Resistant Infections: To the SNF and Back Elizabeth Hudson, DO, MPH Department of Infectious Diseases Panorama City 9/15/12 Superbugs and No Superdrugs Antibiotics are often taken for granted Changes over time Value to society at low price Unique status > decreased development
Priority Antibiotic Pathogens ESKAPE bugs: Enterococcus faecium/faecalis (VRE), Staphylococcus aureus (MRSA, VISA, VRSA), Klebsiella species (ESBL, Carbapenamase producer), Acinetobacter baumannii (multi drug resistant) Pseudomonas aeruginosa (multi drug resistant) Enterobacter species (multi drug resistant) Clostridium difficile Vancomycin Resistant Enterococci (VRE) VRE: resistance from changing some cell wall proteins > decreased vanco binding vana gene seen in VRSA as well from VRE VRE first in Europe in the 80s use of antibiotic to increase animal weight VRE is now endemic in many major hospitals in the US Biggest risk factor for acquiring VRE is previous Vanco and cephalosporins Can lead to bowel colonization with VRE
VRE: Clinical Manifestations VRE can lead to: Bacteremia Urinary tract infections Meningitis Endocarditis Clinically Important VRE Types Vancomycin resistant E. faecalis Easier to treat Vancomycin resistant E. faecium Have concurrent high level resistance to beta lactams and aminoglycosides
VRE Treatment Base on in vitro susceptibilities Ampicillin (+/ sulbactam) (if Amp sensi) plus gentamicin or streptomycin E. faecalis: Linezolid, Synercid, Tigecycline, Daptomycin E. faecium: Synercid, Linezolid, Tigecycline, possibly high dose Daptomycin MRSA Methicillin resistant Staphylococcus aureus (MRSA) was described in 1961 Methicillin resistance is mediated by PBP 2a, a penicillin binding protein encoded by the meca gene Originally from CoNS gives resistance to PCN, Cephalosporins The meca gene is located on a mobile genetic element called staphylococcal chromosome cassette (SCCmec) >new strains!
MRSA Health Care Associated (HA MRSA): severe, invasive disease in hospitalized patients strains tend to have multidrug resistance and carry SCCmec type II Community Acquired (CA MRSA): young, healthy individuals with no recent health care exposure Usually causes skin and soft tissue infections carry SCCmec type IV or V and for cytotoxin Panton Valentine leukocidin (PVL) Increased virulence MRSA Manifestations MRSA can lead to: Bacteremia Endocarditis Osteomyelitis Pneumonia Severe skin and soft tissue infections
MRSA Lab Detection The most accurate methods to detect MRSA are: polymerase chain reaction (PCR) for detection of the meca gene and latex agglutination tests for the protein product of meca, penicillin binding protein 2a Traditional microbiology laboratory techniques Rapid testing > evolving area MRSA Treatments For invasive disease, IV therapy is needed Vancomycin Most experience Need to monitor levels Daptomycin: MRSA bacteremia, L sided endocarditis, csssi Monitor CK level Not for MRSA pneumonia (pulm surfactant inhibits)
MRSA Treatments Linezolid: Approved for MRSA pneumonia and csssi Toxicities and interactions limit use Static drug Tigecycline: Approved for csssi in MRSA Increased mortality risk Quinupristin dalfopristin(synercid): Approved for csssi; used if vanco fails Need central line to give Myalgias, hyperbili CA MRSA Treatment Usually these cause SSSI Can use oral antibiotics: Bactrim DS (2 DS BID for 14 days) Linezolid (600 mg Q12) Doxycycline Clindamycin: watch out if erythromycin resistant and clinda sensi Check D test for inducible resistance flattening of the clindamycin zone adjacent to the erythromycin disk (a "D zone"), indicates resistance
VISA (no, not the credit card!) VISA and hvisa: Staph aureus with a reduced susceptibility to vancomycin unusually thickened cell wall capable of binding vancomycin See in patients on dialysis or with MRSA bacteremia related to CVC or prosthetic graft material, and prolonged vancomycin exposure VRSA VRSA: vancomycin resistance via plasmidmediated transfer of the vana gene cluster from VRE 7 cases in US since 2002 (most in MI) Chronically ill people 100% mortality after 6 months:? If VRSA cause
Treatment VISA/VRSA Best treatment of VRSA/VISA is unknown Lab testing shows most of these isolates are also usually susceptible to the daptomycin, linezolid, and quinupristin dalfopristin Increasing the dose of vancomycin not helpful Quinolones should not be used even if susceptible by lab > resistance develops quickly Extended spectrum beta lactamases (ESBL) producing Enterobacteriaceae Beta lactamases are enzymes that open the beta lactam ring, inactivating the antibiotic ESBLs are enzymes that confer resistance to most beta lactam antibiotics (e.g. PCN, cephalosporins, and aztreonam) ESBLs have been found exclusively in Gram negative organisms, primarily in: Klebsiella pneumoniae, K.oxytoca, and Escherichia coli Seen less in Acinetobacter, Burkholderia, Citrobacter, Enterobacter, Morganella, Proteus, Pseudomonas, Salmonella, Serratia, and Shigella spp.
ESBL There are multiple types of ESBLs TEM, SHV, CTX M, OXA Identification of ESBLs is lab dependent and cumbersome for the best labs One clue organism is sensitive to some 2nd generation cephalosporins (e.g. cefoxitin, cefotetan), but resistant to third generation cephalosporins Risk factors for acquisition similar to those of other superbugs : Length of hospital stay Presence of central venous or arterial catheters Gut colonization (may be reservoir) Prior administration of any antibiotic SNF resident Undergoing hemodialysis ESBL Treatment The only current proven therapeutic option for severe infections caused by ESBLproducing organisms is the carbapenem family: Imipenem: increased risk of seizures Meropenem Ertapenem (does not cover Pseudomonas)
Carbapenamases and Gram Negatives Carbapenamases are carbapenem hydrolyzing beta lactamases that confer carbapenem resistance Various classes including A, B C, and D First seen in the early 1990s in NE US and now throughout the world Carbapenamase A: KPC group Most clinically important of the Class A Carbapenamases is the KPC (Klebsiella pneumoniae carbapenemase) group These enzymes reside on a transmissible plasmid and confer resistance to all beta lactams KPC can be transmitted from Klebsiella to other genera, including E. coli, Pseudomonas aeruginosa, Citrobacter, Salmonella, Serratia, and Enterobacter spp
Carbapenamase A: KPC group Many KPC producing organisms have Imipenem or Meropenem MICs that remain in the susceptible range: look for Imi/Mero MICs are very high Recovery of an isolate that is susceptible to third generation cephalosporins but resistant to Imipenem Carbapenamase A: KPC group To improve detection can: Use Ertapenem to check susceptibility for all types of bacteria Modified Hodge test (only for E coli and K pneumo) This test involves streaking a clinical isolate near an Imipenem disk that has been placed on an agar plate containing a susceptible control organism Growth of the control organism around the Imipenem disk in the region of the streak suggests carbapenemase activity in the clinical isolate
Treatment for Carbapenamase Producers The optimal treatment of infection due to carbapenemase producing organisms is uncertain, and antibiotic options are limited Drugs that have been successful are: Tigecycline, Colistin, and Aztreonam Acinetobacter spp. Acinetobacter spp has been traditionally classified as an opportunistic pathogen of relatively low pathogenicity Known to cause nosocomial infections SNF patients, ICU patients Emergence of community acquired Acinetobacter infections highly virulent with a propensity to cause invasive disease in non critically ill patients
Acinetobacter spp. Hardy, can stay in environment and on people for a long time Colonizes ~ 10 % of HCWs Can see many different kinds of infections Bloodstream VAP UTIs Endocarditis Meningitis Acinetobacter species are innately resistant to many classes of antibiotics, including penicillin and often aminoglycosides Try Carbapenems and Colistin Clostridium difficile (C. difficile) Antibiotic associated diarrhea and colitis were well established soon after widespread use of antibiotics In 1978, C. difficile was identified as the causative pathogen in the majority of cases, Attributed largely to clindamycin then later to cephalosporins as use increases
Clostridium difficile (C. difficile) From 2003 to 2006, C. difficile infections were observed to be more frequent, more severe, more refractory to standard therapy, and more likely to relapse than previously described Attributed to a new strain designated BI, NAP1 Fluoroquinolone use has strongly correlated with the emergence of this strain Seeing more community associated infection since late 2000s More colonization/asymptomatic carriers C diff Epidemiology Dramatic increases in the incidence and severity of healthcare associated C. difficile infection have occurred over since 2000, particularly in patients over age 65 Rate of nosocomial C. difficile associated diarrhea (CDAD) in the US doubled from 31 per 100,000 to 61 per 100,000 between 1996 and 2003 C. difficile carriage occurs in 20 to 50 percent of adults in hospitals and long term care facilities (3% in healthy people) About 20 percent of patients with negative admission stool cultures become infected during their hospitalization. Asymptomatic can act as reservoir of illness for others.
Risk Factors for C diff Antibiotic use: how? Disrupt normal colonic flora, providing a niche for C. difficile to multiply and elaborate toxins. In a small series of patients with CDAD, for example, absence of Bacteroides species (a predominant species in normal colonic flora) was noted during CDAD but returned following resolution of symptoms Development of C. difficile antibiotic resistance to clindamycin or fluoroquinolones appears to play an important role in disease due to strains with increased virulence Risk Factors for C diff Perioperative antibiotic prophylaxis also confers risk for C difficile Think: Does pt really need IE prophlyaxsis for a procedure? Advanced Age PPI use: controversy
Clinical Manifestations Carrier state : reservoir Diarrhea with colitis Manifestations of C. difficile associated diarrhea with colitis include watery diarrhea up to 10 or 15 times daily with lower abdominal pain and cramping, Low grade fever, and Leukocytosis: usually quite elevated (e.g. >20K) Unexplained leukocytosis in hospitalized patients (even in the absence of diarrhea) may reflect underlying C. difficile infection Pseudomembranous colitis : sigmoidoscopic examination in these patients demonstrates the presence of pseudomembranes, which is sufficient to make a presumptive diagnosis of C. difficile infection Clinical Manifestations Fulminant colitis: severe lower quadrant or diffuse abdominal pain, diarrhea, abdominal distention, High fever, hypovolemia, lactic acidosis, and marked leukocytosis (e.g. 40 K or higher) Toxic megacolon is a clinical diagnosis based upon the finding of colonic dilatation (>7 cm in its greatest diameter) accompanied by severe systemic toxicity Check ARX Watch for perforation Aggressive diagnostic and therapeutic interventions are warranted in the setting of fulminant C. difficile infection: Medical and sometimes surgical therapy needed
Diagnosis Clinical diagnosis; don t wait for lab confirmation in right clinical scenario! Kaiser So Cal uses real time PCR: rapid and accurate Depending on when sample to lab get results back within 24 hours. So sensitive that once done, do not recommend rechecking C diff for 2 weeks unless extenuating circumstances Colonoscopy or sigmoidoscopy can be a useful adjunctive tool for diagnosis of C. difficile in the following settings: High clinical suspicion for C. difficile with negative laboratory assay(s) Prompt C. difficile diagnosis needed before laboratory results can be obtained Failure of C. difficile infection to respond to antibiotic therapy Atypical presentation with ileus or minimal diarrhea Treatment of C diff: Non Severe Oral Flagyl or Oral Vancomycin Is one better than the other? Not clear from studies Dosage: Flagyl: 500 mg PO three times daily or 250 mg four times daily for 10 to 14 days. Vanco: 125 mg PO four times daily. Patients with an underlying infection requiring prolonged duration of antibiotics should continue CDIAD treatment throughout the antibiotic course plus one additional week after its completion Repeat stool assays are NOT warranted during or following treatment in patients who are recovering or are symptom free.
Treatment of C diff: Severe Disease There is no consensus definition for severe CDI, nor is there agreement as to the most important clinical indicators that should be used to differentiate severity Patients with acute C. difficile infection (CDI) may develop signs of systemic toxicity with or without profuse diarrhea warranting admission to an intensive care unit or emergency surgery Treatment of C diff: Severe Disease First line therapy: PO Vanco: 125 mg 500 mg Dose depends on severity of illness and clinician choice If no better with PO Vanco, can consider Fidaxomicin (new Macrolide drug just for C diff; absorbed locally only) Adding IV Flagyl may be helpful in severely ill patients with ileus Intracolonic Vanco Surgery: last resort!
Treatment of Recurrent C diff Management of initial recurrence: confirm clinically mild symptoms of recurrence who are otherwise well may be managed conservatively, without further antibiotic therapy Non severe initial recurrence following therapy for CDI can be treated with Flagyl, 500 mg PO Q 8 for 10 14 days Vanco can be used, too, but would reserve for sicker patients C diff back again and again what to do? Tapering dose of vancomycin Rifaximin chaser Fidaxomicin Stool transplant
Beware the Clostridiapocalypse! Movie clip to come