year, hospitalizing two of them, or of…”

22. Fatal Pediatric Infections from CA-MRSA
Case 1
Case 2
Case 3
Case 4
Age
7 years
16 months
13 years
12 months
Syndrome
septic arthritis, sepsis, pneumonia/ empyema
severe sepsis
necrotizing pneumonia, severe sepsis
Antimicrobial susceptibility*
t/s, tet, cip, gent, ery, clind, vanc
t/s, cep, cip, gent, ery, clind, vanc
Toxin test+
SEC positive
SEB positive
All 4 children had multiply non resistant MRSA(North Dakota)—all fairly susceptible
7/97-7yo
1/98-16 mo
1/99-13 yo
2/99-12mo
* t/s=trimethoprim-sulfamethoxazole, tet=tetracycline, cip=ciprofloxacin, t=gentamicin,
ery=erythromycin, clind=clindamycin, and vanc=vancomycin.
+ SEB=staphylococcal enterotoxin B; SEC=staphylococcal enterotoxin C.
Source: Centers for Disease Control and Prevention, Atlanta , October 1999 / HOSPITAL INFECTION CONTROL

23. Minnesota Surveillance Study, 1997
-As a result of number of case reports, prompted one of the first major surveillance studies of CA-MRSA
In 1997, Minnesota Dept of Health received several reports of MRSA infections among young, previously health patients.
Prompted a 3 year survey of 10 Minnesota hospital to better define epidemiologcical profile of these patients
-Definition CAMRSA: Any outpatient or inpatient with culture-confirmed MRSA infection who had no history of hospitalization, surgery, renal dialysis, or residence in long term care facilitiy within 1 year of MRSA; no IVD use, no permanent indwelling catheter or percutaneous medical device present at the time of culture, no known MRSA before study, and who specimen for MRSA was obtained within 48 h after admission
Take home message:
Most cases were among young, especially children less than 10
Naimi,LeDell et al Clin Infect Dis 2001

24. Summary of Age Distribution of CA-MRSA in Minnesota
Mixture of private, suburban, urban, pediatric, community hospitals
-From , # CA-MRSA were relatively the same
This summarizes age distribution:
Median: 16 years
38% less than 10 years
Specifically, 23% were less than 6 years
40% were Native Americans (this is after excluding a hospital with predominantly NativeAmericans)
-71% (251) had CA-MRSA diagnosed and treated while outpatients
-5 hospitals with highest rates of CA-MRSA were located in both metro and greater Minnesota area

25. Clinical Presentation

26. Maybe as simple as this…
courses.washington.edu, accessed from web 2/28/06

27. Or more severe as this…
accessed Feb 28, 2006

28. MRSA Pneumonia/Empyema
This film is to represent a teenager we took care of and was one of the first cases of CA-MRSA to be reported in the literature.
No traditional risk factors
Healthy
No previous hospital admission
He presented with 1 month history of dry nonproductive cough, generalized malaise, 16 pound weight loss, 2 week history of intermittent fevers.
Characteristic of a staph pneumonia with empyema (he also had thymic abscess)

29. Clinical Presentation of Children with CA-MRSA
None of CA-MRSA without risk factors had bacteremia without focus
20% CA-MRSA with risk factors had bacteremia
33% of HA-MRSA had bacteremia
Abscesses were more common with CA-MRSA without risk factors
27% of CA-MRSA without risk factors had abscesses
0% of CA-MRSA with risk factors had abscess
8% of HA-MRSA had abscess
Clinical syndrome for all MSSA were similar to CA- MRSA without identified risk factors: more presented with cellulitis/abscesses
Herold, Immergluck, et al JAMA 1998

30. Summary of Risk Factors for CA-MRSA
Four categories of risk factors for CA-MRSA
Only one risk factor, low overall risk for CA-MRSA
Highest risk: children from ethnic minorities and socially disadvantaged have highest risk of CA-MRSA skin and soft tissue infections
Eady, Cove, Curr Opin Infect Dis, 2003

31. What Drugs Can Treat This Bug?

32. “D Test” – positive reaction
Inducible
clindamycin resistance
(erm-mediated)
…another example mm
Photos courtesy of J. Jorgensen and K. Fiebelkorn.

33. “D Test” – negative reaction
NO induction
(msrA-mediated erythromycin resistance)

34. MRSA—Erythromycin/Clindamycin Story
Mechanism
Pathway
Erythro
Clinda
Efflux
msrA R S
Ribosome alteration
erm R*
msrA=macrolide streptogramin resistance
Erm=erythromycin ribosome methylase
*may test resistant or may test susceptible and require induction to show resistance
ERM:
Confers resistance to macrolide, lincosamide, streptogramin B (MLS)
MLS resistance occurs via methylation of 23 S rRNA and reduces binding of MLS agents to the ribosome
MLSbi=inducible resistance to lincosamide (clinda); “D” test required
MLSBc=constitutive resistance to lincosamide; shows clinda resistance in routine ASTs

35. Treatment of CA-MRSA Options are better than hospital acquired-MRSA
Almost all are clindamycin susceptible
Trimethoprim-sulfamethoxazole
Role of quinolones
CA MRSA are usually susceptible to clindamycin
There have been reports of resistance to Clindamycin
Frank, A et al Pediatr Infect Dis J 2002; 21:
Correlation between CA and clinda susceptible , P<0.0001
Patient had Clinda susceptible isolate and then relapsed on therapy, PFGE were identical for isolates.
? Of developing clindamycin resistance if it is an isolate that is resistant to erythromycin.
Mechanism of resistance to erthyromicin is cross resistance (target modification) between macrolides and clindamycin
MLS (Macrolide, lincosamide, streptogramin A&B)
50S ribosomal attachment, decreased affinity

36. HA-MRSA susceptibility pattern
Profile 1
Clindamcin R
Erythromycin R
Oxacillin R
Penicillin R
Vancomycin S
Profile 2
Cefazolin S
Clindamycin R
Erythromycin R
Oxacillin R
Penicillin R
Vancomycin S
Hospital acquired profiles---show typical multiply resistant
First one—resistant to all beta-lactam
2nd Profile-If any beta lactam is tested and tests “susceptible”, cannot be reported as such and should be reported as “resistant”

37. CA-MRSA often susceptible to:
Clindamycin
Erythromycin
Fluoroquinolones
Linezolid
Rifampin
Tetracyclines
Trimeth-sulfa
Vancomycin
Typical pattern for CA-MRSA—not multiply resistant

38. Treatment Regimens Severe infections, multi drug resistant infections
Vancomycin
Daptomycin
Linezolid (pneumonia)
Quinopristin/dalfopristin
Limited infections, less severe
TMP-SMZ
Linezolid
?No treatment
Data from Univ of Texas southwestern-abstract—MRSA infection in children with subcutaneous absceses<5 cm, incision and drainage in absence of administration of antibiotic

39. Data in Atlanta Area
Adult studies
Pediatric studies

40. Risk Factors for CA-MRSA Colonization in Adults
HIV infection
Lower risk if HIV infected and receiving antibiotics within 3 months before admission
History of skin or soft tissue infection
Hospitalization within preceding year
Receipt of antibiotics within 3 months before admission
Based on Surveillance case control study at Grady Hospital,
937 patients swabbed anterior nares
16.3% positive for MSSA
7.3% positive for MRSA (30% USA 300 Ca-MRSA, 40% USA 100, 19% USA 500, 11% other)
76.3% negative for MSSA
Hidron, AI, Kourbatova, EV, et al, Clin Infect Dis 2005

41. Susceptibility of Isolates, by pulsed-field type
Take home message:
CA-MRSA is distinct from HA-MRSA (USA 300 v. USA 100 or 500 or non )
USA 300 uniformly susceptible to Clinda, Rifampin, Bactrim, and Vanco
HA MRSA not susceptible to bactrim, and partially susceptible to Clinda
Hidron, AI, Kourbatova, EV, et al, Clin Infect Dis 2005

42. Preliminary Data for Atlanta Children
3169 Staphylococcus aureus isolates from 1/ /2004
656 (21%) CA-MRSA isolates by phenotype
485 (15%) HA-MRSA isolates by phenotype
Based on data collected from Egleston and Scottish Rite Hospitals

43. Proportional S.aureus isolates at Scottish Rite

44. Proportional S. aureus isolates at Egleston

45. Incidence of SSTI due to S
Incidence of SSTI due to S. aureus isolates among Scottish Rite ER Patients,
Isolates/10,000 ER visits

46. Incident CA-MRSA Isolates from SSTI’s at Egleston and Scottish Rite ER Patients
Isolates/10,000 ER visits

47. Where do we go from here?
Surveillance of children who are colonized with CA-MRSA
Understand risk factors for colonization and subsequent infections due to CA-MRSA
Understand household transmission of CA-MRSA
Develop strategies for eradication of colonization