Benjamin Westley MD FAAP FACP Module 6: Stewardship in fever/sepsis, neutropenia, osteoarticular infection, and endocarditis Benjamin Westley MD FAAP FACP 4120 Laurel St Suite 204 Anchorage, AK 99508

Objectives Discuss initial management of various complex infectious- disease scenarios Fever Sepsis Neutropenia and fever Osteoarticular infection Endocarditis Disclaimer! These patients are complex and generally managed with formal infectious disease consultation where available The primary role of a stewardship program is typically to ensure an appropriate empiric regimen and to identify whether further infectious disease consultation might be appropriate

Guidelines Sepsis1 Neutropenia and fever2 Fever in the ICU3 Bone/joint infections4,5 Endocarditis6 Intravascular catheter infections7 Cardiac device infections12

Empiric sepsis therapy Immediate work-up for source as directed by symptoms Blood cultures x2 Chest x-ray Urine If source determined, use appropriate regimen for source and level of illness If source NOT determined, must consider and treat for occult bacteremia and/or intra-abdominal source Vancomycin PLUS piperacillin/tazobactam, OR Vancomycin PLUS cefepime PLUS metronidazole Strongly consider need for CT imaging of the abdomen Some programs use PCT levels to guide initiation and duration of therapy

Fever and neutropenia Obtain blood cultures x2 Other workup as directed by symptoms Cefepime 2g iv q8h ALONE if hemodynamically stable and no source If source known (lung, skin and soft tissue, abdomen) then use the regimen for NOSOCOMIAL infection E.g. HCAP regimen, or anti-pseudomonal intra-abdominal regimen If no source and hemodynamically unstable, add vancomycin and consider addition of second gram negative drug (e.g. tobramycin)

Fever and neutropenia If fever persists >4-7 days add antifungal (e.g. micafungin) Antibiotics are generally continued until the ANC is >500 cells/uL The following patients should receive ID consultation Neutropenia and septic shock Neutropenia and bacteremia or fungemia Neutropenia and intra-abdominal infection Neutropenia and lung nodules Prolonged neutropenic fever >4-7 days Determining final regimen construction and duration is challenging and best done with ID assistance

New fever in the hospital Common scenario with multiple possible causes Nosocomial infection (e.g. IV catheter, CAUTI, HAP) Drug fever DVT Atelectasis Central fever after neurological injury Sinusitis Gout/pseudogout Work-up PRIOR to antibiotics EXAM!!!! Blood cx x2 CXR or urine as directed by clinical history and exam

New fever in the hospital Most new fevers in the hospital DO NOT require new antibiotics or a change in prior antibiotic Workup as directed and await results If hemodynamically UNSTABLE, then MUST give empiric SEPSIS regimen once evaluation done based on likely source If a line infection is strongly suspected and patient is unstable, consider removing the line; however, in general, fever in a patient with a central line does not require empiric line removal/line change

Line infections 3 types: Intraluminal, hematogenous, or tunnel/exit site Controversy regarding culturing IDSA- Culture from each line and peripheral NHSN- Culture from 2 peripheral sites only Standard cultures are fine Do not need isolator cultures or fungal cultures If a pathogen grows in the blood, and there is no other obvious source, then it is a line infection Coag negative staph from a single site is likely a contaminant If it repeatedly grows, then consider real

Line infections If line infected, remove line Especially if: Staphylococcus aureus Candida species Gram negatives Duration of therapy from date of line removal: Coagulase negative Staphylococcus: 5 – 7 days Enterococcus and gram negative rods: 7 – 14 days Staphylococcus aureus AT LEAST 14 days (consult ID) Candida species: AT LEAST 14 days from first negative culture (consult ID)

Line infections If line MUST be salvaged: 2 weeks from negative culture WITH antimicrobial lock therapy (usually vancomycin) Attempt only with poorly-pathogenic organisms (e.g. coagulase negative Staphylococcus) Tunneled lines with soft tissue infection of the tunnel tract CANNOT be salvaged and MUST be removed

Bone/joint infections Hematogenous Most common in children Staphylococcus aureus, Beta-hemolytic strep Gonococcal Contiguous or innoculation (e.g. wound or trauma) Polymicrobial Prosthetic joint

Bone/joint infection Hematogenous Contiguous Prosthetic joint Vancomycin +/- ceftriaxone AFTER blood and joint cultures Contiguous Get cultures Probably vancomycin plus something else- highly individualized Prosthetic joint Get joint and blood cultures first Vancomycin Add gram negative coverage if hemodynamically unstable or GNR seen in gram stain

Bone/joint duration of therapy Hematogenous At least 3 weeks if isolated to joint, guided by clinical, lab, and imaging resolution 6 weeks if concomitant bone infection Parenteral therapy for gram positives Can consider oral quinolones for susceptible GNR Consider ID consult Prosthetic joint 6 weeks if removed and antimicrobial impregnated spacer placed 3 – 6 months for Staphylococcus species in combination with rifampin if Debride And Implant Retention (DAIR) is being attempted Consult ID

Bone/joint in children Virtually always hematogenous Excellent data that children can be treated with oral therapy once CRP falls and clinically improving8-11 3 weeks for joint, 6 weeks for bone guided by CRP and imaging Shorter courses probably reasonable9 Outpatient IV therapy and PICC lines are rarely needed for bone/joint infections in children9-11

Vertebral osteomyelitis Native- NO hardware or preceding procedures Monomicrobial, hematogenous S aureus, beta-hemolytic strep, brucella, TB If no sepsis or neurologic impairment, HOLD ANTIBIOTICS until AFTER tissue obtained for cultures AND pathology IR guided aspiration usually attempted first Send for bacterial, AFB, and fungal cultures If non-diagnostic, generally repeat by operative technique If no sepsis or neurologic impairment, withhold empiric antimicrobial therapy until a microbiologic diagnosis is established If blood grows S aureus, can assume this is etiology and do NOT have to biopsy

Vertebral osteomyelitis Treatment varies by organism 6 weeks of IV therapy vs. highly bioavailable oral therapy Trend inflammatory markers Avoid re-imaging unless clinically failing as MRI improvement greatly-lags clinical resolution These are difficult to treat infections: ID consultation early in the course of workup and management is advised

Orthopedic hardware infections Mono-microbial vs. poly-microbial Early vs late onset Unremoved hardware remains a nidus of infection Washout with or without removal, followed by prolonged systemic therapy If hardware not removed, oral convalescent or suppressive therapy for a prolonged period may be needed Rifampin generally added for Staphylococcal infections when hardware remains in place These are complex infections without easily generalized recommendations: Recommend ID consultation

Endocarditis Duke criteria: 2 major, 1 major and 3 minor, or 5 minor Multiple positive blood cultures for typical organism Valvular vegetation or new valve regurgitation Minor: Predisposing valve condition or IVDU Fever >38C Emboli Immune phenomena (glomerulonephritis, osler nodes, + RF) Positive blood culture not meeting major criteria Abnormal echocardiography without vegetation

Endocarditis Get blood cultures first! Preferably 3 sets. TTE ok for initial imaging; if high suspicion and negative, do TEE Vancomycin PLUS ceftriaxone Covers Staphylococcus, Streptococcus, Enterococcus, and HACEK organisms Treatment varies by organism, type of valve (prosthetic vs. native) Gentamicin no longer used for native valve Staphylococcus Decisions regarding surgical indications are complex Strongly consider ID consultation

Cardiac device infections Staphylococcus species most common Categories Superficial/incisional Pocket site Wires/bacteremia Blood cultures in all cases If bacteremic get TEE LIMITED superficial skin or incisional infection may be treated with 7- 10d of PO anti-staphylococcal antibiotic In MOST cases the pocket will need to be debrided and the ENTIRE device removed Consult ID

References http://www.survivingsepsis.org/Guidelines/Pages/default.aspx Clinical Infectious Diseases 2011;52(4):e56–e93 Crit Care Med 2008; 36:1330–1349 Clinical Infectious Diseases 2013;56(1):e1–25 Clinical Infectious Diseases® 2015;61(6):e26–46 Circulation. 2015;132:00-00 Clinical Infectious Diseases 2009; 49:1–45 Journal of Pediatric Orthopedics 1982; 2:255-62 Clinical Infectious Diseases 2009; 48:1201–10 Pediatrics 2009;123;636-642 Pediatrics. 2012 Oct;130(4):e821-8 Circulation 2010;121;458-477