INFECTIOUS DISEASE UPDATE 2014: New Bugs, Few Drugs

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1 INFECTIOUS DISEASE UPDATE 2014: New Bugs, Few Drugs Tom Moore, MD, FACP, FIDSA Clinical Professor, Dept of Medicine University of Kansas-Wichita High proportions of resistance reported in all regions (both healthcare settings and community) AMR negatively affects patient outcomes/gdp Treatment options disappearing Strategies to combat resistance: Improved surveillance Increased vaccine use Basic hand hygiene Reduction of non-health uses of antimicrobials Better diagnostic tests What about US? Nearly 50% of global antibiotic use Good surveillance, but no national plan CDC top priorities ( urgent ) Clostridium difficile Carbapenemase-producing Enterobacteriaceae MDR Neisseria gonorrhoeae 1

2 Completely Resistant Gonorrhea Completely Drug Resistant Gonorrhea Jan 2009: 31 yo Kyoto sex worker Presented for routine testing; IM Ceftriaxone Repeat screening positive 2 wks later; retreated Screening repeatedly positive despite repeat Rx New cases Jan 2010: France July 2010: Sweden Sept 2011: Slovenia May 2012: Spain (2 cases) NOTE: HIV risk: 3 in 1000 GC risk: 25% (men); 66% (women) THE GOOD NEWS Initiatives have led to stabilization in HAIs 2000: 0.40 infections/1000 device-days 2008: 0.15 infections/1000 device-days Initiatives have led to significant drops in incidence of MRSA, VRE, most MDR-GNR THE BAD NEWS Rates of MDR E. coli and K. pneumoniae have remained relatively stable recently but KPC strains (and worse) are coming There is no SPACE to ESKAPE Serratia Enterococcus Pseudomonas S. aureus Acinetobacter Klebsiella Citrobacter Acinetobacter Enterobacter Pseudomonas Enterobacter 2

3 NHSN Report Organism % (rank) CLABSI CAUTI VAP SSI S. aureus 15.6 (1) 12 (2) 2 24 (1) 30 (1) E. coli 11.5 (2) 4 (9) 27 (1) 6 (6) 9 (3) Coag neg staph 11.4 (3) 21 (1) (2) Klebsiella spp. 8 (4) 8 (5) 11 (3) 10 (3) 4 (7) P. aeruginosa 8 (5) 4 (10) 11 (2) 17 (2) 6 (5) E. faecalis 7 (6) 9 (3) 7 (5) <1 6 (4) C. albicans 5 (7) 7 (7) 9 (4) 2 1 Enterobacter spp. 5 (8) 5 (8) 4 (8) 9 (4) 4 (6) A. baumannii 2 (14) 2 (13) 1 7 (5) <1 MDR defined as: Resistance to >1 antimicrobial in >3 different classes: Antipseudomonal penicillins 3rd generation cephalosporins Fluoroquinolones Aminoglycosides Carbapenems Percentage of GNR resistant to ALL commonly used antimicrobial classes* Ps. aeruginosa 84/3724 (2%) K. pneumoniae 223/3029 (7%) A. baumannii 489/1454 (34%) *β-lactams, carbapenems, FQs, aminoglycosides Data from National Healthcare Safety Network Incidence of carbapenem-resistant Acinetobacter baumannii: 1999: 5% 2000: 12% 2006: 31% 2008: 57% 2010: 63% % MDR Acinetobacter MDR-GNR MICU SICU All ICUs Major teaching Not major teaching <200 beds beds >400 beds Extended Spectrum Beta-lactamase (ESBL) Amp-C Hydrolyzes: Penicillins Cephalosporins (1st, 2nd, 3rd generation) Cefoxitin Beta-lactamase inhibitor combinations Carbapenems usually remain active 3

4 MDR-GNR Community-acquired ESBLs First discovered in India; now global Found in 90% of Enterobacteriaceae in India Texas 2007: 40 patients with UTIs due to ESBLproducing E. coli 30/40 isolated from outpatients 7 (18%) had NO comorbidities and NO contact with the healthcare system Pennsylvania 2007: 291 Extended spectrum cephalosporin-resistant GNR (17 Acinetobacter, 274 Enterobacteriaceae) MDR-GNR Carbapenem-Resistant Enterobacteriaciae (CRE) 1st reported in USA in 2001, now widespread 2001: 1 hospital, 1 state; 2012: 200 hospitals, 42 states Associated with high mortality (40-50%) Often carry genes that confer high levels of resistance to many other antibiotics Readily transfer resistance genes to other GNR Definition: Nonsusceptible to one carbapenem AND R to all 3rd gen ceph (ceftriaxone, cefotaxime, ceftazidime) Types: KPC, MBL CREs Klebsiella Pneumoniae Carbapenemase Confers resistance to all β-lactams including extended-spectrum cephalosporins and carbapenems The predominant mechanism of carbapenem resistance in Enterobacteriaceae in the US Occurs primarily in Klebsiella pneumoniae Also reported in other Enterobacteriaceae Case reports of KPC in Pseudomonas aeruginosa KPC CREs Rapid dissemination across USA in < 2 years Similar to CA-MRSA USA 300 & C. difficile NAP1 strains 70% of database consists of ST258 strain could represent clonal dissemination of a K. pneumoniae clone that has acquired the KPC gene OR could represent widely disseminated clone of susceptible K. pneumoniae that is good at picking up the KPC gene CREs Tigecycline & Colistin (Polymixin) Resistance Jan 2007-Oct 2009 at CDC 344 strains of KPC-producing Enterobacteriaceae (16 E. coli, 328 Kp) Colistin MIC <2 mcg/ml = 312/344 (91%) Tigecycline susceptible = 342/344 (99%) Both strains also resistant to colistin CREs Metallo-β-Lactamases (MBLs) Hydrolyze all β-lactams Highly mobile genes NDM (New Delhi MBL) VIM (Verona integron-encoded MBL) IMP (Imipenemase MBL) New MBL from New Delhi (NDM-1) Swedish man traveled to New Delhi for medical care, acquired a UTI due to K. pneumoniae UK: 22 cases in 17 hospitals Associated with medical care in India or Pakistan 10 cases recently reported in patients WITHOUT foreign travel 4

5 NDM-1 isolates Antibiotic MIC 90 % susceptible Imipenem Meropenem 32 0 Pip/tazo >64 0 Ceftazidime >256 0 Cefepime >64 0 Aztreonam > Cipro >8 0-8 Gentamicin >32 3 Tobramycin >32 0 Amikacin >64 0 Minocycline >32 0 Tigecycline Colistin Duration of MDR-GNR Carriage 33 LTCF patients colonized with MDR-GNR followed for 1 year with monthly rectal swabs 1 Median duration of colonization = 144 days Clearance seen in only 3 (9%) LTCF (LTACH/NH) patients the MAJOR drive in the US for spread of MDR bacteria 2 1 O Fallon E, et al. Clin Infect Dis 2009;48: Munoz LS. Clin Infect Dis 2009;49: Strategies to Combat MDR-GNR Empiric combination therapy using a carbapenem with other antibiotic classes should be used first-line in critically ill patients at risk for MDR-GNR PK/PD optimization of antibiotics with GNR activity can overcome resistance associated with MDR-GNR Strategies to limit antibiotic exposure--specifically, shorter courses of antibiotics--attenuates the emergence of resistant GNR Active surveillance of MDR-GNR with isolation should be an active component of infection control bundles Strategies to Combat MDR-GNR Hand hygiene Education Monitoring of adherence Immediate feedback for staff who miss Access should be ensured Stations should be well-stocked and clear of clutter Clin Inf Dis 2011;52(suppl 2):1-58 Strategies to Combat MDR-GNR Contact Precautions Performing hand hygiene before donning gown/gloves Donning gown/gloves before entering room Removing gown/gloves before exiting room Ball up gown, insert in glove Performing hand hygiene before exiting room Strategies to Combat MDR-GNR Healthcare Personnel Education Minimizing use of devices CVCs, ETTs, Foleys Cohorting patients and staff Laboratory notification Screening for CREs Antimicrobial stewardship! 5

6 Most common outpatient diagnoses (2010) Acute URI 2.7 million (2.7%) Otitis media 1.5 million (1.5%) Acute pharyngitis 1.0 million (1%) UTI 1.0 million (1%) Source: CDC/NCHS, National Hospital Ambulatory Medical Care Survey Source: CDC, NCHS, NAMCS Use of antibiotics (PCN, macrolides) promotes persistence/shedding of resistant S. pneumoniae High antibiotic Rx rates correspond with incidence of invasive pneumococcal disease (IPD) with nonsusceptible strains IPD Rates Rx Low High p value Penicillins Cephalosporins <0.001 Macrolides <0.001 Erythromycin <0.001 TMP/SMX Source: Clin Inf Dis 2011;53(7):631-9 New Pathogens MERS-CoV Mimivirus Borrelia miyamotoi Emmonsia 1 Dimorphic fungus causing disseminated disease w/skin lesions in late-stage AIDS, S. Africa Bradyrhizobium enterica 2 Bacterium causing colitis in umbilical cord stem cell transplant recipients 1 N Engl J Med 2013;369: N Engl J Med 2013;369:1867 Mimivirus Acanthamoeba polyphaga mimivirus (APMV) 2nd largest capsid diamter or all known viruses 1,181,404 bp (next largest virus = 450,000 bp) Largest = Megavirus chilensis Mimivirus ( mimicking microbe ); Gram-positive! Accidentally discovered in 1992 within amoeba Acanthamoeba polyphaga in Bradford, England Isolated from Tunisian woman with CAP; serologic evidenc in other patients supportive Clin Infect Dis 2013;57:e127-e134 6

7 Borrelia miyamotoi 1st identifed in Japan (1995) 1st human cases in Russia (2011) 1st identification in USA (2013) 18 people in southern New England, upper NY State Transmitted by deer ticks Flu-like illness, no rash Fever, HA, nausea, myalgias Rx: Doxycycline MERS-CoV Middle East Respiratory Syndrome Coronavirus (MERS-CoV); EMC/2012 ssrna (+) Betacoronavirus 1st reported in 2012 after genome sequencing of a virus isolated from sputum of pts who became ill in 2012 outbreak of a new flu As of 4/27/2014: 339 confirmed cases in KSA; 102 deaths 1st case of MERS-CoV in USA: Indiana 5/2/2014 N Engl J Med 2013;368: MERS-CoV Distinct from SARS, but sometimes referred to as Saudi SARS 1st confirmed case 60 yo Saudi w/cap and ARF; died 6/24/2012 Egyptian virologist Ali Mohamed Zaki isolated virus then posted findings on ProMED Samples from multiple patients point to a common source Arose from a single zoonotic event 2011 (bats?camels?) Circulating in human population >1 yr w/o detection MERS-CoV Tropism Unique tropism for NONCILIATED bronchial epithelial cells Binds to dipeptyl peptidase 4 (DPP4; CD26)--this molecule expressed on surface of bronchial epithelial cells, kidneys Transmission Human-to-human Close contact Patients to HCWs MERS-CoV Natural reservoir = camels Egyptian tomb bat initially suspected Evidence implicating camels: Virus very similar (99.9% match) to coronavirus in dromedary camels Virus frequently found in camels to which known human cases have been exposed Widespread transmission in camels (as demonstrated by Ab) At least 1 person ill known to have drunk camel milk Camel meat consumption high in KSA, UAE 7

8 Epidemics Measles Foodborne outbreaks Listeria from cantaloupe Salmonella enterica from contaminated turkey; MDR, raising farm to fork concerns Why not irradiation? Fungal meningitis Aspergillus from contaminated steroid injections: 741 cases, 55 deaths, 18 states 7500 compounding pharmacies in US; not subject to regulation Measles 2000: Thought to have been eradicated Most infections in unvaccinated persons Vaccine refusal for kids ( ): 1.8% Recent outbreak ( ) among vaccinated persons, NYC Influenza Pandemic influenza H1N1 Arose from Western hemisphere in the summer--! H5N1 733 cases (mortality 59%) H7N9 133 cases (mortality 28%) Universal vaccine Microbiome NIH Director Francis Collins: Researchers carrying out this work are like 15th century explorers describing the outline of a new continent NIH-sponsored study using 16S rrna to define the flora at 15 anatomical sites in 300 persons* 1st comprehensive picture of what a normal human microbiome looks like (at least in modern times) *Nat Rev Microbiol 2013;11: N Engl J Med 2013;368: Public Health Genomics 2013;16:

9 Clostridium difficile CDI C. difficile infections are at an all-time high C. difficile infections kill 14,000/yr in US Between , CDI deaths increased 400% Half of infections occur in <65 yrs but >90% of deaths occur in >65 yrs Half of CDI are present on admission Clostridium difficile Infection (CDI) Current Issues CDI rates continue to increase Increasing incidence of severe CDI; higher mortality and higher rates of colectomy in elderly Recent reports of cases with no prior antibiotic exposure Epidemic strain (BI/NAP1/027) reported from hospitals in an expanding list of states Effectiveness of metronidazole has decreased New agents for CDI are in clinical trials but none have yet been approved Community-Associated CDI 10 pregnant women 23 generally healthy persons Many had no prior antimicrobial use 9

10 IDSA guidelines for CDI Treatment of CDI Clinical definition Supportive clinical data Recommended treatment Definition of CDI Presence of symptoms (usually diarrhea) >3 unformed stools over 24 hrs x 2 days Ileus (toxic megacolon) Positive stool test for the presence of toxigenic Clostridium difficile or its toxins or colonoscopy revealing pseudomembranes Prior antimicrobial use is NOT included in the definition Initial episode, mild or moderate Initial episode, severe Initial episode, complicated First recurrence WBC <15000 AND Creat <1.5X pre-morbid level WBC >15000 OR Creat >1.5X premorbid level Hypotension or shock, megacolon, perforation, severe colitis on CT scan Metronidazole 500 mg PO tid x days Vancomycin 125 mg PO qid x days or Fidaxomicin 200 mg PO bid x 10 days If no complete ileus: Vancomycin 500 mg PO/NGT qid and/or Metronidazole mg IV q8hrs If complete ileus: Metronidazole IV PLUS rectal instillation of Vancomycin Same as for initial episode Second recurrence Vancomycin, tapered/pulsed or Fidaxomicin 200 mg PO bid x 10 d IDSA guidelines for CDI Treatment of a 1st episode of CDI Discontinue inciting antibiotics as soon as possible to reduce the risk of CDI recurrence If severe CDI is suspected, start empiric treatment immediately If stool toxin assay result is negative, the decision to stop or continue CDI treatment must be individualized Avoid antiperistaltic agents Treatment options as noted in table IDSA guidelines for CDI Treatment of Recurrent CDI Patients with first recurrence can be treated with the same drug as initial therapy Exception: recurrence is severe - use vancomycin or fidaxomicin Do not use metronidazole beyond first recurrence and avoid using >14 days Second or more recurrence: Fidaxomicin, Vancomycin taper and/or pulse dosing Risk for recurrent C. difficile infection Ongoing or new exposure to antibiotic Age >65 yrs Underlying co-morbid chronic illness Reduced serum albumin <2.5 g/dl ICU stay Prolonged hospitalization Reduced serum IgG antibodies to Toxin A CDI Potential Strategies for Treatment Use an antimicrobial treatment that, in theory, spares the normal flora (Rifaximin, Fidaxomicin) Avoid antimicrobial treatment entirely by using toxin binders (Questran, Tolevamer) Use a biotherapeutic approach to restore the protective effect of the flora (probiotics, non-toxigenic C. difficile) Supplement or increase the antibody response to C. difficile toxins (vaccines, MAb, IVIG) Kyne L. Lancet 2001;357:189 Pepin J. Clin Infect Dis 2005;40:

11 Bacteriotherapy is not a new concept Dysbiosis Transfaunation First described in the 17 th Century by Fabricius Aquapendente Courtesy Jeff Bender Lawley TD, Clare S, Walker AW, Stares MD, et al. PLoS Pathogen 2012;8(10): e doi: /journal.ppat Hope Floats --NEJM study Lozupone. Nature 2012;489:220 CDI: Prevention and Control Key strategies Prevention of horizontal transmission Decreasing risk factors to acquire C. difficile once exposure has occurred Emphasize compliance with the practice of hand hygiene Alcohol-based agents appear less able to remove spores HOWEVER no increase in CDI rates in hospitals using alcohol-based agents CDI: Prevention and Control Antimicrobial Use Minimize antimicrobial duration and number of agents prescribed Good antimicrobial stewardship Restriction of cephalosporin and clindamycin use Probiotics No recommendation in IDSA guidelines 11