PCC Conference 8-30-06 Marcia Lux, MD. By way of introduction… New to the Division of GIM 7/1/06 Harvard Medical School, 2001 Columbia Presbyterian Internal.

PCC Conference8-30-06

PCC Conference8-30-06

Marcia Lux, MD

By way of introduction…By way of introduction…

• New to the Division of GIM 7/1/06

• Harvard Medical School, 2001• Columbia Presbyterian Internal Medicine Residency, 2001-2004

• Hospitalist CPMC, 2004-2006• Case 1: July 2004• Case 2: May 2006

Case 1:Case 1:

• 86F readmitted for diarrhea• PMH:

• mild dementia• HTN• DM• CAD s/p MI 1979• ischemic CM EF 25%

History of present illness:History of present illness:

• Multiple CPMC admissions 2003-04• 1/03 syncope PPM• 12/03 fall UTI, CHF• 2/04 NSTEMI, MSSA bacteremia ?veg on PPM wire s/p Vanco x 6wks, UTI, CHF

• 3/04 CHF, unexplained leukocytosis• 4/04 constipation• 5/04 hypoxia ?PE, CHF, contrast-induced ARF, UTI

HPI Cont.HPI Cont.

• June 27, 2004-Readmitted• 10d diarrhea, abdominal pain, dizziness

• Copious, foul smelling, bed bound

• No f/c/n/v• WBC 14.9• Cdif toxin positive• Rx’d Flagyl 500 po TID x 10d• d/c’d on hospital day #2

HPI Cont.HPI Cont.

• Readmitted 7/7/04, cont abd pain, diarrhea, subjective fevers

• 120/80, HR 75, T98, bibasilar rales o/w benign exam

• WBC 14.6, Cr 1.2, stool Cdif +• CXR mild PVC, AXR normal• Rx’d Flagyl 500 TID, Vanco 750mg PO QOD (CrCl 26) approved by ID on Hosp Day #1

HPI Cont.HPI Cont.

• GI Consulted, HD#1• NPO/Bowel rest, judicious IVF• Clinically deteriorating, ongoing diarrhea, dehydration, lethargy, delerium

• Sigmoidoscopy HD #6, severe pseudomembranes

• Vanco dosing adjusted: 250 PO QID

HPI Cont.HPI Cont.

• Labs: WBC 24.9, HCO3 13-16• DNR• HD #13, more alert, WBC 13.8• HD #14 PICC placed for TPN, tolerating clears

HPI Cont.HPI Cont.

• HD #14, 5:30 pm- RN note: “BP 80/50, beeper 3281 paged, no answer”

• 8pm-RN note: “BP 75/48, lopressor held, beeper 4778 paged, no answer”

• 5:30 am- RN note: “pt.w/ agonal breathing, unresponsive, 4778 aware, will evaluate”

• Pronounced by House MD at 6 AM• Family declined autopsy

Historical BackgroundHistorical Background

• C dif first described 1935 gram-positive anaerobic bacillus

• “difficult clostridium”-difficult to grow in culture

• Found in stool specimens from healthy neonates leading to misclassification as a commensal organism

• 1970s: “clindamycin colitis” pseudomembranous colitis in hospitalized pts

• 1978: C dif recognized as causative organism

Confusing terminologyConfusing terminology

• Antibiotic-associated diarrhea• C. difficile is one of many causes(approx 20-30%)

• Clostridium difficile-associated diarrhea• diarrhea + positive stool test

• Clostridium difficile colitis• underlying pathologic process

• Pseudomembranous colitis• endoscopic demonstration of exudative lesions

• Toxic megacolon• radiologic and surgical diagnosis

Disruption of protectivecolonic flora (abx/chemo)

Colonization with toxigenic C. difficileby fecal-oral transmission

Toxin A and B production

A/B: Cytoskeletal damage, loss of tight junctions.A: Mucosal injury, inflammation, fluid secretion.

Colitis and Diarrhea

Epidemiology & RFsEpidemiology & RFs

• Leading cause nosocomial enteric infection

• Approx 3 million cases/yr• RISK FACTORS:

• Elderly• debilitated • GI surgery• infected roommate • enteral feeding• prolonged course of abx/multi-agent tx

Subject population C. difficile positive

Pseudomembranous colitis 95-100%

Antibiotic-associated diarrhea

20-30%

Hospital in-patients 20%

Healthy adults 0-3%

Healthy neonates and infants

25-80%

Adapted from Kelly CP & LaMont JT (1998). Clostridium difficile infection. Annual Review of Medicine 49, 375-390.

Cdif incidence by populationCdif incidence by population

Clinical ManifestationsClinical Manifestations

• Carrier State: “fecal excretors” asymptomatic-->majority of patients

• Diarrhea without colitis: mild, 3-4 loose BM/d +/- cramps

• Colitis w/o pseudomembranes: more severe systemic c/o, n/v, profuse diarrhea, fever, leukocytosis, abd pain

• Pseudomembranous colitis

Clinical ManifestationsClinical Manifestations

• Fulminant colitis:• Rare, 2-3% of patients, esp elderly• Serious: ileus, perforation, megacolon, death

• High fever, chills, marked leukocytosis (>40K)

• May not have diarrhea if ileus or megacolon• Risk of perforation w/ sigmoid/colonoscopy• Tx surgical

• Unusual presentations:• Long latency period (1-2months)• Absence of antibiotic exposure

Antibiotics associated with C Dif diarrhea and colitis

Antibiotics associated with C Dif diarrhea and colitis

Frequent Occasional Rare/Never

Ampicillin Other PCN Aminoglycoside

Amoxicillin Sulfa Tetracycline

Cephalosporins Erythromycin Flagyl

Clindamycin Quinolones Vancomycin

Radiographic FindingsRadiographic Findings

Endoscopic findingsEndoscopic findings

DIAGNOSISDIAGNOSIS

• Endoscopy (pseudomembranous colitis)

• Culture• Cell culture cytotoxin test• ELISA toxin test• PCR toxin gene detection

ELISA toxin testsELISA toxin tests

• Can detect toxin A, toxin B, or both

• Rapid, cheap, and specific• Less sensitive, depends on rapid processing by lab

• Toxin A tests will miss rare C. difficile isolates that produce toxin B only

TREATMENTTREATMENT

1. Discontinue offending agent or modify to less offensive agent (successful in 20% to 25%)

2. Replace fluids and electrolytes3. Avoid antiperistaltic agents: may worsen diarrhea or precipitate toxic megacolon

4. If conservative measures not effective or practical, rx metronidazole 500 mg TID X 10d

[ can also use IV flagyl as good excretion into GI tract via bile and exudation from inflamed colon]

Treatment cont.Treatment cont.

5. Re-treat first-time recurrences with the same regimen used to treat the initial episode

6. Avoid vancomycin if possible: equal efficacy but can lead to VREF. Cannot use IV vanco. Can use vancomycin enemas if NPO

7. Do not treat nosocomial diarrhea empirically without testing, <30% have C. dif infection

Recurrent C. dif InfectionRecurrent C. dif Infection

• 10-25% of patients will relapse• Si/sx similar to initial attack• Most often occurs w/i 1-2 wks but can be up to 2 months later

• Pathogenesis unclear: reinfection vs. failure to mount adequate immune response vs. survival in diverticula

Treatment of RecurrenceTreatment of Recurrence

• First relapse: treat conservatively if mild sx otherwise repeat Flagyl x 10-14d

• Other therapies with some potential efficacy• Pulsed vancomycin taper (4+weeks)• Cholestyramine• Fecal enema (yuck!)

Resistance?Resistance?

• Generally NOT considered a clinically significant problem

• Flagyl resistant strains have been isolated in vitro

• No resistance to vancomycin has been reported

Case 2Case 2

• 54F, no prior hospitalizations• CC: fever, malaise, HA, dry cough x2d

• HPI:denied SOB or pleurisy, +sweats, no chills/rigors, no sick contacts, no prior respiratory illness, no flu shot

• ROS: +4-5/d watery diarrhea and diffuse arthralgias

Case 2, contCase 2, cont

• PMHx:• HTN- well controlled on monotherapy• Morbid obesity

• SHx: telephone operator for Verizon, lived alone, never married, non-smoker

• In ER: T 103.8, 130/80, HR 125, RR 24, O2 94% RA

• PE: mild distress, area of crackles in left lower lung field, benign abdomen

LABS & CXRLABS & CXR

• WBC 18K• 73% PMN, 0 bnd

• Na 134• Cr 1.1• AST 244• ALT 187• CK 2200

QuickTime™ and aTIFF (Uncompressed) decompressor

are needed to see this picture.

ER Dx: CAP; Rx: CTX/Azithro and admit

Pneumonia Severity IndexPneumonia Severity Index

• Age 54 44

• Temp > 40F 15

• Pulse > 125 10

____

• Total 69

• Class I (age < 50)

• Class II <70

• Class III 71-90

• Class IV 91-130

• Class V >130

Class Mortality (%)I 0.1II 0.6III 2.8IV 8.2V 29.2

Case 2, contCase 2, cont

• Admit Hospitalist service• Continue CTX/Azithro• Supportive care, IVFs• CK peaked 3400 without renal compromise

• AST/ALT normalized by HD 1

• Pt stable for discharge on Friday but uncomfortable with the plan……….

After 3days of hospitalization without being seen by an

MD……

After 3days of hospitalization without being seen by an

MD……

• Urine Legionella: positive

TerminologyTerminology

• Legionellosis: infectious process caused by Legionella spp..• 1) Legionnaires’ disease: PNA caused

by Legionella species (1976 Philadelphia American Legion Conference)

• 2) Pontiac Fever: acute febrile, self-limited illness linked to Legionella (Pontiac, MI)

• 3) Extrapulmonary Legionella infxn

EpidemiologyEpidemiology

• Incidence linked to degree of water contamination

• Accounts for 2-10% of CAP• Lower incidence for outpatients vs. inpatients

• Nosocomial: 12-70% of hospital water supplies contaminated, also reported outbreaks in NH and LTAC facilities

Risk FactorsRisk Factors

• Advanced age• Cigarette smoking

• Chronic lung disease

• Immunosuppression

• Nosocomial: transplant recipients or any surgery

0

5

10

15

20

25

30

35

LungDz

Tob NoRFs

Age<55

n = 71

age < 55

33

29

24

14

CLINICAL MANIFESTIONS:Legionnaires’ Disease

CLINICAL MANIFESTIONS:Legionnaires’ Disease

Sign/Symptom Frequency (%)Cough 41-92

Chills 42-77

Fever > 38 F 88-90

Fever > 40 F 20-62

Dyspnea 25-62

Headache 40-48

Myalgia/Arthralgia 20-40

Diarrhea 21-50

Nausea/Vomiting 8-49

Neurologic Sx 4-53

Chest pain 13-35

Legionella vs. other CAPLegionella vs. other CAP

• GI symptoms, esp. diarrhea• Neurologic findings, esp. confusion

• Fever > 39 F• Sputum w/ many PMNs but no organisms

• Hyponatremia• Hepatic dysfunction• Hematuria• No response to B-Lactam or aminoglycoside abx

PE and Lab findingsPE and Lab findings

• Bradycardia relative to temp elevation

• Rash• Hypophosphatemia• Rhabdomyolysis• Thrombocytopenia• Leukocytosis• DIC

Extrapulmonary LegionellaExtrapulmonary Legionella

• RARE!• Cellulitis• Sinusitis• Septic arthritis• Perirectal abscess

• Pancreatitis• Peritonitis• Pyelonephritis

• Most commonly affects heart:

• Pericarditis• Myocarditis• PV Endocarditis

• Surgical wound infections

Laboratory DiagnosisLaboratory Diagnosis

• Culture:• 3 different media, 3-5 days

• DFA staining:• low Se, high Sp

• Serology:• 4-fold rise in antibody titer

• URINE ANTIGEN

Culture is the Gold Standard

• Culture + antigen testing recommended if legionella is suspected on ddx

Urine AntigenUrine Antigen

• Detects L. pneumonophila serogroup 1(90% of community acq’d Legionella PNA)

• Sensitivity correlates with disease severity, may miss mild cases

• Enzyme immunoassay• Remains positive for days, even after initiation of treatment

• Rapid urinary antigen test: results in 15 min with se/sp 80%/97%

TreatmentTreatment

• Mortality: 16-30% if untreated or treated with wrong antibiotics

• Susceptibility testing not routinely available but significant resistance has not been demonstrated

• Antibiotic choice requires high intracellular penetration• Macrolides, Quinolones, Tetracycline, Rifampin

• ATS recommendations for tx of CAP incorporate either a respiratory quinolone or Azithromycin as standard therapy

TreatmentTreatment

• New macrolides (Azithromycin) or respiratory quinolones (Levaquin) are tx of choice

• No head to head RCT, retrospective studies suggest Levaquin better for severe illness

• Duration of tx: 10-14d • Azithromycin duration 7-10d• Use IV abx if prominent GI symptoms

PrognosisPrognosis

• Mortality <5% if early initiation of appropriate antibiotics

• Defervescence and symptomatic improvement within 3-5d

• Some pts will report prolonged symptoms, usu dyspnea and fatigue for many months following resolution of acute infection

SUMMARYSUMMARY

• Legionella and C. dif are common problems whose disease spectrum bridges primary care and hospital medicine

• C. dif is an extremely common nosocomial infection which can be severe

• Legionella is a frequent cause of CAP that also tends to have a more severe acute presentation