Multi-drug resistant pathogens Helmut Albrecht, MD Division of Infectious Diseases

Disclosures Grant/Research Support–MSD, J&J, VIIF, Gilead (no payment to me) Consultant–France Foundation (non profit project with Duke), VIIF, Gilead (no honoraria) Speaker’s Bureau–(no honoraria)

Agenda State of the union The players (Resistant pathogens) What to do about them

Antibiotics “Deaths in the US declined by 220 per 100,000 with the introduction of sulfonamides and penicillin. This far outweighs any other medical advance in the past century.” Armstrong et al. JAMA 1999;6:61ff From 1983 to 2010, FDA approval of new antibiotics has continuously declined, from 4 per year in the early 1980s to less than 1 antibiotic per year now The last class of drugs with a novel mechanism of action against GN bacteria goes back 40 years. A review of drugs currently in trials revealed no such new drugs. For the US, antibiotic resistance is responsible for nearly 100,000 deaths caused by hospital-acquired infections per year at an estimated annual cost of $23 billion. Roberts et al CID 2009;49:1175ff

Why do we see more resistance? Sicker inpatient population Patients chronically ill Larger immunocompromised population More instrumentation/new procedures Presence of devices Increasing resistance in community Emerging pathogens Complacency regarding antibiotics Increased use of (empiric) broad-spectrum antibiotics Ineffective infection control and compliance Crowding of patients in confined areas Decreasing nurse/patient ratio

Why do we see more resistance? Sicker inpatient population Patients chronically ill Larger immunocompromised population More instrumentation/new procedures Presence of devices Increasing resistance in community Emerging pathogens (Superbugs!) Complacency regarding antibiotics Increased use of (empiric) broad-spectrum antibiotics Ineffective infection control and compliance Crowding of patients in confined areas Decreasing nurse/patient ratio

My patient is really ill… What is the price of prescribing a little more than needed if I do not want to think that hard? Healthcare dollars (irrelevant, if title true) C. difficile (potentially deadly) Side effects (potentially deadly) Resistance (relevant?)

Getting It Right Bloodstream Infections % Mortality

Getting It Right Ventilator-associated Pneumonia % Mortality It is a lot more difficult to get it right if the bacteria are multi-drug resistant

Scope of the problem Nosocomial infections > 8 million excess hospital days Approximately 80,000 deaths >75% resistant to at least one drug class > 50% of inpatients receive antibiotics 30-50% of these receive them inappropriately Cost of res. pathogens 100 million - 30 billion US$/year Phelps Med Care 1989

NEW SUPERBUGS

Adapted from Livermore and Woodford, Trends in Microbiol, The Gram Negative Cell Wall Porin channels Efflux system PBPs B-lactamases

Bush classification of β-lactamases in GN bacteria Functional Group Major Subgroups AttributesKnown types in All Chromosal >>> plasmid, SPICE-A bacteria, all β-lactams except carbapenem, not inhibited by beta-lactamase inhibitors b Plasmid >>> chromosomal, broad-spectrum β-lactamases (TEM, SHV), usually inhibited by β-lactamase inhibitors be Plasmid >>> chromosomal, ESBLs, variably inhibited by β-lactamase inhibitors a,b,c Metallo β-lactamases, ESBLs including carbapenems (not monobactams) not inhibited by β-lactamase inhibitors 24 4All Mixed group (incl. B. fragilis) Inhibited by β-lactamase inhibitors 9

Substrate Profile Penicillinase Cephalosporinase Broad spectrum Extended broad spectrum Carbapenemase

Substrate Profile Penicillinase Cephalosporinase Broad spectrum Extended broad spectrum Carbapenemase

19 Months ESBL Klebsiella pneumoniae Outbreak New York Hospital Medical Center of Queens 432 ceftazidime-resistant Klebsiella pneumoniae 155 patients colonized (61%) or infected (39%) 53% crude mortality rate Not detected for 12 months! Meyer et al. Ann. Int. Med. 119:

Substrate Profile Penicillinase Cephalosporinase Broad spectrum Extended broad spectrum Carbapenemase

Is Klebsiella bad? It depends! Most Klebsiella infections are easy to deal with, but some are worse than others Because the host is bad?! Because the bug is bad?! Because the drugs are bad?!

Susceptibility Profile of KPC- Producing K. pneumoniae AntimicrobialInterpretationAntimicrobialInterpretation AmikacinIChloramphenicolR Amox/clavRCiprofloxacinR AmpicillinRErtapenemR AztreonamRGentamicinR CefazolinRImipenemR CefpodoximeRMeropenemR CefotaximeRPipercillin/TazoR CetotetanRTobramycinR CefoxitinRTrimeth/SulfaR CeftazidimeRPolymyxin B MIC >4  g/ml CeftriaxoneRColistin MIC >4  g/ml CefepimeRTigecyclineS

Drugs with Most Reliable Activity Against ESBL-producing Enterobacteriaceae Drugs with Most Reliable Activity Against ESBL-producing Enterobacteriaceae Carbapenems Carbapenems (Cephamycins) (Cephamycins) (Fluoroquinolones) (Fluoroquinolones)

Carbapenem Resistance: Mechanisms EnterobacteriaceaeCephalosporinase + porin loss Carbapenemase P. aeruginosaPorin loss Up-regulated efflux Carbapenemase Acinetobacter spp.Cephalosporinase + porin loss Carbapenemase

Carbapenemases ClassificationEnzymeMost Common Bacteria Class AKPC, SME, IMI, NMC, GES Enterobacteriaceae (rare reports in P. aeruginosa) Class B (metallo-  -lactamse) IMP, VIM, GIM, SPM NDM P. aeruginosa Enterobacteriacea Acinetobacter spp. Class DOXAAcinetobacter spp.

Carbapenemases in the U.S. EnzymeBacteria KPC, NDMEnterobacteriaceae Metallo-  -lactamase P. aeruginosa OXAAcinetobacter spp. SMESerratia marcesens

Klebsiella Pneumoniae Carbapenemase KPC is a class A  -lactamase  Confers resistance to all  -lactams including extended- spectrum cephalosporins and carbapenems Occurs in Enterobacteriaceae  Most commonly in Klebsiella pneumoniae  Also reported in: K. oxytoca, Citrobacter freundii, Enterobacter spp., Escherichia coli, Salmonella spp., Serratia spp., Also reported in Pseudomonas aeruginosa (Columbia, thankfully we are talking the country, not us!)

Susceptibility Profile of KPC- Producing K. pneumoniae AntimicrobialInterpretationAntimicrobialInterpretation AmikacinIChloramphenicolR Amox/clavRCiprofloxacinR AmpicillinRErtapenemR AztreonamRGentamicinR CefazolinRImipenemR CefpodoximeRMeropenemR CefotaximeRPipercillin/TazoR CetotetanRTobramycinR CefoxitinRTrimeth/SulfaR CeftazidimeRPolymyxin B MIC >4  g/ml CeftriaxoneRColistin MIC >4  g/ml CefepimeRTigecyclineS

KPC Enzymes Located on plasmids; conjugative and nonconjugative bla KPC is usually flanked by transposon sequences bla KPC reported on plasmids with:  Normal spectrum  -lactamases  Extended spectrum  -lactamases  Aminoglycoside resistance

Geographical Distribution of KPC-Producers Frequent Occurrence Sporadic Isolate(s)

KPC Outside of United States France (Nass et al AAC 49: ) Singapore (report from survey) Puerto Rico (ICAAC 2007 ) Columbia (Villegas et al AAC 50: & ICAAC 07) Brazil (ICAAC 2007) Israel (Navon-Venezia et al AAC 50: ) China (Wei Z, et al AAC 51: )

Inter-Institutional & Inter-State Spread of KPC-Producing K. pneumoniae

Carbapenemase – Producing Enteric GNR; U.K. < 10% susceptible to usual Rx >40% resistant to tigecycline, >90% susceptible to colistin

NDM1 Carbapenemase First described from India 2008 Novel resistance mechanism Gene compatible with multiple types of plasmids- greatly enhances global spread Already in California, Illinois and Mass. Some strains sensitive to only polymyxins (highly neuro and nephro-toxic) or Tigecycline No new drugs close to release

Phenotypic Tests for Carbapenemase Activity Modified Hodge Test  100% sensitivity in detecting KPC; also positive when other carbapenemases are present  100% specificity Procedure described by Lee et al. CMI, 7,

New transmission mechanisms NDM-1: 77 cases in 13 European countries  60% from England  Travel to India (including medical tourism) ESBLs  Travellers diarrhea  Foodborne outbreak  Adoption

25% of E. coli ESBL (3% Europe, 79 % India, 50% Egypt, 22% Thailand) Antibiotic use not predictive except for ciprofloxacin 5/21 persistently colonized

156 pts affected 35% of kitchen surfaces colonized 6 of 44 (14%) of food workers fecal carriers 2 y.o. from China Adopted Secondary transmission in family

Modified Hodge Test Lawn of E. coli ATCC :10 dilution of a 0.5 McFarland suspension Imipenem disk Test isolates Described by Lee et al. CMI, 7,

Which is more dangerous?

Resistance in gram-positive organisms PRSP 4% 30-50% 48% VTSP< 0.2% % MRSA 20-25% 25-50% GISA 0 <0.1 <0.1 VRE <

Evolution of E. faecium resistance MIC 90 of E. faecium Penicillin Ampicillin % VRE % Grayson et al, AAC 1.Community acquired (ca-) MRSA strains generally CANNOT be distinguished from hospital acquired strains by the presence of: 1.MEC-A gene 2.SCC pattern 3.Panton-Valentine leukocidin

Why is this different? Outbreaks in new populations Different disease spectrum (boils, CAP) Spider bite history Specific clones SCCmec type IV Panton-Valentine Leukocidin (PVL) Susceptible to many antibiotics

Populations with ca-MRSA Children Inmates Military recruits Native populations MSM HIV+ patients Religious communities Football teams Wrestlers Gymnasts Fencing teams IDU Homeless

Disease Syndrome Skin/soft tissue (non-Trauma) Abscess Cellulitis Folliculitis Other/Unknown Wound (Traumatic) Urinary Tract Infection Sinusitis Bacteremia Pneumonia Osteomyelitis Septic arthritis Bursitis No. (%) 1, 266 (77%) 751 (59%) 528 (42%) 88 ( 7%) 212 (17%) 157 (10%) 64 ( 4%) 61 ( 4%) 43 ( 3%) 31 ( 2%) 21 ( 2%) 15 ( 1%) 19 ( 1%) Clinically Relevant CA-MRSA Disease (GA/MD/MN n=1,674, 78%) Fridkin et al. NEJM, 2005

MRSA skin infection: differential diagnosis Common misdiagnosis: “spider bite”, complete with history of having been bitten!

Range of the brown recluse

déjà vu

Phage type 80/81: PCN-R clone of SA Neonatal outbreaks in Australia in 50’s Became pandemic in adults/children in hospitals/communities Highly transmissible and virulent Carried leukocidin Robinson et al Phage type 80/81 carried PVL MLST 30 Current SWP clone of CA-MRSA descendant – acquired SCC IV déjà vu II

Okuma et al. J Clin Micro 2002

Distribution of Virulence and Resistance Determinants CA-MRSA (France, Switzerland, USA, Oceania) Gene/Gene Product Total n=117 (%) SCCmec IV PVL lukE-lukD (leukocidin) γ-hemolysin γ -hemolysin variant enterotoxin a enterotoxin b enterotoxin c enterotoxin h enterotoxin k 117 (100%) 116 (99%) 13 (11%) 100 (85%) 23 (20) 9 (8%) 20 (17%) 29 (25%) 24 (21%) Vandenesch et al. EID Aug 2003

PVL associated with severe disease Necrotizing pneumonias Septic syndrome Empyema Most CA-MRSA strains PVL + Causal role in severe disease presentations is not proven

Centers for Disease Control Campaign 12 steps to prevent antimicrobial resistance Prevent Infection Vaccinate Remove catheters Diagnose and Treat Effectively Target the pathogen Access the experts Use Antimicrobials Wisely Practice antimicrobial control Use local data Treat infection, not colonization Know when to say no to vancomycin Stop treatment when infection is cured or unlikely Prevent transmission Isolate the pathogen Brake the chain of contagion

How To Prevent Resistance  Adequate infection control  Appropriate use of antibiotics

Strategies for Managing Outbreaks of Resistance Lack of association of resistance with a plasmid mechanism Plasmid-mediated mechanism Ahmad M et al. Clin Infect Dis 1999;29: Amenable to strict infection control procedures Necessitates antibiotic restriction before significant reduction in resistance occurs Favors clonal or oligoclonal epidemiology Polyclonal epidemiology

Optimal Use of Antimicrobial: It’s Role in Preventing Resistance Will optimal use, including control of antibiotic use, prevent or slow the emergence of resistance? “It is unlikely that the resistance problem will rapidly wane, simply by being more prudent in our use of antimicrobial agents; on the other hand, it is certain that if we do not cut back on the use of these agents, the resistance problem will worsen.” Williams Science 1998;279:1153

What to do to slow antibiotic resistance Aggressively attack misuse Animal feeds and “treatment” of inanimate objects Upper respiratory tract infection Colds Sinusitis Pharyngitis Bronchitis - acute Fever without evidence of bacterial infections ICUs Children Chronic care facilities

Appropriate Use of Antibiotics The appropriate empiric treatment for the patient with Sneezococcus congestii Coughobacillus snifficile is Tylenol, decongestants and antitussives not antibiotics If the patient is really sick and may have pneumonia with Tyrannococcus rex or other superbugs you may want to consider Bumfacillin or Gorillamycin

SHEA and IDSA Recommendation for Hospitals Implementation of a system for periodic monitoring of antimicrobial resistance in community and nosocomial isolates Implementation of a system for periodic monitoring of antibiotic use according to hospital location and/or prescribing service Monitoring of relationship between antibiotic use and resistance, assignment of responsibility through practice guidelines or other institutional policies Application of contact isolation precautions in patients known or suspected to be colonized or infected with epidemiologically important microorganisms

Can we win the global battle? Keep on developing new antibiotics Surprise your opponent (combination, rotation) Use the optimal dose of the right antibiotic for the appropriate duration of therapy Know as much about antibiotics as your ID folks alternatively call them to help you

Double coverage? Reasonable data for some gram-positives No good data for gram-negatives May still be reasonable to cover 2 organisms and in specific situations Double coverage across the board will result in increased financial burden, resistance, drug- associated morbidity, and potentially antagonism

= = Synergy vs. antagonism = 3 vs = 0

Can we win the global battle? Keep on developing new antibiotics Surprise your opponent (combination, rotation) Use the optimal dose of the right antibiotic for the appropriate duration of therapy Know as much about antibiotics as your ID folks, alternatively call them to help you

Know Antibiotic Principles! Drug levels and activity Volume of distribution (Obesity, third spacing) Compartments Protein binding Time vs. concentration-dependant killing >MIC > 50% DI vs. Cmax/MIC >8-10 Aminoglycosides and quinolones Combining drugs Synergy vs. antagonism

You have homefield advantage – use it

Empiric Therapy Empiric therapy is not an educated guess but a sophisticated decision based on intimate knowledge of The bug The host The local environment All available options Antimicrobials Principles of antimicrobial therapy Supportive and critical care

Take home Empiric therapy is overrated Diagnostic effort is underrated Consider going narrow (may be diagnostic) Your empiric therapy will save some, not save some (if you do not get it right), or in some cases kill someone