Bacterial Pathogens in the Hospital and Community: The Need for Newer Antibiotics

So What Happened?  Antibiotic overuse/misuse

So What Happened?  Antibiotic overuse/misuse  Fitness of organisms clonal spread

Tennessee Cleveland Mexico Colombia Brazil Argentina Uruguay Chile South Africa Singapore Malaysia Thailand Philippines Hong Kong Taiwan South Korea Spain France BM ? Finland Spain 23F – one pneumococcal clone

Bad Bugs, No Drugs 1 The Antimicrobial Availability Task Force of the IDSA 1 identified as particularly problematic pathogens – A. baumannii and P. aeruginosa –ESBL-producing Enterobacteriaceae –MRSA –Vancomycin-resistant enterococcus Declining research investments in antimicrobial development 2 1. Infectious Diseases Society of America. Bad Bugs, No Drugs: As Antibiotic Discovery Stagnates, A Public Health Crisis Brews. July, Accessed March 17, Talbot GH, et al. Clin Infect Dis. 2006;42:

Between 1962 and 2000, no major classes of antibiotics were introduced Fischbach MA and Walsh CT Science 2009

A Changing Landscape for Numbers of Approved Antibacterial Agents Bars represent number of new antimicrobial agents approved by the FDA during the period listed Number of agents approved Infectious Diseases Society of America. Bad Bugs, No Drugs. July 2004; Spellberg B et al. Clin Infect Dis. 2004;38: ; New antimicrobial agents. Antimicrob Agents Chemother. 2006;50:1912 Resistance

The Problems Gram negatives –Resistant Enterobacteriaceae β-Lactamases –Pseudomonas/Acinetobacter –N. gonorrheae Gram positives –MRSA –Pneumococcus

The Gram Negatives

Prevalence of Isolates of Multidrug-Resistant Gram Negative Rods Recovered Within The First 48 h After Admission to the Hospital Pop-Vicas and D'Agata CID 2005;40:

Enterobacteriaceae The rapid and disturbing spread of: –extended-spectrum ß-lactamases –AmpC enzymes –carbapenem resistance metallo-β-lactamases KPC and OXA-48 β-lactamases –quinolone resistance

Copyright restrictions may apply. Livermore, D. M. J. Antimicrob. Chemother :i29-36i; doi: /jac/dkp255 Rise in the proportions of E. coli from bacteraemias in England, Wales and Northern Ireland resistant to fluoroquinolones (white), oxyimino-cephalosporins (grey) and both (black)

Increase in numbers of Group 1, 2 and 3 β-lactamases from 1970 to 2009 Group 1/class C cephalosporinases Group 2/class A and class D β-lactamases Group 3/class B metallo- β-lactamases Bush K and Jacoby G AAC 2010

Bush K and Jacboy G AAC 2010 Major families of β-lactamases of clinical importance

Extended-Spectrum β-Lactamases β-lactamases capable of conferring bacterial resistance to –the penicillins –first-, second-, and third-generation cephalosporins –aztreonam –(but not the cephamycins or carbapenems) These enzymes are derived from group 2b β- lactamases (TEM-1, TEM-2, and SHV-1) –differ from their progenitors by as few as one AA

CTX-M-type ESBLs Until 2000, most ESBL producers were hospital Klebsiella spp. with TEM and SHV mutant β-lactamases Now, the dominant ESBLs across most of Europe and Asia are CTX-M enzymes, which originated as genetic escapes from Kluyvera spp Currently recognized as the most widespread and threatening mechanism of antibiotic resistance, both in clinical and community settings –80% of ESBL-positive E. coli from bacteraemias in the UK and Ireland are resistant to fluoroquinolones –40% are resistant to gentamicin Livermore, DM J. Antimicrob. Chemother 2009

Carbapenemases Ability to hydrolyze penicillins, cephalosporins, monobactams, and carbapenems Resilient against inhibition by all commercially viable ß-lactamase inhibitors –Subgroup 2df: OXA (23 and 48) carbapenemases –Subgroup 2f : serine carbapenemases from molecular class A: GES and KPC –Subgroup 3b contains a smaller group of MBLs that preferentially hydrolyze carbapenems IMP and VIM enzymes that have appeared globally, most frequently in non-fermentative bacteria but also in Enterobacteriaceae

KPC (K. pneumoniae carbapenemase) KPCs are the most prevalent of this group of enzymes, found mostly on transferable plasmids in K. pneumoniae Substrate hydrolysis spectrum includes cephalosporins and carbapenems

Nordmann P et al. LID 2009 K. pneumoniae carbapenemase-producing bacteria

Bush K and Jacboy G AAC 2010 Major families of β-lactamases of clinical importance

AmpC β-lactamases Once expressed at high levels, confer resistance to many β-lactam antimicrobials (excluding cefepime and carbapenems) In E. coli, constitutive over expression of AmpC β-lactamases can occur because – of mutations in the promoter and/or attenuator region (AmpC hyperproducers) – the acquisition of a transferable ampC gene on a plasmid or other transferable elements (plasmid- mediated AmpC β-lactamases)

Emerging Metallo-β-Lactamases with Mobile Genetics (SENTRY Program )

Enterobacteriaceae: Breakpoints revised Agent CLSI 2009CLSI 2010 SIRSIR Cefazolin ≤8 16≥32 ≤1 2≥4 Cefotaxime ≤ ≥64 ≤1 2≥4 Ceftriaxone ≤ ≥64 ≤1 2≥4 Ceftazidime ≤8 16≥32 ≤4 8≥16 Aztreonam ≤8 16≥32 ≤4 8≥16 Cefipime ≤8 16≥32 ≤8 16≥32

Neisseria gonorrhoeae Wang SA et al. Ann Int Med 2008

Prevalence of and risk factors for quinolone- resistant Neisseria gonorrhoeae infection in Ontario Oto KV et al. CMAJ 2009

Treatment of N. gonorrhoeae Only current CDC-recommended options for treating N. gonorrhoeae infections are from a single class of antibiotics, the cephalosporins. –Ceftriaxone, available only as an injection, is the recommended treatment for all types of gonorrhea infections (i.e., urogenital, rectal, and pharyngeal). –Cefixime is the only oral agent recommended for treatment of uncomplicated urogenital or rectal gonorrhea Reduced susceptibility to cefixime being described in Japan and other countries

The Gram Positives Staphylococcus aureus –MRSA –Reduced-vancomycin susceptibility MRSA MDR Streptococcus pneumoniae

MRSA DeLeo and Chambers JCI 2009 adapted from Klevens et al. JAMA I2007

Worldwide Prevalance of MRSA Among S. aureus Isolates Grundmann H et al. Lancet 2006;368:874.

Community -Associated MRSA Sports participants Inmates in correctional facilities Military recruits Children in daycare Native Americans, Alaskan Natives, Pacific Islanders Men who have sex with men Hurricane evacuees in shelters Foal watchers Rural crystal methamphetamine users

MRSA Infections Among Patients In The Emergency Department Adult patients with acute, purulent skin and soft- tissue infections presenting to 11 University- affiliated EDs during August 2004 S. aureus was isolated from 320/422 patients 59% overall were MRSA (15% to 74%) 97% of MRSA were USA300 –74% were a single strain (USA ) 98% of MRSA had SCCmec type IV and the PVL toxin gene Moran GJ et al. NEJM 2006; 355:

Portland 54% Portland 54% Albuquerque 60% Albuquerque 60% Phoenix 60% Phoenix 60% Los Angeles 51% Los Angeles 51% New Orleans 67% New Orleans 67% Minneapolis 39% Minneapolis 39% Philadelphia 55% Philadelphia 55% New York 15% New York 15% Kansas City 74% Kansas City 74% Atlanta 72% Atlanta 72% Charlotte 68% Charlotte 68% MRSA Infections Among Patients In The Emergency Department Moran GJ et al. NEJM :

Chambers H

S. aureus resistant or with reduced susceptibility to vancomycin VRSA, VISA and hVISA

Streptococcus pneumoniae Most important pathogen in mild-to-moderate RTIs Greatest morbidity Greatest mortality

MMWR Feb Invasive Pneumococcal Disease in Children 5 Years After Conjugate Vaccine Introduction The overall incidence of IPD among children aged <5 years declined from 99 cases/100,000 during to 23 cases/100,000 in 2005

Impact of PCV7 Vaccination On NVT-IPD in Children <5 Years, USA ABCs data vs 1998/99.

Serotype distribution of S. pneumoniae isolated from invasive disease in children and adults (France: 2007) Dortet L et al. Diag Micro ID 2009

Multi-locus sequence typing of MDR serotype 19A isolates (n = 97) Pillai D et al. BMC Genomics 2009

Minimum spanning tree of MDR and non-MDDR serotype 19A Pillai D et al. BMC Genomics 2009

Emergence of a multidrug-resistant clone (ST320) among invasive serotype 19A pneumococci in Spain Distribution of penicillin-resistant serotype 19A isolates belonging to different clones throughout the study period. The bars indicate the proportion of each serotype 19A clone among penicillin-resistant pneumococci

S. pneumoniae Serotype 19A in Children, South Korea From 1991 through 2006, 538 strains of S. pneumoniae were obtained from various clinical specimens Choi EH et al. EID 2008

S. pneumoniae Serotype 19A in Children, South Korea Choi EH et al. EID 2008

Novel  -lactams –Ceftaroline –Ceftobiprole Oral penem –Faropenem Hebeisen P et al. Antimicrob Agents Chemother Sader HS et al. Antimicrob Agents Chemother Granizo JJ et al. Clin Ther Schurek KN et al. Expert Rev Anti Infect Ther

Spectrum of Activity Organism MIC 90 (  g/mL) CTLCBPFAR Pen-S   Pen-I Pen-R CTX-R*0.51ND ‡ Davies TA et al. ICAAC Sahm DF et al. ICAAC Van Bambeke F et al. Drugs McGee L et al; Morrissey I et al. ICAAC *Multiple mutations in PBP1a, 2b, and 2x. ‡ MIC 90 of 2 mg/L vs. cefuroxime-resistant strain

Clinical Utility ABxRouteIn vivo Efficacy Cross- Resistance Limitations CTLIVGood lung penetration in rabbit model None - all active against MDR strains Presumed or reported cross- hypersensitivity to  -lactams CBPIVEqual to CTX in murine model FARPOEradication of S. pneumoniae; NI to AMX  CLV, CPX Boswell FJ et al; Jones RN et al. J Antimicrob Chemother Azoulay- Dupuis E et al. Antimicrob Agents Chemother Echols R et al; Kowalsky S et al; Lentnek A et al; Drehobl M et al. ICAAC Jacqueline C et al; Young C et al; Rubino CM et al. ICAAC

Novel Glycopeptides Dalbavancin –Once weekly IV dosing Oritavancin Telavancin Versus vancomycin: –Additional mechanisms of action –Renal and hepatic excretion –No known nephrotoxicity or dose adjustments Malabarba A et al. J Antimicrob Chemother. 2005

Spectrum of Activity Organism MIC 90 (  g/mL) VANDAL* ‡ ORI* ‡ TEL* ‡ Pen-S Pen-NS MDRND Streit JM et al. Diag Micro Infect Dis Lin G et al. ICAAC Thornsberry C et al. ICAAC Draghi DC et al; Grover PK et al; Fritsche TR et al. ICAAC *Rapidly bactericidal ‡ Also active against macrolide- and FQ-resistant strains

Clinical Utility ABxRouteIn vivo Efficacy Cross- Resistance AEs DALIVAnimal model of PCN- resistant NBPP Partial with vancomycin; clinical significance unclear Redman syndrome with TEL; Rare  in platelets ORIIVHigh AUC:MIC ratios in ELF and plasma in murine NBPP TELIVGood penetration into ELF and AMs in human volunteers; Phase III trial pending Gotfried M et al. ICAAC Lehoux D et al. ICAAC

Novel Fluoroquinolone Garenoxacin (PO/IV) –Bactericidal –MIC 90 = 0.06  g/mL for penicillin-, macrolide-, and  6 drug- resistant S. pneumoniae –MIC 90 = 1  g/mL for CIP- and LEV- resistant S. pneumoniae –More potent than MOX Wu P et al. Antimicrob Agents Chemother Jones RN et al. Diag Micro Infect Dis

56 Polymyxins a group of polypeptide antibiotics that consists of 5 chemically different compounds (polymyxins A-E), were discovered in 1947 Only polymyxin B and polymyxin E (colistin) have been used in clinical practice the primary route of excretion is renal

57 Colistin The target of antimicrobial activity of colistin is the bacterial cell membrane Colistin has also potent anti-endotoxin activity –The endotoxin of G-N bacteria is the lipid A portion of LPS molecules, and colistin binds and neutralizes LPS

58 Colistin Active: –Acinetobacter species, –Pseudomonas aeruginosa, –Enterobacteriaciae

59 Colistin 160 mg (2 million IU) ever 8 h 240 mg (3 million IU) every 8 h for life- threatening infections

60 Colistin Dose adjustment for renal failure Adverse effects: –nephrotoxicity (acute tubular necrosis) –neurotoxicity (dizziness, weakness, facial paresthesia, vertigo, visual disturbances, confusion, ataxia, and neuromuscular blockade, which can lead to respiratory failure or apnea)

61 MIC distribution MIC break point to identify bacteria susceptible to colistimethate sodium is ≤4 mg/L. MIC is >8 mg/L should be considered resistant

62 Use of Parenteral Colistin for the Treatment of Serious Infection Due to Antimicrobial-Resistant P. aeruginosa Colistin was used as salvage therapy for 23 critically ill patients with multidrug-resistant P. aeruginosa infection –Peumonia (n = 18) –Intra-abdominal infection (n = 5). Colistin was administered for a median of 17 days (range, 7-36 days). A favorable clinical response was observed in 14 patients (61%); only 3 patients experienced relapse Linden et al CID 2003

Safety and effectiveness of colistin compared with tobramycin for MDR A. baumannii infections A retrospective cohort study of patients treated with colistin or tobramycin for A. baumannii infections in ICUs 240 mg (3 MUs) 8 hourly and adjusted for renal failure 32 patients, with similar admission APACHE scores and serum creatinine, were treated with each antimicrobial 63 Gounden R et al. BMC Infect Dis 2009

Safety and effectiveness of colistin compared with tobramycin for MDR A. baumannii infections There were no significant differences between the colistin and tobramycin groups in –ICU mortality (p = 0.54) –Nephrotoxicity (p = 0.67) –Change in creatinine from baseline to highest subsequent value (p = 0.11) –Time to microbiological clearance (p = 0.75) 64 Gounden R et al. BMC Infect Dis 2009

Ceftobiprole (Zeftera ® ) June 30, Health Canada has authorised the marketing of ceftobiprole medocaril for injection (Zeftera and marketed by Janssen Ortho ) for the treatment of complicated skin and soft tissue infections including diabetic foot infections

Ceftobiprole in vitro Activity vs Staphylococci Sahm DF et al. Poster E-0113 presented at the 46 th ICAAC; Sept , 2006; San Francisco, CA. In vitro activity does not necessarily correlate with clinical results. Staphylococci Tested# Isolates MIC Range (μg/ml) MIC 90 (μg/ml) S. aureus1773< OSSA498< ORSA1275< CoNS617< Oxacillin-susceptible162< Oxacillin-resistant455<

Ceftobiprole in vitro Activity vs Streptococci and Enterococci OrganismTotalMIC Range (μg/ml) MIC 90 (μg/ml) E. faecalis 1, >32 4 Vanco-R E. faecalis 3 17<0.015 – 41 E. faecium Amp-S Amp-R 1, >32>32 S. pneumoniae Pen-S Pen-I0.008 – Pen-R Hebeisen P et al. Antimicrob Agents Chemother 2001;45: Jones RN et al. J Antimicrob Chemother 2002;50: Arias Antimicrob Agents Chemother 2007; 51(6): ; 4. Kosowska et al. Antimicrob Agents Chemother 2005;49: In vitro activity does not necessarily correlate with clinical results

Ceftobiprole in vitro Activity vs Gram-Negatives Pathogen E. coli E. coli (ESBL+) K. pneumoniae K. pneumoniae (ESBL+) S. marcescens P. mirabilis E. cloacae E. aerogenes Citrobacter species Total MIC Range (  g/ml) > >32 < MIC 90 (  g/ml) 0.06 > > or > Brown NP et al. Poster E-0112, presented at 46th ICAAC, Sept, 2006; San Francisco, CA; 2. Hebeisen P et al. Antimicrob Agents Chemother 2001;45: ; 3. Issa NC et al. Diagn Micro Infect Dis 2004; 4. Jones R et al. J Antimicrob Chemother 2002; 50: In vitro activity does not necessarily correlate with clinical results.

Comparative in vitro activity vs P. aeruginosa (n=403) Antimicrobial agent MIC 50 (  g/ml) MIC 90 (  g/ml) MIC Range (  g/ml) Ceftobiprole >32 Ceftazidime >32 Cefepime –>32 Piperacillin- Tazobactam 16> >128 Brown NP et al. Poster E-0112, presented at 46th ICAAC, Sept, 2006; San Francisco, CA In vitro activity does not necessarily correlate with clinical results.

Daptomycin (Cubicin ® ) On September 24, 2007, Health Canada approved daptomycin intravenous infusion (Cubicin, Cubist Pharmaceuticals, Inc, and marketed by Oryx Pharmaceuticals, Inc) for the treatment of complicated skin and skin structure infections caused by certain gram-positive infections and for bloodstream infections, including right-sided infective endocarditis, caused by S. aureus.

Daptomycin (Cubicin ® ) New drug class (lipopeptide) Rapidly bactericidal New mechanism of action: acts by binding to cell membrane and disrupting the cell membrane potential No cross resistance Dose: 4-6 mg/kg once daily

Daptomycin’s Mechanism of Action Irreversibly binds to cell membrane of Gram- positive bacteria –Calcium-dependent membrane insertion of molecule Rapidly depolarizes the cell membrane –Efflux of potassium –Destroys ion-concentration gradient

Daptomycin In Vitro* Antimicrobial Activity Against Other Gram-positive Organisms Daptomycin MIC Values (µg/mL) OrganismNRangeMIC 50 MIC 90 E. faecalis (VR-strains) – E. faecalis (VS-strains) 917 ≤0.06 – E. faecium (incl. VR-strains) – 4 24 S. epidermidis (incl. MR- strains) – 10.5 MIC=minimum inhibitory concentration; C. jeukium=Corynebactrium jeikeium; E.faecalis=Enterococcus faecalis; S.epidermidis=Streptococcus epidermidis; S. haemolyticus=Staphylococcus haemolyticus; S. dysgalactiae=Streptococcus dysgalactiae; VR=vancomycin resistant; VS=vancomycin susceptible *The clinical significance of in vitro data has not been established. CUBICIN ® Product Monograph September 2007.

Daptomycin Favorable initial trials in skin and soft tissue infections with qd dosing; significantly less need for step-down oral therapy (4 mg/kg) Less effective than ceftriaxone in community- acquired pneumonia (CAP) Bacteremia and endocarditis studies with larger single daily dose (6 mg/kg)