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PCC Conference 8 -30 -06 Marcia Lux, MD PCC Conference 8 -30 -06 Marcia Lux, MD

By way of introduction… • New to the Division of GIM 7/1/06 • Harvard 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: • 86 F readmitted for diarrhea • PMH: • • • mild Case 1: • 86 F readmitted for diarrhea • PMH: • • • mild dementia HTN DM CAD s/p MI 1979 ischemic CM EF 25%

History of present illness: • Multiple CPMC admissions 2003 -04 • 1/03 syncope PPM 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 6 wks, UTI, CHF • 3/04 CHF, unexplained leukocytosis • 4/04 constipation • 5/04 hypoxia ? PE, CHF, contrast-induced ARF, UTI

HPI Cont. • June 27, 2004 -Readmitted • • 10 d diarrhea, abdominal pain, HPI Cont. • June 27, 2004 -Readmitted • • 10 d 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 10 d d/c’d on hospital day #2

HPI Cont. • Readmitted 7/7/04, cont abd pain, diarrhea, subjective fevers • 120/80, HR HPI Cont. • Readmitted 7/7/04, cont abd pain, diarrhea, subjective fevers • 120/80, HR 75, T 98, 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 750 mg PO QOD (Cr. Cl 26) approved by ID on Hosp Day #1

HPI Cont. • GI Consulted, HD#1 • NPO/Bowel rest, judicious IVF • Clinically deteriorating, 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. • • Labs: WBC 24. 9, HCO 3 13 -16 DNR HD HPI Cont. • • Labs: WBC 24. 9, HCO 3 13 -16 DNR HD #13, more alert, WBC 13. 8 HD #14 PICC placed for TPN, tolerating clears

HPI Cont. • HD #14, 5: 30 pm- RN note: “BP 80/50, beeper 3281 HPI Cont. • HD #14, 5: 30 pm- RN note: “BP 80/50, beeper 3281 paged, no answer” • 8 pm-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 Background • C dif first described 1935 gram-positive anaerobic bacillus • “difficult clostridium”-difficult Historical 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 • 1970 s: “clindamycin colitis” pseudomembranous colitis in hospitalized pts • 1978: C dif recognized as causative organism

Confusing terminology • Antibiotic-associated diarrhea • C. difficile is one of many causes(approx 20 Confusing 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 protective colonic flora (abx/chemo) Colonization with toxigenic C. difficile by fecal-oral transmission Disruption of protective colonic flora (abx/chemo) Colonization with toxigenic C. difficile by 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 & RFs • Leading cause nosocomial enteric infection • Approx 3 million cases/yr Epidemiology & 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

Cdif incidence by population Subject population C. difficile positive Pseudomembranous colitis Antibiotic-associated diarrhea 95 Cdif incidence by population Subject population C. difficile positive Pseudomembranous colitis Antibiotic-associated diarrhea 95 -100% Hospital in-patients 20% Healthy adults 0 -3% Healthy neonates and infants 25 -80% 20 -30% Adapted from Kelly CP & La. Mont JT (1998). Clostridium difficile infection. Annual Review of Medicine 49, 375 -390.

Clinical Manifestations • Carrier State: “fecal excretors” asymptomatic-->majority of patients • Diarrhea without colitis: Clinical 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 Manifestations • Fulminant colitis: • • • Rare, 2 -3% of patients, esp Clinical Manifestations • Fulminant colitis: • • • Rare, 2 -3% of patients, esp elderly Serious: ileus, perforation, megacolon, death High fever, chills, marked leukocytosis (>40 K) May not have diarrhea if ileus or megacolon Risk of perforation w/ sigmoid/colonoscopy Tx surgical • Unusual presentations: • Long latency period (1 -2 months) • Absence of antibiotic exposure

Antibiotics associated with C Dif diarrhea and colitis Frequent Occasional Rare/Never Ampicillin Other PCN 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 Findings Radiographic Findings

Endoscopic findings Endoscopic findings

DIAGNOSIS • • • Endoscopy (pseudomembranous colitis) Culture Cell culture cytotoxin test ELISA toxin DIAGNOSIS • • • Endoscopy (pseudomembranous colitis) Culture Cell culture cytotoxin test ELISA toxin test PCR toxin gene detection

ELISA toxin tests • Can detect toxin A, toxin B, or both • Rapid, ELISA 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

TREATMENT 1. Discontinue offending agent or modify to less offensive agent (successful in 20% TREATMENT 1. Discontinue offending agent or modify to less offensive agent (successful in 20% to 25%) 2. Replace fluids and electrolytes 3. Avoid antiperistaltic agents: may worsen diarrhea or precipitate toxic megacolon 4. If conservative measures not effective or practical, rx metronidazole 500 mg TID X 10 d [ can also use IV flagyl as good excretion into GI tract via bile and exudation from inflamed colon]

Treatment cont. 5. Re-treat first-time recurrences with the same regimen used to treat the 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 Infection • 10 -25% of patients will relapse • Si/sx similar Recurrent 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 Recurrence • First relapse: treat conservatively if mild sx otherwise repeat Flagyl Treatment of Recurrence • First relapse: treat conservatively if mild sx otherwise repeat Flagyl x 10 -14 d • Otherapies with some potential efficacy • Pulsed vancomycin taper (4+weeks) • Cholestyramine • Fecal enema (yuck!)

Resistance? • Generally NOT considered a clinically significant problem • Flagyl resistant strains have Resistance? • Generally NOT considered a clinically significant problem • Flagyl resistant strains have been isolated in vitro • No resistance to vancomycin has been reported

Case 2 • 54 F, no prior hospitalizations • CC: fever, malaise, HA, dry Case 2 • 54 F, no prior hospitalizations • CC: fever, malaise, HA, dry cough x 2 d • 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, cont • PMHx: • HTN- well controlled on monotherapy • Morbid obesity Case 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, O 2 94% RA • PE: mild distress, area of crackles in left lower lung field, benign abdomen

LABS & CXR • WBC 18 K • 73% PMN, 0 bnd • • LABS & CXR • WBC 18 K • 73% PMN, 0 bnd • • • Na 134 Cr 1. 1 AST 244 ALT 187 CK 2200 ER Dx: CAP; Rx: CTX/Azithro and admit

Pneumonia Severity Index • Age 54 • Temp > 40 F • Pulse > Pneumonia Severity Index • Age 54 • Temp > 40 F • Pulse > 125 • Total Class I II IV V 44 15 10 ____ 69 • • • Class I (age < 50) Class II <70 Class III 71 -90 Class IV 91 -130 Class V >130 Mortality (%) 0. 1 0. 6 2. 8 8. 2 29. 2

Case 2, cont • • • Admit Hospitalist service Continue CTX/Azithro Supportive care, IVFs Case 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 3 days of hospitalization without being seen by an MD…… • Urine Legionella: After 3 days of hospitalization without being seen by an MD…… • Urine Legionella: positive

Terminology • Legionellosis: infectious process caused by Legionella spp. . • 1) Legionnaires’ disease: Terminology • 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, selflimited illness linked to Legionella (Pontiac, MI) • 3) Extrapulmonary Legionella infxn

Epidemiology • Incidence linked to degree of water contamination • Accounts for 2 -10% Epidemiology • 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 Factors • • • Advanced age Cigarette smoking Chronic lung disease Immunosuppression Nosocomial: Risk Factors • • • Advanced age Cigarette smoking Chronic lung disease Immunosuppression Nosocomial: transplant recipients or any surgery 33 29 24 14

CLINICAL MANIFESTIONS: Legionnaires’ Disease Sign/Symptom Frequency (%) Cough 41 -92 Chills 42 -77 Fever 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 CAP • • GI symptoms, esp. diarrhea Neurologic findings, esp. confusion Legionella 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 findings • • Bradycardia relative to temp elevation Rash Hypophosphatemia Rhabdomyolysis PE and Lab findings • • Bradycardia relative to temp elevation Rash Hypophosphatemia Rhabdomyolysis Thrombocytopenia Leukocytosis DIC

Extrapulmonary Legionella • Most commonly affects heart: • Pericarditis • Myocarditis • PV Endocarditis Extrapulmonary Legionella • Most commonly affects heart: • Pericarditis • Myocarditis • PV Endocarditis • Surgical wound infections • • RARE! Cellulitis Sinusitis Septic arthritis Perirectal abscess Pancreatitis Peritonitis Pyelonephritis

Laboratory Diagnosis • Culture: • 3 different media, 3 -5 days • DFA staining: Laboratory 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 Antigen • Detects L. pneumonophila serogroup 1(90% of community acq’d Legionella PNA) • Urine 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%

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

Treatment • New macrolides (Azithromycin) or respiratory quinolones (Levaquin) are tx of choice • Treatment • 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 -14 d • Azithromycin duration 7 -10 d • Use IV abx if prominent GI symptoms

Prognosis • Mortality <5% if early initiation of appropriate antibiotics • Defervescence and symptomatic Prognosis • Mortality <5% if early initiation of appropriate antibiotics • Defervescence and symptomatic improvement within 3 -5 d • Some pts will report prolonged symptoms, usu dyspnea and fatigue for many months following resolution of acute infection

SUMMARY • Legionella and C. dif are common problems whose disease spectrum bridges primary SUMMARY • 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