Update in Infectious Diseases 2012 Keith B. Armitage, MD Professor of Medicine Case Western Reserve University

Disclosures No conflicts

Topics Clostridium difficile infection (CDI) Update on antimicrobial agents Miscellaneous updates

Clostridium difficile infection CDI > MRSA for nosocomial infection Long term care facilities “Epidemic strain” NEJM 12/05; NAP1 strain Increase in frequency and severity 10x increase in reports of CDI as primary cause of death 1999-2009 Change in antimicrobial risk Quinolones >> cephalosporins > clindamycin

Clostridium difficile New testing method PCR 85 % to 95 % sensitive; quick turnaround time Prior toxin assays- 28 % sensitive! Relapses- 20 %- predicted by age, severity of presentation, hospital exposure, prior CDI relapse New therapies Fidaxomicin Stool transplants

Audience Response Question For hospitalized patients with suspected or proven mild to moderate CD- I most often start with : 1. oral metronidazole 2. oral vancomycin 3. IV metronidazole 4. oral vanco + IV metronidazole 5. fidaxomicin

Clostridium difficile- treatment options Oral or IV metronidazole Mild to moderate Inferior to vancomycin for severe CDI Oral vancomycin 125 mg dose adequate Impact on the gastrointestinal microbiome Cost- more and more pharmacies are compounding vs. Fidaxomicin

Clostridium difficile Fidaxomicin First in class macrocyclic antibiotic Theoretical advantages More active against NAP1 strain Inhibits spore and toxin production Less impact on the normal flora Decrease VRE colonization High fecal concentration with minimal systemic absorption Cost $ 2800 for a 10 day course

Fidaxomicin Initial two licensing studies- non inferior to vancomycin with fewer relapses in the non-NAP1 strain Meta-analysis – superior for recurrence and global cure, including NAP1, but no difference in an intention to treat analysis Subgroup analysis suggests benefit

Fidaxomicin Recent multicenter trial in 1164 patients with first recurrence- vancomycin vs. fidaxomicin Same response to therapy Superior in preventing second relapse ? More data needed to justify cost?

Clostridium difficile-multiple relapses Long tapering courses Fidaxomicin ? Probiotics Not helpful in patients with relapses Stool transplants Strong results in case series Sonication, filter, instill via nasogastric tube No comparator trials

Clostridium difficile- treatment options Nitazoxanide Rifaximin Used as chaser in multiple recurrences- small study Tigecycline Dose not promote CD growth despite broad spectrum Very limited data in CDI

Clostridium difficile CDI and PPIs 2012 FDA warning 1.4 to 2.75x risk in patients on PPIs Relationship of dose and duration unknown FDA recommends lowest dose for lowest duration in patients at risk for CDI

Update on antimicrobial agents New antimicrobial agents for gram positive infections in the past fifteen years Daptomycin Linezolid Synercid Ceftaroline Telavancin Tigecycline

Update on antimicrobial agents New antimicrobial agents for gram negative infections in the past decade, or in the pipeline………. Tigecycline ? otherwise

Audience Response Question For outpatients with suspected Staphylococcus aureus skin and soft tissue infections, I most prescribe: 1. Augmentin 2. Bactrim 3. Clindamycin 4. Doxycycline 5. Linezolid 6. One of the above plus Keflex

New antimicrobial agents for gram positive infections Linezolid Not new, but…… Best oral bioavailability SSRIs Cytopenias Cost

New antimicrobial agents for gram positive infections Daptomycin IV only Not in the lung Once a day Weekly CPK Tends to not be particularly helpful in the VISA strains

Vancomycin dosing/levels New dosing recommendations Vancomycin levels Serious infections; increased MICs- trough 15-20 ‘minor infections’- 5-10 Dosing apps

Ceftaroline Novel cephalosporin that has activity against MRSA Maintains the broad spectrum gram negative activity of advanced generation cephalosporins Skin and soft tissue, community acquired pneumonia

Tigecycline Tetracycline antibiotic Broad spectrum, including MRSA Does not cover “P P P” Pseudomonas, Proteus, Providencia Used primarily in patients intolerant to other antibiotics; multiple allergies 2012 meta-analysis- small increase in mortality Tolerance

Telavancin semi-synthetic derivative of vancomycin Once a day Meta-Analysis- Telavancin vs. vancomycin Non inferior vs. vancomycin Associated with higher eradication rates and trend towards better clinical response All cause mortality equivalent High rate of adverse events, including elevations in serum creatinine

Brief Updates-2012 FDA advisories Cefepime/seizures- Too high doses in patients with renal impairment Azithromycin/cardiovascular risk Class effect on QT; torsades de pointes Large database- increased cardiovascular death vs. amoxicillin Similar to quinolones Highest in patients with cardiovascular risk factors Quinolones/retinal detachment Possible increased risk

Vaccines HSV vaccine trial- no efficacy Zoster vaccination New age recommendation ACIP > 60 (FDA > 50) Currently contraindicated in high level immunosuppression Safe in low levels of Imuran, mtx, steroids > 20 mg prednisone for 3 weeks Large database analysis of patient with Crohn’s and RA showed no risk of adverse reactions Larger trials needed for confirmation

Vaccines Pertussis vaccination in adults 2012 ACIM recommends T-dap booster for all adults- regardless of age Pneumococcal conjugate vaccine in healthy adults 13-valent conjugate vaccine approved December 2011 in adults > 50 Antibody responses =/> than pneumococcal polysaccharide vaccine Recommended by ACIP for routine use in adults- pending additional data June 2012- ACIP recommended use in immunocompromised adults age > 19 May give in addition to polysaccharide vaccine- one or more year later Evolving recommendations- recommend ACIP web site or app

Vaccines Influenza 2012-2013 2010: all persons > 6 A/California/7/2009 (H1N1), A/Victoria/361/2011 (H3N2), and B/Wisconsin/1/2010 Vaccinate as soon as vaccine available…… Fluzone high dose- indicated for persons age > 65 4x antigen Shown to invoke stronger immune response, but protective efficacy not clear; studies ongoing Do not use in patients with prior vaccine reaction Egg allergy- hives only 30 minutes observation trivalent inactivated vaccine only

Mycobacterium New recommendation for latent TB Rifapentine- longer half life and greater potency than rifampin Three month course of weekly directly observed therapy of rifapentine/INH non-inferior to nine months of INH CDC recommends rifapentine/INH as alternative to nine months of INH in patients > 12 months Advantage of DOT

Chronic Fatigue Syndrome- 2012 Retraction of two studies that initially associated CFS with retrovirus infection

HIV Rapid in-home testing approved but not yet commercially available 2012 US Department of Health and Human Services recommended therapy for HIV infected patients regardless of CD4 count Pre-exposure prophylaxis: July 2012 FDA approved tenofovir-emtricitabine (truvada) among confirmed HIV negative individuals at high risk for sexually acquired HIV Counseling about factors Evaluation for HIV prior to initiation crucial to avoid selection of mutations

H3N2 Variant Influenza CDC reports > 150 cases of H3N2 variant influenza caused by reassortment of swine H3N2 and H1N1; most cases have occurred since July 2012 All patients reported contact with swine (including fairs) Mild diseases- two hospitalizations; no deaths CDC recommends frequent hand washing and avoiding contact with pigs that appear ill