Invasive Staphylococcal Infections

Transcription

1 Invasive Staphylococcal Infections Henry F. Chambers, M.D. Professor of Medicine, UCSF San Francisco General Hospital Disclosures AstraZeneca advisory board Cubist research grant, advisory panel Genentech advisory board Merck stock Theravance advisory board

2 Case 1 45 year old man with cirrhosis due to alcohol presents with one week of fever, malaise, diffuse arthralgias and shortness of breath T=39.1 C, P=128, BP=115/65, RR=20 New 3/6 holosystolic murmur at the Lt. sternal border, radiating to axilla TTE: 1 x 1.5 cm mitral valve vegetation 2 of 2 blood cultures growing latexagglutination test coagulase positive but tube coagulase negative staphylococci Which one of the following organism is most likely causing endocarditis in this patient? 1. Micrococcus luteus 2. Staphylococcus aureus 3. Staphylococcus epidermidis 4. Staphylococcus lugdunensis 5. None of the above, the blood cultures are contaminated

3 Staphylococcus lugdunensis Coagulase negative. The tube free coagulase test is negative The latex bound coagulase (i.e., clumping factor) test may be falsely positive and confuse physicians Spectrum of disease: virulent, aggressive, similar to S. aureus. Bacteremia, NV and PV endocarditis Bone and joint infection Pacemaker, other device-related infections Susceptible to many antibiotics (only rarely meca positive) Coagulase-negative staphylococci Commensals, not invasive, rarely disseminate, relatively benign clinical course Spectrum of disease Vascular catheter-associated bacteremia Prosthetic device (joint, valve), pacemaker, device-related infections Neonatal sepsis Peritoneal dialysis catheter infections Virulence factors: biofilm formation Multiple drug resistant (reservoir for S. aureus)

4 Coagulase-negative staphylococci Therapy is NOT required if: Positive intravascular catheter tip culture without signs of infection Positive intravenous catheter culture with negative peripheral cultures Catheter salvage may be an option Removal of prosthetic device generally required for cure CoNS Prosthetic Valve Endocarditis Prosthetic valve TEE to assess valve ring abscess; abscess is an indication for surgery MS CoNS: Nafcillin 2 gm q4h x 6 wks + Rifampin 300 mg q8h x 6 wks + Gentamicin 1 mg/kg q8h x 2 wks MR CoNS: Vancomycin mg/kg 3 divided dose instead of Nafcillin Endocarditis with implantable cardiac devices Device removal associated with improved 1-year survival, especially if valve is also infected Therapy as above

5 Case 2 Catheter-Associated Bacteremia 38 y/o man, new CHF, alcoholic cardiomyopathy, Hct = 13. He is transfused and on hospital day 3 an upper + lower endoscopy performed. Postprocedure T = 38 o C. The site of the previous IV, d/ c d post-procedure is tender and red. Two peripheral blood cultures are drawn. The next day he is afebrile and 1 blood culture is growing GPC in clusters. Cultures are repeated and vancomycin is administered. The following day the organism is identified as MSSA and repeat blood cultures show no growth to date. Case 2: Catheter-Associated Bacteremia Which of the following has been shown to improve outcome of S. aureus bacteremia? 1. Treatment with daptomycin instead of vancomycin for MRSA. 2. Echocardiography to rule out endocarditis. 3. Infectious diseases consultation. 4. Gentamicin combination therapy instead of single drug therapy with vancomcyin or nafcillin.

6 Get an Infectious Disease Consult!! Amer J Med 123:631, 2010 J Infect 59:232, 2009 Emerg Infect Dis 18:1072, 2012 Infect Dis Clin Pract 20:261, 2012 Clin Infect Dis 46:1000, 2008 Clin Microbiol Infect 16:1783, 2010 Case 2 Catheter-Associated Bacteremia You would 1. Continue vancomycin pending blood culture results, d/c if those are negative. 2. Switch from vancomycin to cefazolin pending blood culture results, d/c if those are negative. 3. Continue vancomycin pending blood culture results, plan to treat for at least 14 days if those are negative. 4. Switch from vancomycin to cefazolin pending blood culture results, plan to treat for at least 14 days.

7 Predictors of Complicated Staphylococcus aureus Bacteremia Community-onset Septic shock Persistent or secondary focus of infection Prolonged bacteremia on therapy (>48-72h) Fever > 3 days on therapy Elderly patient (age > 60 years) MRSA Use of vancomycin instead of a β-lactam Duration of treatment < days Nafcillin vs. Other β-lactmas for MSSA Cefazolin similarly efficacious and better tolerated than nafcillin/oxacillin Antimicrob Agents Chemother 55:5122, 2011 Clinical Infectious Diseases 59:369, 2014 Antimicrob Agents Chemother 58:5117, 2014 Clin Microbiol Infect 17:1581, 2011 Ceftriaxone, other β-lactams may be less efficacious Clin Microbiol Infect 17:1581, 2011 Int J Antmicrob Agents 44:235, 2014 (But see Int J Clin Pharm 36:1282, 2014)

8 Duration Duration of Therapy: S. aureus Bacteremia Indications 14 days Fever resolves by day 3 Sterile blood culture after 2-3 days Easily removed focus of infection No metastatic infection (e.g., osteo) Negative echo, no evidence of endocarditis No predisposing valvular abnormalities No implanted prosthetic devices (No DM, immunosuppression) 4-6 weeks Failure to meet one or more of above criteria Osteomyelitis, endocarditis, epidural abscess, septic arthritis (3 wk), pneumonia (3-4 wk), complicated UTI Clin Infect Dis 49:1, 2009; Clin Infect Dis 52:285, 2011 You would Case 1: Catheter-Associated Bacteremia 1. Continue vancomycin pending blood culture results, d/c if those are negative. 2. Switch from vancomycin to cefazolin pending blood culture results, d/c if those are negative. 3. Continue vancomycin pending blood culture results, plan to treat for at least 14 days if those are negative. 4. Switch from vancomycin to cefazolin pending blood culture results, plan to treat for at least 14 days.

9 Case 1: Catheter-Associated Bacteremia And if those blood cultures turn positive Obtain an ECHO Search for secondary or metastatic focus Treat for a minimum of 4-6 weeks What about Echocardiography? Consider obtaining TTE is all cases of S. aureus bacteremia and especially for the following Positive blood cultures for 3 or more days Intracardiac device (pacer, valve) Secondary/metastatic focus of infection Relapse or recurrence Suspected endocarditis on other grounds Some say community-onset, HD, h/o IVDU but data less convincing Circulation.132: , 2015.

10 The Facts about Echocardiography? TEE is more sensitive than TTE TEE can visualize smaller vegetations: 5 mm TEE is better than TTE for prosthetic valve endocarditis Few data that it improves outcome Compliance is poor 379 ECHOS in 877 SAB cases (43%) in one Michigan hospital* *Medicine 92:182, 2013; Lancet Infect Dis 11:208, 2001 Case 3 66 yo M with 4 days prior to admission Admission exam (day 1) VS: T 39.5C, HR 128, BP 110/60, RR 22 3/6 systolic murmur L sternal border Vasculitic lesions Labs Admission blood cultures: MRSA, vancomycin MIC = 2 µg/ml 2/2 blood cultures from day 3: Gram-positive cocci in clusters Creatinine 1.2 mg/dl on admission, now 1.8 Vancomycin trough: 17.5 µg/ml Hospital course (day 4) On vancomycin + gentamicin (low dose)

11 Case 3 You are asked to see the patient for treatment recommendations. You would 1. Continue vancomycin + gentamicin 2. Continue vancomycin + gentamicin and add rifampin 3. D/c gentamicin, continue vancomycin 4. Switch to daptomycin 5. Switch to ceftaroline FDA Approved Agents for MRSA Infections Other than ABSSSI Agent Dose Indications Daptomycin IV 6 mg/kg q24h Bacteremia, R-sided endocarditis* Linezolid PO/IV 600 mg q12h MRSA pneumonia (Also a 1 st Line agent) Vancomycin mg/kg q8-12h Serious MRSA Infections Telavancin IV 10 mg/kg q24h HAP/VAP *DO NOT USE DAPTOMYCIN FOR PRIMARY PNEUMONIA!

12 First Line Choices for MRSA Bacteramia Vancomycin Daptomycin See, Holland et al: JAMA 312:1330, 2014 Recommended Vancomycin Dosing For serious infections (pneumonia, bacteremia) mg/kg IV q8-12h (loading dose of mg/kg) Target trough concentrations of µg/ml; target AUC 24 /MIC = 400 (or > 211?*) Adjust for renal function, actual body weight For less serious infections (SSTI): 15 mg/kg q12h (1 gm q12h) Routine measurement of trough not necessary Clin Infect Dis 52:285, 2011, *Antimicrob Agents Chemother 56:634, 2012

13 Vancomycin Target Attainment AUC/MIC = 400 vs AUC/MIC = 200 Patel, Clin Infect Dis 52:969, " 100" 80" 60" 40" 20" **"Clinical,""""" micro"" response" "Mortality,"" bacteremia" and"endocardibs" 200"@"15"q12h" 200"@"30"q12h" 400"@"15"q12h" 400"@"30"q12h" 0" 0.25" 0.5" 1" 2" 4" ** Moise-Broader, Clin Pharmacokinet 43:925, 2004 (LRTI) Brown, Antimicrob Agents Chemother 56:634, 2012 (Bacteremia) Vancomycin MICs by Method * Hsu, Int J Antimicro Agent 32:378, 2008 * MIC 4-8 µg/ml = VISA, MIC > 16 µg/ml = VRSA

14 MIC Method Matters 182 patient cohort with S. aureus bacteremia End-point: 30d all-cause mortality Troughs, media µg/ml (IQR): 19.5 (15-24) AUC/MIC calculated based on vanco dose AUC/MIC, median (IQR) BMD: 436 ( ) versus E-test: 272 ( ) AUC/MIC mortality breakpoint BMD: 373 versus E-test: 130 Other findings No difference for Etest MIC < 1.5 µg/ml vs > 1.5 µg/ml. 90% of survival difference due to variables other than AUC/MIC Holmes, Antimicrob Agents Chemother 57:1654, 2013 Duration of Staph. Aureus Bacteremia SFGH Data

15 Meta-analysis, 38 studies, 8291 episodes MIC < 1.5 µg/ml (low) versus MIC > 1.5 µg/ ml (high) Mortality low = 25.8%, high = 26.8% Adjusted risk difference = 1.6% (-2.3 to 5.6%), p = 0.43 Kalil, JAMA 312:1552, Management of Persistent MRSA Bacteremia on Vancomycin Therapy Median time to clearance of MRSA bacteremia is 7-9 days Persistent bacteremia around day 7 of therapy should prompt assessment to determine if a change in therapy is indicated: Search for and remove other foci of infection (source control!) Evaluate clinical response Assess micro data (vanco MIC, results of f/u bld cx) Consider change if: 1) Unsatisfactory clinical response, regardless of MIC or 2) Vanco MIC = 2 No change if: 1) Clinically responding and 2) Vanco MIC < Day of vancomycin therapy

16 Case 4: Persistent Bacteremia Mr. Q is a 53 year old diabetic. He was hospitalized four weeks ago for hyperosmolar coma and was readmitted a week ago for fevers to 39 o C. A CT scan showed findings consistent with a 4 cm psoas abscess. Three blood cultures were drawn and empirical therapy begun with vancomycin and piperacillin-tazobactam. All three blood cultures grew MRSA with a vancomycin MIC of 2 by microbroth dilution. TEE is negative. Treatment was de-escalated to vancomycin alone with documented trough concentration of 15 µg/ml. One of two blood cultures obtained on day 5 of therapy now is reported as positive for Gram-positive cocci in clusters. Which of the following is the most likely explanation for the persistently positive blood culture? 1. Vancomycin resistance MRSA strain 2. Treatment failure due to the MIC = 2 3. Undrained psoas abscess 4. Subtherapeutic levels of vancomycin 5. Contamination of the blood culture with coag-neg staph Case 5: Vancomycin Treatment Failure 38 y/o woman, injection drug user with TCV endocarditis Presented with pleural effusion (exudate, sterile), multiple septic pulmonary emboli, 2/2 blood cultures positive for MRSA (vanco MIC < 0.5 µg/ml, dapto MIC < 1) TTE: 2 x 2.4 cm TCV vegetation Vancomycin 1.25 g q8h (troughs µg/ml) Blood cultures: Vanco day 2: 2/2 MRSA Vanco day 3: 2/2 MRSA Vanco day 4: 1/2 MRSA (MIC = 1) Vanco day 5: 2/2 NG Vanco day 9: 2/2 NG

17 Case 5: Vancomycin Treatment Failure Vanco days Afebrile Slowly declining WBC, Serum creatinine 1.53, GFR ~38 ml/min Antibiotic day 18 Vancomycin discontinued Daptomycin 500 mg (10 mg/kg) q24 hours started Day 19 (dapto day 2) Fever spike to 39C 2 blood cultures drawn, eventually grow MRSA (vancomycin MIC=1, dapto MIC = 1) Persistent S. aureus Bacteremia/Treatment Failure Risk Factors Definitions vary: >3d or >5d or >7d What factors are consistently identified as being correlated? Endocarditis, endovascular source Metastatic infection Retained catheter or foreign body Use of vancomycin instead of β-lactam for MSSA Controversy over vancomycin MIC > 1 µg/ml (E-test) Scand J Infect Dis 38:7, 2006; Arch Intern Med 167:1861, 2007; Diag Microbiol Infect Dis 67:228, 2010; J Antimicrob Chemother 65:1015, 2010; Clin Infect Dis 52:975, 2011

18 What to do when vancomycin is not working? 1. Source control!!! 2. Get and ID consult 3. Abandon vancomycin Do not add rifampin Do not add gentamicin 4. Switch to another agent(s) Which? Daptomycin

19 Daptomycin Endocarditis Trial Non-inferior to comparator overall Cure rate MSSA: 44.6 v 48.6% Cure rate MRSA: 44.4 v 31.8% Duration of bacteremia: no difference v comparator Microbiologic failure: 19/120 daptomycin vs. 11/115 comparator (9/53 vancomycin, 2/62 nafcillin) Rising MICs 6/19 isolates from daptomycin failures (5 MRSA) (often mprf mutants) 1/9 (4/9 if local results used) from vancomycin failures Fowler, et al, NEJM 355:653, 2006 Do we have the right dose for daptomcyin? Dose was chosen based on concerns for toxicity, not guarantee of efficacy Daptomycin has concentration dependent killing Higher dose may provide protection against emergence of resistance IDSA guidelines committee recommends that if daptomycin is used for treatment failure, it be used at a dose of 10 mg/kg/d

20 Daptomycin MIC Distribution for Vancomycin Susceptible and Non-Susceptible Strains Percent of Strains Daptomycin MIC, µg/ml Data on file. Cubist Pharmaceuticals; Sader, Antimicrob Agents Chemother. 2006;50:2330. Daptomycin Beta-Lactam Combination Seven cases of relapse (n=2) and/or persistent bacteremia (7-22d) 1 endocarditis, 1 csssi, 5 unknown Prior regimens 7 vanco, 5 dapto, 5 dapto+gent Dapto 8-10 mg/kg + Naf or Ox 12 g/day Negative 24-48h 2 relapsed (1 death) 3 rising dapto MIC (MIC > 1 in 2 cases) Dhand, et al. Clin Infect Dis 53:158, 2011

21 MprF Structure Ceftaroline

22 Outcomes in S. aureus Bacteremia treated with Ceftaroline Group Success Mortality Endocarditis 23/33 (70%) 8/35 (23%) Pneumonia 21/29 (72%) 6/30 (20%) Micro evaluable 109/120 (91%) n/a Evaluable 101/129 (78%) n/a Duration of bacteremia: 6 days, 2.5 days after starting ceftaroline Casapaso, et al. Antimicrob Agents Chenother, 2014 Ceftaroline Salvage Therapy MRSA Invasive Disease 10 patients, case series, San Diego 5 endocarditis 2 pneumonia (neg BC) 3 bone and joint (1 bacteremia) Duration of + BC pre-ceftaroline: 5-19 Vanco MICs (µg/ml): 0.5 (2); 1(4); 2 (4, 1 by E-test) Dose 600 mg q8h Time to BC clearance with ceftraoline: 2-7 days Cures: 7/10 micro, 6/10 clinical Failures: AICD, PJI, pneumonia (comfort care) Lin, et al, J Infect Chemother 19:42, 2013

23 Ceftaroline Prospective Treatment Trial for S. aureus Bacteremia Index blood culture positive within 24h (N=15) Ceftaroline 600 mg q8h IV MRSA 4/6 relapse-free success MSSA 3/9 relapse-free success Patient with +BC 3 h after first dose also failed Time to clearance of bacteremia Median: 3 days Range: 0 to 5 days Fowler, et al. Abstract L-400, ICAAC 2014 Ceftaroline: Alone or in Combination for S. aureus bacteremia 31 patients, 9 endocarditis Days of +BC on ceftar: 3.4 (mean), 1-8 (range) Ceftaroline alone (n=21) 8 failures 3 toxicity (GI, rash) 3 recurrence (catheter, endocarditis) 2 deaths (osteo/epidural, pneumonia/comfort care) Ceftaroline combos (n=10) (5 dapto/dapto+) 10 successes Polenakovik & Pleiman. Int J Antimicrob Agents 42:450, 2013

24 26 patients, salvage regimens Pre combo: 10 d median SAB (2-23 d) Post combo: 2 d median SAB (1-6 d) Clinical Therapeutics 36:1317, 2014 Telavancin

25 Telavancin Salvage Therapy MRSA Bactermia 14 patients, case series 11 endocarditis: 2 R-sided, 7 L-sided, 2 MV PVE Duration of + BC pre-telavancin: 4-31 d (median 13d) Duration of Vanco therapy: 3-26 days (n=14) Duration of Telavnacin therapy: 3-17 (n=6) Vanco MICs (µg/ml): 2 Dapto MICs(µg/ml): (1 isolate >1 µg/ml) Time to BC clearance with telavancin: 1-2 days Discharged alive: 8 (57%) Deaths: 6, all with L-sided endocaritis Ruggero, et al, Infect Dis (Lond). 47(6):379, 2015 Treatment of Bacteremia and Other Serious Staph. aureus Infections Source control is paramount Prefer a β-lactam for MSSA infections Vancomycin remains a drug of choice for MRSA but has issues. High clinical and microbiological failure rate (25-50%) Yet, no alternative agent(s) has been shown to be superior to vancomycin (they are non-inferior) Switch to other agent(s) for treatment failure