JP Pretorius

1
PROPHYLACTIC ANTIMICROBIAL THERAPY

• JP Pretorius
• Principal Specialist Surgeon
• Dept of Surgery and Division of Intensive Care
• University of Pretoria
• Pretoria Academic Hospital

2
Outline Red hot terminology

• Classification of wounds
• Why is there a need to get it right first time?
• Early appropriate therapy
• Source control
• Definitions and terminology
• Surgery and antibiotic prophylaxis
• What is collateral damage
• Empiric therapy (educated 1st choice)
• Directed therapy (MCS results)
• De-escalation (adjusted choice)
• Stopping / Discontinuing therapy
• Community acquired infection
• Health Care Associated infection
• Nosocomial infection
• Changing trends in antibiotic resistance
• Choices for empiric therapy
• Choices for pathogen defined therapy (directed)
• Doses / Duration / Pk / Pd / Efficient
  administration

3
INDEPENDENT PREDICTORS OF INFECTION

• Preoperative shock
• Number of organs injured
• Concomitant central nervous system injury

4
Determinants of surgical wound infection
Microbial concentration and virulence
Foreign material
Injury to wound tissues
Resistance to peri-operative ABs
Risk fo surgical wound infection

General/Local host immunity
Peri-operative antibiotics
5
Risk of Surgical Site Infectionand Degree of
wound contamination

• Altemeier classes 1 4
• Class 1 Clean surgery 1 2 risk
• Class 2 Clean contaminated surgery 5 15 risk
  (elective colectomy or hysterectomy)
• Class 3 Contaminated surgery 15 30 risk
  (enterotomy with spillage)
• Class 4 Dirty surgery gt 30 risk (established
  infection ie intra-abdominal abcess)
• Simplistic but still valid!

6
Patient characteristics associated with
increased risk for surgical site infection

• ?

7
Patient characteristics associated with increased
risk for surgical site infection

• Extremes of age
• Diabetes / periopeative hyperglycaemia
• Concurrent tobaco use
• Remote infection at time of surgery
• Obesity
• Malnutrition
• Low preoperative S-albumin
• Concurrent steroid use
• Prolonged preoperative stay
• Prior site irradiation
• Colonization with S aureus

8
Procedural factors associated with increased risk
for surgical site infections
?
9
Procedural factors associated with increased risk
for surgical site infections

• No preoperative antiseptic showering
• Shaving of site night prior to procedure
• Use of razor for hair removal
• Improper preop skin preparation
• Improper antimicrobial prophylaxis
• Delayed redosing of ABs in prolonged cases
• Inadequate OR ventilation
• Increased OR traffic
• Break in sterile technique and asepsis
• Perioperative hypothermia / hypoxia
• Poor surgical technique

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Major Pathogens in Surgical Wound Infections
?
11
Major Pathogens in Surgical Wound Infections

• S aureus
  20 of infections
• Coagulase (-) staphylococci 14
• Enterococci 12
• E coli
  8
• P aeruginosa 8
• Enterobacter spp 7
• Proteus mirabilis 3
• Klebsiella pneumoniae 3
• Other streptococcal spp 3
• Minimal infective inoculum - gt 105 organisms
• Foreign bodies reduce this by 3 logs

12
Typical Microbiologic Flora at Surgical Sites
S aureus, CoNS S aureus, CoNS S aureus, CoNS S
aureus, CoNS, streptococci S aureus, CoNS,
streptococci, GNR S aureus, CoNS, streptococci,
GNR S aureus, CoNS, strep pneumoniae GNR S
aureus, CoNS GNR, anaerobes GNR, anaerobes GNR,
anaerobes GNR, streps, oropharygeal anaer S
aureus, streps, oroph anaer GNR, enterococ, group
B strep GNR

1. Placement of prostheses, grafts, implants
2. Cardiac
3. Neurosurgery
4. Breast
5. Ophthalmic
6. Orthopaedic
7. Noncardiac thoracic
8. Vascular
9. Appendectomy
10. Biliary tract
11. Colorectal
12. Gastroduodenal
13. Headneck intraoral
14. Obstetric Gyneacological
15. Urologic

13
Antibiotic prophylaxis for longer than 24 hours
not only has no benefit, but is now recognized to
be detrimental
14
Unfortunately.. reducing prophylaxis to less
than 24 hours has not become popular despite
evidence that prolonged prophylaxis increases the
risk of nosocomial bloodstream infections. It is
imperative for surgeons to modify their practices.
15
Current recommendation for all elective surgical
procedures

• Single-dose prophylaxis with a first- or second
  generation cephalosporin - even in
• Cardiac-
• Vascular-
• Orthopedic-
• Neurosurgical procedures (where a 24 hour
  regimen has been traditional)

16
EVENa SINGLE dose of antibiotic
administered appropriately, increases the risk of
such nosocomial infections as 1. Pneumonia2.
Antibiotic associated colitis
17
AND Intraoperative redosing is prudent
if1. the operation gt 3hrs2. blood loss gt
1.5L Once the incision is closed, parenteral
antibiotics no longer have an impact on the risk
of infection! Prolonged prophylaxis sets the
stage for emergence of resistant organisms
18
According to reports from the Centers for Disease
Control

• Antibiotic prophylaxis may be administered
  appropriately based on the patients RISK FACTORS
• Abdominal procedure
• Any operation gt 2 hrs
• Contaminated or dirty field
• gt 3 comorbid medical illnesses
• Stratification done by
• Number of risk factors present
• Degree of wound contamination

19
The incidence of wound infection increased
significantly as the number of risk factors
increased

• 1 risk factor dirty wound 7 wound infection
  rate
• 4 risk factors the same dirty wound 27 wound
  infection rate

20
Published Guidelines for Antibiotic Prophylaxis
in Surgical patients

• Single dose prophylaxis
• 1st Generation Cephalosporin (Cefazolin) for most
  procedures (Workhorse)
• Multiple dosing with Cefazolin
• 48 hrs in cardiac cases
• 24 hrs in vascular cases
• The AB chosen, must cover the spectrum of
  expected organisms. eg Single dose 2nd generation
  cephalosporin for abdominal trauma, appendectomy,
  colorectal procedures
• Anti-MRSA drugs used only for prophylaxis on
  documented incidence of surgical site infections
  in your hospital (Condon threshold MRSA gt 20 )

21
RECENTLYThe Medical Letter on Drugs and
Therapeutics recommended that multiple doses may
be inappropriate for ANY surgical prophylaxis!!!!
22
eg Prophylaxis of Endocarditis

• The less is more trend reflected by the AHA
  recommendations
• Most cases of endocarditis are not attributable
  to an invasive procedure
• Cardiac conditions are stratified in relation to
  endocarditis risk as high / moderate /negligible
• Overall fewer procedures require prophylaxis
• When using prophylaxis, prescribe fewer
  antibiotics and for shorter terms

23
Timing of prophylaxis

• Burke 1961 the surgical wound is best protected
  when antibiotics are administered before the
  incision is made.
• Classen 1992 30 yrs later timelines for
  administration - still a major problem!!!!
• New York States peer-review programme 1996
• only 86 received ABs although indicated
• 44 different ABs used for 2256 patients
• Nichols 1972 some standardization for colon
  preparation pre-op oral neomycin, erythromycin
  or metronidazole
• lt 2/3 received either oral or timely parenteral
  AB before elective colon surgery

24
Timing continued -

• Liberal definition of TIMELY 2 hrs up to the
  time of the skin incision
• NY State study only 61 received timely AB
  prophylaxis
• In 26 ABs were administered prematurely
• Adequate tissue concentrations of ABs at time of
  skin incision 46 of aortic surgery patients
  
• - 73 of colectomy patients
• - 60 of hip surgery patients

25
Penicillin Allergy

• Serious penicillin allergy is less common than
  medical records portray
• Uncritical history taking, labels patients who
  are not penicillin allergic
• Epidemiologic studies show incidence of 7/1000 of
  general population (anaphylactic allergy to
  penicillin)
• First reaction is worst
• Cross-reactivity between ceph and pen allergy is
  only about 5. Thus can give ceph, provided it is
  not an anaphylactoid reaction
• Childhood pen allergies can be outgrown
• Critically ill patients may be anergic and unable
  to react

26
Hospital Infection Control Practices Advisory
CommitteeRecommendations for Surgical
Antimicrobial prophylaxis

• Administer AB only when indicated select based
  on published recommendations for a specific
  operation. Assure efficacy against most common
  pathogens
• Administer AB intravenously, timed to ensure
  bactericidal serum and tissue concentrations when
  the incision is made
• Maintain therapeutic concentrations during
  operation and, at most, a few hours after closure
• Elective colorectal operations mechanical
  preparation with enemas, cathartic agents,
  non-absorbable oral ABs the day before surgery
  in addition to timely IV antimicrobial drugs.
• High risk caesarean section patients, administer
  IV ABs immediately after cord is clamped

27
The keys to rational antibiotic prophylaxis in
surgical patients include1. Timely and
accurate diagnosis2. Rapid and definitive
therapy3. Astute differentiation of infection
from contamination and sterile inflammation
28
Definitions as an aid to planning prophylaxis

• Contamination presence of pathogenic
  microorganisms on normally sterile tissue without
  an inflammatory response requires only a single
  dose off antibiotic for prophylaxis
• Infection invasion of a pathogenic microorganism
  into normally sterile tissue with a local
  inflammatory host response necessitates
  therapeutic antibiotics
• Antibiotics are NOT APPROPRIATE for sterile
  inflammation due to a noninfectious trigger, such
  as severe tissue injury

29
Thank you !
30
Example Endocarditis Prophylaxis

• Negligible mitral valve prolapse with
  midsystolic click, no regurgitation, no thickened
  leaflets
• - implanted non-valve devices (pacemakers and
  defibrillators)
• Moderate single dose ampicillin
• High ampicillin with gentamycin
• Avoid broad-spectrum agents eg 3rd generation
  Cephalosporins!!!!!!

31
Example Endocarditis ProphylaxisGastrointestinal
and Genitourinary procedures

• Moderate risk single oral dose of amoxicillin or
  IV ampicillin
• High risk an aminopenicillin with gentamycin 30
  minutes before surgery
• another dose of ampicillin alone 6 hrs
  thereafter
• AIM maximal coverage against enterococci, the
  major pathogens in endocarditis folowing GI/GU
  surgery.

32
Optimising Antibiotic Treatment in Serious
Infections
33
Intra-abdominal InfectionTHE PROBLEM

• Important cause of ICU morbidity and mortality.
• ICU admission for IAI 30 succumb.
• Tertiary peritonitis gt50 mortality.
• Association between progressive organ dysfunction
  and occult intraperitoneal infection.
• Marshall JC CCM 2003

34
2. Intra-abdominal Infection.THE PERITONEAL
CAVITY

• Normally lt100ml of fluid, with scattered
  macrophages and lymphocytes.
• Diaphragmatic movement / contraction generates
  negative pressures.
• Peritoneal fluid moves upward towards specialized
  fenestrae in diaphragmatic peritoneum, draining
  into the lymphatic system.
• Vigorous inflammatory response
• increased vascular permeability
• protein-rich exudate
• cytokines and chemokines
• influx of monocytes and neutrophils

35
3. Intra-abdominal InfectionTHE INFLAMMATORY
RESPONSE

• Tissue factor expression of peritoneal
  macrophages.
• Coagulation cascade is activated.
• Accelerated generation of fibrin.
• Fibrin polymerizes to form adhesions and capsules
  of abscesses.
• Rich somatic nerve supply thus severe pain.
• Pain localises to area of maximal inflammation.
• Normal innate immune response is rapid and
  effective
• a) Neutrophil phagocytosis is impaired
  by complicated peritonitis.
• b) Fibrin deposition can impede
  microbial clearance.

36
4. Intra-abdominal InfectionPATHOGENESIS

• Disruption of adjacent GIT
• Spillage of complex indigenous flora.
• Stomach and Duodenum
• Sterile
• Sparse gm-positive organisms,
  lactobacilli and
• occasionally Candida.
• Proximal small bowel.
• Gm-negative organisms
• Distal small bowel and colon
• Anaerobes
• Importance in stable patterns of
  intestinal colonization.
  (Colonization resistance)
• CANDIDA.???

37
5. Intra-abdominal InfectionPATHOGENESIS cont.

• In the critically ill normal colonization
  resistance is disrupted over time.
• Due to anti-anaerobic antibiotics
• Leads to colonization by Candida and
  vancomycin-resistant Enterococci.
• Explains the typical flora of tertiary
  peritonitis.
• Enterococci more often in post op peritonitis
• Nasal MRSA colonization risk factor for MRSA
  peritonitis.

38
6. Intra-abdominal InfectionPATHOGENESIS
SUMMARY.

• Acute loss of integrity of gut wall acute
  spillage with generalized peritonitis.
• Slow leakage of gut content inflammatory
  response with abscess formation.
• After both vigorous systemic response leading
  to acute organ system dysfunction.

39
Proportions of Bacterial Isolates ()in
Community-acquired Peritonitis
Dupont H. Antimicrob Agents Chemother
2000442028-33 Roehrborn A. Clin Infect Dis
2001331513-9
40
Proportions of Bacterial Isolates () in
Nosocomial or Postoperative Infections
Montravers P et al. Clin Infect Dis.
199623486-494 Dupont H. Antimicrob Agents
Chemother 2000442028-33 Roehrborn A. Clin
Infect Dis 2001331513-9
41
Microbiology

• Gram negative aerobic organisms are associated
  with acute lethality
• Anaerobic organisms predispose to abscesses
• 
  Onderdonk Infect Immunol 1997
• Eradication of anaerobes predisposes to
  overgrowth of E.coli and colonization with
  Candida spp and VRE
  Berg Infect Immunol 1981
  
  Thomakos
  Chemotherapy 2003
  
  Donskey NEJM 2000

42
Classification of Peritonitis

• Primary peritonitis
• Primary bacterial peritonitis in nephrotic or
  cirrhotic patients, primary pneumococcal,
  streptococcal peritonitis
• Granulomatous peritonitis (Mycobacterium spp.,
  Histoplasma spp.)
• Secondary peritonitis
• Perforation of the GIT postoperative,
  spontaneous or traumatic
  Infection of pelvic or intraabdominal viscus with
  peritoneal involvement
• Bowel wall necrosis
• Continuous ambulatory peritoneal dialysis
• Tertiary peritonitis
• Peritonitis in critically ill patients that
  persists or recurs at least 48hrs after
  apparently adequate surgical management.
  Differentiated by more resistant organisms and
  poor response to surgery and antibiotics

Wittmann DH. World J Surg 199014145-7
Marshall CCM 2003
43
Classification of peritonitis

• Severity
• Outcome is determined by age, delay in diagnosis
  and therapy, inappropriate therapy, APACHE,
  anatomic source of infection, presence of
  resistant pathogens
  Barie
  Curr Opin Crit Care 2001
• Published trials of antibiotic therapy have
  enrolled patients with a mean APACHE of 8
  
  Barie Arch
  Surg 1997
• Severe infection may reasonably be defined as an
  APACHE 15

44
Microbiology of Peritonitis
Primary Peritonitis Secondary Peritonitis Tertiary Peritonitis
Gm-negative bacteria Gm-negative bacteria Gm-negative bacteria
Eschecheri coli E. coli 32-61 Pseudomonas
Klebsiella Enterobacter 8-26 Enterobacter
Klebsiella 6-26 Acinetobacter
Proteus 4-23
Gm-positive bacteria Gm-positive bacteria Gm-positiv bacteria
S. aureus (MRSA) Enterococci 18-24 Enterococci
Enterococci Streptococci 6-55 Coagulase-negative
Pneumococci Staphylococc 6-16 Staphylococci
Anaerobic bacteria
Bacteroides 25-80
Clostridium 5-18
Fungi 2-15 Fungi Candida
45
Tertiary Peritonitis THE DANGER

• Unsatisfactory response to both antibiotics and
  surgical source control measures.
• Flora similar to flora of upper GIT of the
  critically ill.
• Flora common causes of nosocomial ICU acquired
  infections.
• ? Role for translocation.
• ? Antibiotic pressure
• Mortality gt 50
• No optimal therapeutic strategy

46
The Microbiology of Tertiary Peritonitis

• Most surgeons do not dare to leave these patients
  without antibiotics before the decision to
  reoperate
• These interval antibiotics may have a major
  impact on the microbiology and the efficacy of
  subsequent treatment. (Although many other
  factors contribute to survival)
• The microbiology of postoperative peritonitis
  differs significantly from that of
  community-acquired disease, and specific
  antibiotic therapy is required, DESPITE the
  doubtful impact on survival.
• The treatment of CAIAI by 3rd generation
  cephalosporins and metronidazole is not adequate
  for tertiary peritonitis because
• gm() bacteria are not covered
• gm() bacteria outnumber gm(-) bacteria
• Enterobacter which is most threatening, is
  also not sufficiently covered.
• Roehrborn A, CID 2001

47
Intra-abdominal InfectionDIAGNOSIS

• Difficult in the critically ill.
• History unobtainable.
• Level of conciousness masks physical examination.
• Important Clinical setting
• Unexplained signs of sepsis
• Unexplained organ
  dysfunction
• Radiographic studies the
  whole range.

48
Appropriate Treatment
Goal directed resuscitation and organ
support Early appropriate parenteral
antibiotic Surgical procedure that controls the
source of infection Avoid or minimize blood
transfusion Glucose control, steroids, ARDS-NET
ventilation Early enteral nutrition Xigris /
Immunomodulation Monitoring Mazuski JE.
Surgical infections 20023161-173

Van den Berghe NEJM 2002
Rivers
NEJM 2001
Annane JAMA2002

ARDS NET
Marik CCM 2002

Chang Vox Sang 2000

Bernard NEJM 2001
49
Appropriate TreatmentSource Control

• Drainage (open vs percutaneous)
• Debridement (early vs. delayed)
• Diversion of bowel content.
• Restore intestinal continuity.
• Open abdomen techniques.
• Intra-abdominal pressures.
• Planned relaparotomy.
• 
  Marshall JC, CCM 2003 3182228

50
Appropriate TreatmentSelecting an Antibiotic
Regimen

• Consider patient specific toxicity.
• Cost.
• Local microbiological surveillance for resistance
  patterns
• ? Duration of treatment
• Adequate source control adjuvant
  treatment for
• 5 - 7 days.
• ? Role of anti-enterococcal therapy
• ? Role of antifungal therapy
• ? Role of antibiotic therapy in tertiary
  peritonitis does it
• contribute.
• Resistance to common empiric regimens.
• Narrow spectrum agents according to MCS
• Avoid anti-anaerobic activity.

51
Principles of Antibiotic Therapy

• Initiated as soon as the diagnosis established
  and surgery planned
• Early administration
• Parenteral route
• AB must differ from antibiotic prophylaxis used
  in the unit
  
  Mazuski Surgical
  infections 2003

AB must target Enterobacteriaceae and anaerobes
directly responsible for the immediate prognosis
and development of abscesses
Bartlett JG. Med Clin North Am. 199579599-617
AB should also target ß- lactam susceptible gram
pos cocci
Solomkin IDSA Guidelines CID 2003
52
Defining Appropriate Therapy
Considerations in determining appropriate therapy

• Site of perforation
• Dose and dosing frequency( PK/PD)
• Prior antibiotic treatment
• Nosocomial / Health Care Associated / Community
  Acquired.
• Prevalent pathogens (ESBL, acinetobacter)
• Severity

Raymond DP et al. Surg Infect 2002 Kollef MH.
Clin Infect Dis 200031(Suppl 4)
53
Appropriate versus Inappropriate Empiric Therapy
for IAI Mortality
In a retrospective analysis, mortality was
substantially higher for IAI patients who receive
inappropriate versus appropriate therapy.
Bare M, et al. Presented at the 12th European
Congress of Clinical Microbiology and Infectious
Diseases, Milan, Italy 2002.
54
Effect of Inappropriate Initial Antibiotic Therapy
Retrospective study (1999-2001) 20 hospitals in
Germany Assessment of appropriateness of initial
AB and outcome
5 11 27 57
4 3 12 81
Resolved with initial or stepdown therapy
Resolved with second-line therapy
Resolved after reoperation
Increased length of stay 14.4 versus 16.8 days
Appropriate
Inappropriate
Death
Sendt W. et al. IDSA 2002. P 566
55
Appropriate Versus Inappropriate Therapy Cost
of Hospital Stay
Appropriately treated IAI patients incurred
significantly lower hospitalization costs versus
inappropriately treated patients 348 patients
from three Scottish hospitals from 1993 to 1997
Davey P, et al. Presented at the International
Society of Pharmacoeconomics and Outcomes
Research Sixth Annual International Meeting May,
2001.
56
Kollef MH, et al. Chest. 1999115462.
Inadequate Antimicrobial Treatment Effect on
Mortality

• Prospective cohort study by Kollef et al
• 2000 patients admitted over an 8-month period to
  a 19-bed medical ICU and an 18-bed surgical ICU
• Study aim to determine if inadequate empiric
  antibiotic therapy is a risk factor for mortality
• Sponsors CDC, Bayer

57
Definitions

• Inadequate antibiotic therapy was defined at the
  time culture and susceptibility reports became
  available
• Absence of antimicrobial agents directed at a
  specific type of organism (eg, absence of
  antifungal agents for Candidemia)
• Administration of an antibiotic to which the
  organism was resistant (eg, use of ceftazidime
  for Klebsiella with ceftazidime MIC gt256)

58
Impact of Inadequate Empiric Choice
Antimicrobial Treatment Mortality
Inadequate 52
Adequate 12
RR 4.3 (95 CI, 3.5 to 5.2 p lt0.001)

• Multivariate analysis inadequate antibiotic
  treatment was the most important independent risk
  factor for death

Kollef MH, et al. Chest. 1999115462.
59
More Evidence

• At least 5 other studies have shown comparable
  findings
• Delays in receipt of appropriate therapy have
  also been associated with excess hospital
  mortality
• These concepts have been incorporated into the
  official statement of ATS and IDSA on management
  of hospital-acquired pneumonia (Am J Respir Crit
  Care Med. 2005171388)

60
Why do we get empiric therapy wrong?

• The most frequent reason is resistance to the
  antibiotic chosen

61
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62
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63
Recent Publications confirm resistance linked to
overuse of traditional antibiotics
Neither third-generation cephalosporins nor
quinolones appear suitable for sustained use in
hospitals as workhorse antibiotic therapy.
64
What is collateral damage?

• Adverse effects of antibiotics on ecology of
  normal flora of gut or skin
• Selection of drug-resistant organisms
• Unwanted colonization or infection with MDRs
• Third generation cephalosporins and quinolones
  are the most frequently implicated (VRE, C
  difficile, ESBL K pneumoniae, beta-lactam
  resistant Acinetobacter spp)
• Quinolones (MRSA, resistant Ps aeruginosa
• Neither 3rd generation cephalosporins nor
  quinolones appear suitable as workhorse
  antibiotics in hospitals.

65
How do we get resistant organisms in a hospital?
Horizontal Transfer Via hands
Transfer of Patient from Another facility
Resistant Organisms Selected By antibiotics
Transfer of Resistance Genes
66
The Growing Resistance Problem
67
The Growing Resistance ProblemMechanisms of
resistance

• Altered balance of accumulation (impermeability
  and efflux)
• Loss of porin protein channels in outer
  membrane (All ABs except aminoglycocides)
• Acquired efflux pumps to eject antibiotics (may
  be broad or narrow spectrum)
• Enzymic inactivation
• Beta-lactamases (pen, ceph, carba)
• Aminoglycocide modifying enzymes
• Alteration of target
• Penicillin-binding proteins (beta-lactams)
• Ribosomal methylation (Macrolides)
• DNA gyrase mutation (Floroquinolones)

68
The Growing Resistance Problem

• Well documented and increasing
• Restrict treatment options
• Result in clinical failures
• Some encoded by chromosomally located genes
  limiting potential for spread to other bacteria
• Some encoded by plasmids and transposons
  facilitating spread to other bacterial species
• Induction a reversible regulatory process due
  to an inducer initiating eg enzyme synthesis
  (AmpC beta lactamase in Enterobacter spp)
• Selection an irreversible process individuals
  within a mixed population (eg spontaneous mutants
  producing the same AmpC beta lactamase) increase

69
Resistance Due to Selection
Spontaneous mutation occurs in the absence of
drug selection in a sensitive population
Sanders CC, Sanders WE. J Infect Dis
1986154792-800
70
ESBLs

• Extended
• Spectrum
• Beta-
• Lactamases

71
ESBLs

• First described in Klebsiella
• 10-30 of most enteric Gram negative bacilli are
  now ESBL producers
• Leads to resistance to third generation
  cephalosporins plus many other classes
• Biggest risk factor is third generation
  cephalosporin use

72
Challenges in Clinical Management of
Extended-Spectrum ß-Lactamases (ESBLs) in Enteric
Gram-negative Bacilli

• ESBLs
• Enzymes capable of hydrolyzing all ß-lactams
  (penicillin, cephalosporins, monobactam) except
  Carbapenems
• Can be produced by all enteric bacilli (GI tract
  is common reservoir) especially E.coli and K.
  pneumoniae
• Risk factors age gt65 prior cephalosporin or
  quinolones use healthcare exposure
• Often missed in routine in-vitro susceptibility
  testing
• Rapid wide dissemination horizontal transfer
  by plasmids (among gram-negative bacilli) and
  between hospitals/communities
• Carbapenem is the only reliable and highly
  effective agent in treating infections caused by
  ESBL-producing Enterobacteriaceae
• Many ESBL-producing Enterobacteriaceae are
  multi-drug resistant
• Fluoroquinolone, aminoglycoside,
  trimethroprin-sulfamethoxazole
• Treatment failures often observed with
  ß-lactam/ß-lactamase inhibitor combination, even
  when they are susceptible in-vitro
• Carbapenem use independently associated with
  decreased mortality

Paterson DL et al Clin Infect Dis 20033931-37
Paterson DL et al. Ann Intern Med
200414026-32 Warren R et al. Clin Micro Infect
2004 10(Suppl3)188 Gold HS et al. NEJM 1996
3351445-1452
73
Patient Selection

• Contamination vs. infection may often be a gray
  area
• For example where there is
• Extensive contamination shortly pre-op
• Infection of an abdominal viscus removable by
  surgery
• Antibiotics can be given for 24 hrs or less in
  traumatic
• perforations with early operation
• Fabian Surgery1992
  
  
  Bozorgzadeh Am J Surg
  1999
  
  Kirton J
  Trauma 2000
• This should be similar with iatrogenic
  perforation and also
• possibly with early repair of gastro duodenal
  perforation
  Schein Br J
  Surg 1994

74
Patient Selection

• Consensus is that treatment is necessary for
• Colonic perforation gt 12hrs
• Gastro duodenal gt 24hrs
• Similarly Class 2 evidence that antibiotics are
  necessary for 24hrs or less for acute or
  gangrenous appendicitis and cholecystitis without
  perforation or infected peritoneal fluid
• Andaker Acta Chir Scand !987
  
  Schein Br J Surg 1994

75
Duration of Therapy

• 5-7 days has been the recommended duration
  
  Bohnen Arch Surg 1992
• Protocol directed therapy i.e.2 days for limited
  infection
• 5
  days for extensive infection
• Have been as successful as historical controls
• 
  Andaker Acta Chir Scand
  !987
  Schein Br J Surg 1994
• Therapy directed to clinical response is
  successful and limits duration
  
  
  Lennard Ann
  Surg 1982
  
  Smith J hosp Infect 1985
  
  Taylor Am Surg 2000

76
Duration of Therapy

• Persistence of signs of sepsis indicates a need
  for surgical intervention, not prolonged
  antibiotics
  
  Lennard Ann Surg 1982
  
  Lennard Arch Surg
  1980
• There is limited data that prolonged courses
  might work where source control cannot be
  achieved
  Visser Eur J Surg 1998
• High cost in terms of resistance

77
Antibiotic Regimens

• Mild to moderate community acquired infection
• amoxicillin / clavulanate
• cefuroxime ceftriaxone cefotaxime /
  metronidazole
• Severe community acquired infections or
  nosocomial sepsis
• amoxicillin / clavulanate aminoglycoside
• piperacillin / tazobactam
• carbapenems
• cefepime metronidazole
• cipro -levofloxacin metronidazole
• aminoglycoside metronidazole or clindamycin

78
Antibiotic Regimens

• There is little guidance in the literature on
  which regimen is superior
• Antimicrobials have been designed to test
  equivalence and most patients entered into
  studies have had non-severe community acquired
  infections
• Since most regimens appear to be equivalent, cost
  considerations, toxicity and likely organism are
  more important considerations

Solomkin CID 2003 Mazuski Surgical Infections 2002
79
Antibiotic Regimens

• The expanded gram negative spectrum of some
  agents confers no advantage in CAIAI and may
  contribute to increased resistance
• Agents routinely used to treat nosocomial sepsis
  in the ICU should not be used for CAIAI

Solomkin CID 2003 Mazuski Surgical Infections
2002 Shlaes CID 1997 McGowan New Horiz 1996
80
Antibiotic Therapy

• Enterococci controversial
• Treatment failure due to enterococci seems more
  common in a higher risk group age APACHE, non
  appendiceal sepsis, post operative or nosocomial
  infection
  Mazuski Surgical Infection
  2002
  Sitges-Serra Br J Surg 2002
  
  Linden
  Curr Infect Dis Rep 2003
• Routine coverage for enterococci is not necessary
  for CAIAI. They should be treated when cultured
  from patients in health care settings
  
  Solomkin CID
  2003

81
Monotherapy with a Broad-Spectrum Beta-Lactam Is
as Effective as Its Combination with an
Aminoglycoside in Treatment of severe Generalized
Peritonitis a Multicenter Randomized Controlled
Trial.

• H. DUPONT, C. CARBON, and J. CARLET for THE
  SEVERE GENERALIZED PERITONITIS STUDY GROUP.
• Antimicrobial Agents and Chemotherapy, Aug. 2000,
  
• p. 2028-2033.

82
Aminoglycosides in Peritonitis

• The 1980s - ? Synergism
• - lack of broad spectrum
  beta-lactams
• Recent literature reviews no clear evidence to
  support the use of aminoglycosides for the
  treatment of peritonitis.
• Aminoglycoside activity is reduced by
  intra-abdominal acidosis and hypoxia, and the
  presence of drug binding purulent debris.
• Despite the marked post-antibiotic effect on
  gm(-) bacilli, no study has proven this for
  intra-abdominal infection.
• Doubt about synergism with beta-lactams the
  emergence of resistant strains such as Ps
  aeruginosa is not prevented.
• Increased incidence of nephrotoxicity.

83
Increasing Antimicrobial Resistance among
Pathogens Causing Hospital-Onset Infections
3rd generation cephalosporin- resistant
Klebsiella pneumoniae
Fluoroquinolone-resistant Pseudomonas aeruginosa
Non-Intensive Care Unit Patients Intensive Care
Unit Patients
Source National Nosocomial Infections
Surveillance (NNIS) System
12 Steps to Prevent Antimicrobial Resistance
Hospitalized Adults
84
Open Management of the Abdomen and Planned
Reoperations in Severe Bacterial Peritonitis.

• Despite this approach, mortality continues to be
  high, (42 in hospital)
• Both short and long term morbidity are
  appreciable.
• (particularly the number of abdominal wall
  defects)
• Value of this technique rests on the fact that
  other conventional surgical methods often fail to
  control severe bacterial peritonitis.

85
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86
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87
Antibiotics and Pancreatic Necrosis

• Death from acute severe pancreatitis results from
  infection and MODS late in the course of illness.
• Necrotising pancreatitis involving at least one
  third of the organ, are at highest risk of
  secondary infection and death.
• Based on recent studies, early antibiotic
  prophylaxis in patients with necrotising
  pancreatitis has been suggested and most
  practitioners use imipenem for this
  task.????????????

88
There is general agreement that the development
and extent of pancreatic necrosis are the most
important indicators of disease severity
Necrosis correlates with length of
hospitalisation, development of complications,
numeric systems and death.
89

• Challenges of caring for the patient with severe
  pancreatitis in the critical care environment.
• Timing / indications for admission and
  monitoring in the Intensive Care or High Care
  Unit.
• Should patients with SAP receive prophylactic
  antibiotics?
• The role of nutritional support in the
  management of patients with SAP.
• What is the role of surgery in the management of
  patients with SAP - indications - optimal
  timing - less invasive approaches
• Interventions for gallstone pancreatitis
• Targeting the inflammatory response in patients
  with SAP
• Nathens CCM 32 (12) 2004

90
Infected Necrosis

• Definitions of pancreatic infections
• Pancreatic infection
• Infected necrosis
• Pancreatic abscess
• Infected pancreatic pseudocyst
• The incidence of infection correlates with the
  presence of intra- and extrapancreatic necrosis
• General infection rate of pancreatic tissue 7-12
• 80 of deaths from acute pancreatitis due to
  septic complications

91
Diagnosis of infective necrosis

• Difficult to distinguish sterile from infected
  necrosis
• Distinction is important, infected necrosis
  without intervention - 100 mortality
• CT-guided FNA - sensitivity 90
• - specificity 99
• continue ...

92
Diagnosis of infective necrosis

• FNA is recommended for patients with acute
  necrotizing pancreatitis whos clinical
  condition
• Deteriorate
• Fail to improve despite progressive supportive
  care
• Surveillance aspiration should be repeated when
  clinically indicated

93
?-amylase pancreatic lipase CRP, LDH
Ulm Protocol for treatment of AP
MILD AP Intestinal Edematous pancreatitis Daily
CRP US ? Biliary lithiasis Impacted stone ??
EPT After AP Laparoscopic CCE
SEVERE AP Necrotizing Pancreatitis ICU treatment
antibiotic prophylaxis Daily CRP, IL-8,
procalcitonin, Apache II scoring
Increasing severity ? cCT Clinical sepsis
FNA
Negative Sterile necrosis Nonsurgical management
Positive Infected necrosis Surgical management
Responders ? Definitive Conservative treatment
Non responders to ICU Clinical sepsis Surgery
Necrosectomy closed Lavage / open packing
94
QUESTION 2 SHOULD PATIENTS WITH SEVERE ACUTE
PANCREATITIS RECEIVE PROPHYLACTIC
ANTIBIOTICS?Recommendations 1. Do not
administer prophylactic systemic antibacterial
or antifungal agents routinely for patients
with necrotising pancreatitis. 2.
Routine selective decontamination of the gut
should not be used for necrotising
pancreatitis. 3. SDD is promising and further
study is warranted in SAP.
95
How can we get AB Rx right?

• The problem -- How to ensure adequate (early
  appropriate) yet not excessive use of
  antimicrobials.
• -- a liberal
  protective approach vs restrictive antibiotic
  control
• High risk patients demand liberal empiric use of
  broad-spectrum antimicrobials to reduce the risk
  of morbidity and mortality due to nosocomial
  infections.
• The use and abuse of broad-spectrum agents,
  prescribed to treat the critically ill,
  dramatically increases the prevalence of MDR
  pathogens.
• MRSA
• VRE
• ESBL producers - Ps aeruginosa, Acinetobacter,
  Klebsiella, Enterobacter
• Candida

96
How can we get ABRx right?

• STRATEGISE!!!
• Close examination of a unit specific antibiogram
  to help devise empiric regimens with the greatest
  likelihood of covering the organisms posing the
  greatest risk.
• Computer-assisted antimicrobial decision-support
  systems to
• Improve antimicrobial selection
• To control costs
• To decrease emergence of resistance
• A patient specific antibiogram.

97
How can we get ABRx right?

• STRATEGISE!!!
• CPIS as an objective measure to guide
  antimicrobial therapy in patients with pulmonary
  infiltrates.
• Invasive management or diagnostic strategy based
  on bronchoscopic sampling.

98
Ertapenem

• The third commercially available carbapenem
• Activity similar to imipenem or meropenem except
  lacks activity against
• Pseudomonas aeruginosa
• Acinetobacter
• Enterococci
• Stenotrophomonas.
• Highly active against ESBL producing organisms
• Conventional dose is 1 gram q 24 hr IV

99
Carbapenem Classification
GROUP 1 Carbapenems (community acquired infections, early hospital acquired infections, non- pseudomonal infections) GROUP 2 Carbapenems (hospital acquired infections pseudomonas activity) GROUP 3 Carbapenems (hospital acquired infections Pseudomonas and MRSA activity)
INVANZ TIENAM Meropenem Doripenem CS-023 ?

• Pseudomonas-sparing carbapenem (INVANZ) is ideal
  for most community-acquired polymicrobial
  infections
• Pseudomonas coverage is not required in most
  community-acquired infections
• Reduces antibiotic pressure on selecting
  MDR-Pseudomonas
• Spare the use of anti-pseudomonal carbapenem in
  community setting

100
Ertapenem

• Activity excellent against Enterobacteriaceae and
  other fermenters, anaerobes and ß- lactam
  susceptible enterococci Livermore
  JAC 2003
• Solomkin Ann Surg 2003
• 633 patients moderate to ? severe peritonitis
• 50 complicated appendicitis randomized to
  receive ertapenem 1g dly vs. tazocin 3.375g 6hrly
• This showed equivalence -favourable responses
  were seen in 19/26(vs.23/26) patients in whom
  pseudomonas was cultured and in 50/56(vs24/37) in
  whom enterococci were cultured

101
Ertapenem vs. Piperacillin/Tazobactam Over 90
Success Rate at End of IV Therapy
100 80 60 40 20 0
92
Ertapenem 1 g once a day (n203)
88
87
81
Piperacillin/Tazobactam 3.375 g every 6 hours
(n193)
Success rate was defined as clinical and
microbiologic resolution of the index infection
requiring no additional antimicrobial therapy.
Success rate,
Data computed from statistical model adjusted for
strata.
End of IV Therapy (approximately 8 days)
Final Assessment (test of cure, primary endpoint
46 weeks post-therapy)
Solomkin JS et al. Ann Surg 2003237235-245.
102
Ertapenem vs. Piperacillin/Tazobactam High
Per-Pathogen Microbiologic Response Rates at Test
of Cure (46 weeks post-therapy)
Pathogens in the B. fragilis group include B.
caccae, B. distasonis, B. eggerthii, B. merdae,
B. fragilis, B. ovatus, B. thetaiotaomicron, B.
stercoris, B. vulgatus, and B. uniformis. n/N
refers to the number of isolates with a favorable
response/total number of isolates.
103
Ertapenem vs. Piperacillin/Tazobactam Showed
Excellent Efficacy in Microbiologically Evaluable
Subgroup
Piperacillin/Tazobactam 3.375 g every 6 hr
(n/N) n193
Ertapenem 1 g once a day (n/N) n203
Solomkin JS et al. Ann Surg 2003237235-245.
104
Summary of Results
Piperacillin/ tazobactam 3.375 g q6h
Ertapenem 1 g once a day
Generalized peritonitis
74 (39/53)
83 (50/60)
abscesses
50 (2/4)
89 (8/9)
Single abscess
82 (55/67)
90 (53/59)
88 (61/69)
87 (65/75)
Localized disease
105
Success Rate according to Infection Site
106
Ertapenem

• Yellin AAC 2002
• Ertapenem 1g and 1.5g/day(51) vs. ceftriaxone 2g
  daily and metronidazole 500mg 8 hrly (59)
  followed by switch to cipro and metronidazole
  after 3 days of IVI therapy for complicated IAI
• 1g group 84 vs. 85 had favourable clinical and
  microbial responses
• 1.5g group 83vs77
• Well tolerated ,safe

107
Ertapenem vs. Ceftriaxone plus Metronidazole
High Microbiological and Clinical Success Rates
at Test of Cure
84
85
Clinical and Microbiological Success (46 weeks
post-therapy)
Yellin AE et al. Int J Antimicrob Agents 2002
20165-173.
108
Ertapenem vs. Ceftriaxone plus Metronidazole In
a Clinical Study of Patients with IAI, Ertapenem
Showed High Eradication Rates
Yellin AE et al. Int J Antimicrob Agents 2002
20165-173.
109
Ertapenem vs. Ceftriaxone plus Metronidazole
Conclusions

• In patients with IAI
• Ertapenem, one gram, one dose, once a day, was
  effective compared with 2 g of ceftriaxone
  administered once daily plus 500 mg metronidazole
  administered in three divided daily doses.
• The tolerability of ertapenem was comparable to
  ceftriaxone plus metronidazole.

Yellin AE et al. Int J Antimicrob Agents 2002
20165-173.
110

• 2 separate OASIS trials confirmed that Ertapenem
• Reduced ESBL-producing organisms during therapy
• Had minimal or no risk of resistance development
  during therapy
• Stable against ESBLs thus minimal selection for
  resistant Enterobacteriaceae
• Is Pseudomonas-sparing thus minimal selective
  pressure on MDR-Pseudomonas

Baseline
End of therapy and/or test of cure
End of therapy
30
25
20
percent
15
10
5
0
R
R
R
Ertapenem1,2
Piperacillin/tazo1
Ceftriaxone/Met2
1 Friedland I et al. 13th ECCMID, Glasgow, UK,
May 10-13, 2003
2 Friedland I et al. 3rd ACCP, San Margherita,
Italy, October 16-19, 2003 (Poster 57)
111
Ertapenem

• Once daily administration and the absence of
  activity against Pseudomonas and Acinetobacter
  could mean a greater role in community acquired
  infections however is the extended gram (-)
  spectrum necessary?
• Should it be reserved for hospital acquired ESBL
  infections exclusively, allowing a reduction in
  usage of other carbapenems, reserving these
  agents for Acinetobacter and Pseudomonas ?
• Should the necessity for appropriate initial
  therapy lead us to utilize ertapenem and
  de-escalation in community acquired infections.

112
Recent Publications confirm role of carbapenems
in treating ESBL infections
The prevalence of extended-spectrum b-lactamase
(ESBL) production by Klebsiella pneumonia
approaches 50 in some countries in eastern
Europe and Latin America Use of carbapenem
(primarily imipenem) was associated with a
significantly lower 14-day mortality than was use
of other antibiotics active in vitro.
113
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114
Are we wasting antipseudomonal therapy?

• UTI quinolones
• CAP quinolones
• Aspiration piperacillin/tazobactam
• Cellulitis quinolones, piperacillin/tazobactam
• Intra-abdominal infections pip./tazobactam

115
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116
Figure. Fluoroquinolone Use and Resistance Rates
in Pseudomonas aeruginosa and Gram-Negative
Bacilli
National fluoroquinolone use data were obtained
from IMS HEALTH Retail and Provider Perspective
(Plymouth Meeting, Pa). The increasing rates of
ciprofloxacin resistance correlate with the
steadily increasing fluoroquinolone use (r
0.976, Plt.001 for P aeruginosa r 0.891, P
.007 for gram-negative bacilli r 0.958, Plt.001
for years of observation). The 1990-1993 data
points represent composite susceptibility3 and
fluoroquinolone use for those 4 years.
117
New antipseudomonal drugs available in the next 5
years
118
Pittsburgh protocol

• ICUs antipseudomonal agents unrestricted
  (except quinolones)
• Outside of ICUs all antipseudomonal drugs need
  prior approval

119
Effects of restricting use of antipseudomonal
drugs
Antibiotic Pre-AMP N3532 Post-AMP N1122 Change in S p-value
Amikacin 86.4 89.6 3.2 0.0119
Aztreonam 55.9 57.2 1.4 0.48
Cefepime 80.0 82.2 2.2 0.0985
Cipro. 56.4 68.8 12.2 lt0.0001
Gentamicin 71.4 76.4 5.0 0.0028
Imipenem 79.9 83.6 3.7 0.0120
Levofloxacin 51.0 62.7 11.7 lt0.0001
Tobramycin 81.8 84.0 2.3 0.0849
Pip/Tazo 77.6 79.6 2.0 0.1570
120
Carmeli- Key take aways

• Stratification of patients at risk of being
  infected with resistant organisms
• 3 risk groups
• Scheme Patients stratified according to 3
  domains

No risk for resistant organisms
Risk for resistant Enterobacteriaceae
Risk for non-fermenters
A
B
C
Patient Characteristics
AB treament
Contact with healthcare system

1. No contact
2. Contact with health care ( e.g. recent admission,
   nursing home, dialysis) without invasive
   procedures
3. Long hospitalisation/ invasive procedures

1. No treatment
2. Recent treatment

1. Young, few co-morbid conditions
2. Older/ multiple co-morbidities
3. Cystic fibrosis, structural lung disease,
   advanced AIDS, neutropenia, other severe
   immunodeficiency disorders

Score of 1 in all 3 domains low risk for
resistant organisms Score of 2 in at least 1
group risk for resistant
enterobacteriaceae Score of 3 in 1 of the groups
risk for infection with nonfermenters
121
It is not rocket science.

• Clean your hands between patients
• Beware taking herpes simplex, C. difficile and
  MRSA home with you!
• Antibiotics are not the answer for every culture
  or every fever
• Optimize empiric therapy based on local
  epidemiology
• Find alternatives to antipseudomonal drugs

122
Areas for Future Research

• Appropriate specimen processing.
• Role of routine Antimicrobial susceptibility
  testing.
• Definition of appropriate duration of AB therapy.
• The impact of prolonged therapy (oral regimens)
• Impact of empirical therapy on tertiary
  peritonitis.
• Confirmation of the pattern of infecting
  organisms in tertiary peritonitis.
• Solomkin JS, CID 2003

123
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124
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125
Reasons for exclusion from clinical and
microbiological evaluability
126
Intra-abdominal Infection
Clinical and Microbiologic Response
Ertapenem 1 g
Piperacillin/Tazobactam
Cure Rate
Cure Rate
n/m
Stratum
n/m
Complicated appendicitis All other
diagnoses APACHE II ? 15 APACHE II gt 15 Overall
without generalized peritonitis.
127
Ertapenem

• Roy Infect Dis Obstet Gynecol 2003 Acute pelvic
  infections

128
Excluded Diagnoses

• Traumatic bowel perforation with operation within
  12 hours
• Perforation of gastroduodenal ulcers operated
  upon within 24 hours
• Simple cholecystitis
• Simple appendicitis
• Infected necrotizing pancreatitis
• Staged abdominal repair or open abdomen technique

129
Appropiate Treatment

• Source control
• Resuscitation
• Physiological support of organ systems.
• Monitoring
• Metabolic
• Respiratory
• Haemodynamic
• Nephrological
• Intra-abdominal pressures
• Antibiotics based on knowledge of the probable
  flora.

130
Optimising Antibiotic Treatment in Serious
Infections

• D Paterson

131
Hospital-acquired MRSA

• ICU vs non-ICU
• Proportion of nosocomial S. aureus isolates which
  are MRSA in non-ICU areas now approaches
  proportion in ICUs
• Hospital size
• Hospitals with less than 200 beds now have same
  proportion of isolates which are MRSA as in
  hospitals with more than 500 beds
• Source CDC 2004

132
Vancomycin current recommendations

• Dose at 1 gram every 12 hours only for wound
  infection, cellulitis etc
• Give 20-25 mg/kg every 12 hours for endocarditis
  and pneumonia (this will often mean 1.5 gram q
  12hr IV)
• Only check trough levels (no need for peak
  levels) aim for 10-20 µg/mL in most patients

133
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134
Linezolid

• An oxazolidinone (only member of that class which
  is currently available)
• Dose is 600mg q12 hr IV or PO
• Second-line agent in pneumonia failing to respond
  to high-dose vancomycin
• Marrow toxicity
• Lactic acidosis, peripheral neuropathy and optic
  neuritis increasingly recognized

135
Daptomycin

• A lipopeptide (the only agent of this class
  currently available)
• IV formulation only (once per day)
• Inactivated by surfactant
• Rapidly bactericidal appears at least as good
  as vancomycin for bacteremia and endocarditis
• Can cause CPK elevations

136
Tigecycline

• Glycylcyline (first of this class available)
• Synthetic modification of tetracycline
• Low blood levels, high tissue levels
• Substantial rates of nausea/vomiting
• Thus far, only approved for skin/soft tissue and
  intra-abdominal infections

137
Despite the availability of new drugs.

• Antistaphylococcal penicillins are still the
  drugs of choice for methicillin susceptible
  Staphylococcus aureus

138
Community-acquired MRSA

• MMWR 199948707 Four pediatric deaths from
  community-acquired MRSA
• MRSA is an emerging community-acquired pathogen
  among patients without established risk factors
  for MRSA eg, no recent hospitalization, no
  recent surgery, no residence in a long-term care
  facility and no injecting drug use

139
CA-MRSA (II)

• The proportion of all community-acquired
  Staphylococcus aureus strains in the US which are
  MRSA, ranges from 9-20, depending on the
  geographic region
• In the U.S., one PFGE type (USA 300 strain) is
  found throughout the country
• CA-MRSA has smaller resistance gene (SCCmecIV)
• CA MRSA has gene for Panton-Valentine leukocidin
  (PVL) toxin

140
CA-MRSA (III)

• Almost 90 of cases are skin infections, often
  first detected as clusters of abscesses (spider
  bites) PVL is a necrotizing cytotoxin
• Various epidemiologic settings
• Sports participants
• Jails, military recruits
• Men who have sex with men

141
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142
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143
CA-MRSA pneumonia following influenza

• 17 cases presented by CDC at IDSA 2004
• Age range 8 months to 62 years
• 4/17 had traditional MRSA risk factors
• Fever of at least 39o C and hemoptysis were
  typical
• 3/17 had radiologically evident
  cavitation/necrosis
• 13/17 admitted to ICU
• 5/17 died, with median of 7 days from symptom
  onset to death

144
VISA/VRSA

• hVISA (heteroVISA)
• Typically patients who fail prolonged vancomycin
  Rx
• Numerous cases, but issues with detection
• VISA
• 13 cases in USA (MIC 8-16)
• 30 near-VISAs (MIC4)
• VRSA
• 4 cases thus far (MIC 32)

145
VRSA

• Four distinct isolates since July 2002
• No relationships between the isolates
• One patient was never known to have received
  vancomycin but had dual VRE and MRSA carriage
• Two isolates known to have mecA and vanA together
• Enterococcus faecalis is known to be the donor of
  vanA in one strain

146
VRE

• Rates appear to have stabilized
• Still an issue because
• Linezolid and daptomycin resistance noted and
  probably increasing
• Potential source of vancomycin resistance in
  staphylococci