Difficult to Treat Bacterial Infections: Have we reached a Dead End?

Transcription

1 Difficult to Treat Bacterial Infections: Have we reached a Dead End? Dr. George M. Varghese MD, DNB, DTMH, FRCP, FIDSA Department of Infectious Diseases Christian Medical College, Vellore, India

2 Outline Bacteria well evolved for survival & lessens learned from history Difficulty in treating due to inability in establishing the diagnosis MDR gram negatives & treatment options Will not discuss: Difficult to eradiate infections eg. biofilm related Immunologically protected sites Immuno-compromised

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5 Bugs versus Drugs (and Humans) The human body has human cells and bacteria! Bacteria are the dominant species on the earth Rapid multiplication rate Natural mutation rate Ability to transfer or move genes via plasmids, transposons etc. Collectively, these properties allow bacteria to survive, change, and eventually flourish under intense selective pressure

6 Search for a Magic bullet Paul Ehrlich ( ) German bacteriologist Father of Chemotherapy Powerful weapon Precise target Selective destruction

7 Discovery of Penicillin Penicillium notatum

8 The Prophecy Dec 11, 1945: There is the danger that the ignorant man may easily underdose himself and by exposing his microbes to non lethal quantities of the drug make them resistant

9 Antibiotic Resistance & Evolution PRP VRE VISA MRSA ESBL MBL VRSA β-lactams Penicillin 3rd gen cephalosporin Vancomycin Carbapenem Emergence Spread Vancomycin and teicoplanin Vancomycin and teicoplanin

10 Lechuguilla caves, New Mexico: National Geographic, April 2012

11 Duration of Evolution 3.85 billion years old: bacteria 210 million years old: mammals 60 million years old: human-like mammals 30 million years old: monkeys 0.2 million years old: Neanderthals million years old: Homo sapiens 70 years old: antibiotics

12 Inability to Establish the Diagnosis 49 year-old lady, a renal allograft recipient 7 years ago; on maintenance immunosupp-pred/tac/mmf 3 months history of Fever, headache & vomiting Reported to have recurrent infections for 1 year: initially UTI, then elbow abscess few months ago 2 months ago she was diagnosed to have bacterial meningitis: CSF analysis showed WBC: 1500 (P97, L3) Glucose: 4 mg/dl, protein: 160mg/dl Cultures - negative

13 Evaluation continued Treated with meropenem for 4 weeks Asymptomatic for 2 weeks; recurrence of symptoms again; restarted on meropenem O/E: GCS 14/15; meningeal signs + CSF analysis: WBC: 30 (P24, L71, M5) Glucose: 31mg/dl, protein: 120mg/dl Culture (bacterial, mycobacterial & fungal): no growth; & Xpert: negative MRI brain: small area of chronic haemorrhage in the inferior cerebellar hemisphere Meropenem completed 2weeks and stopped. Started on ATT Worsening of symptoms in 1 week

14 Evaluation continued Repeat CSF analysis: WBC: 690 (P90, L6, M4) Glucose: 19mg/dl, protein: 178mg/dl Culture: no growth

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16 MDR Gram Negatives ESBL E coli Klebsiella spp. Carbapenem resistance Klebsiella spp. P aeruginosa Acinetobacter baumannii

17 MDR Gram Negatives & Clinical Outcome Limited treatment options Higher mortality rate Longer hospital stay Increased cost

18 Carbapenemases Classification Enzyme Most Common Bacteria Group A Group B (metallo-βlactamse) KPC, SME, IMI, NMC, GES NDM 1 IMP, VIM, GIM, SPM Enterobacteriaceae Enterobacteriaceae P. aeruginosa Acinetobacter spp. Group D OXA Acinetobacter spp. Klbsiella pneumoniae

19 Drugs potentially active against Carbapenamase producers Colistin Tigecycline Fosfomycin Combination therapy

20 Colistin An old drug used in 1950s a.k.a. Polymyxin E, colistimethate sodium Now being used with increasing frequency due to necessity (multidrug resistant Gram-negatives) Risk of neurotoxicity and nephrotoxicity Spectrum of activity Pseudomonas aeruginosa, Acinetobacter spp. E. Coli, Klebsiella, Enterobacter spp. Citrobacter spp, Hemophilus spp. Dose: 9 MIU loading followed by 4.5 MIU Q12H

21 First glycylcycline Tigecycline Structural analogue of minocycline Binds to the 30S subunit of bacterial ribosomes & inhibits protein synthesis Broad spectrum of activity against VRE, MRSA, ESBL+ Enterobacteriaceae, anaerobes No activity against Pseudomonas, Proteus, Providentia Higher dose for critically ill MDR gram neg: 200 mg loading, followed by 100 mg Q12h

22 Colistin + Carbapenems Colistin acts by increasing the permeability of the cell membrane and thus could act synergistically with other antimicrobial agents by facilitating their entrance into the bacterial cell. 1 The mechanism of the observed in vitro synergy is unknown but may relate to high levels of MER entering the bacterial cell via cell membrane disruption by PB 2 1. Kasiakao SK et al. ANTIMICROBIAL AGENTS AND CHEMOTHERAPY, Aug. 2005, p Pankey GA et al. Diagnos3c Microbiology and Infec3ous Disease 63 (2009)

23 Combination Therapy for MDR-Gram Negatives Reference Regimen N Pathogens Outcome Kontopido etal Clin Micr Inf 2014 Monotherapy (Colistin, aminoglycoside, tigecycline) vs. combinations 127 Klebsiella KPC (ICU) Mortality colistin 23.1%; aminoglycoside 22.7%; tigecycline 31.3%; tigecycline+aminoglycosides, 18.1% ; colistin+aminoglycosides, 11.7% ; colistin+tigecycline, 44.4% Qureshi etal Clin Micr Inf 2012 Monotherapy vs. combinations (colistin or tigecycline + carbapenem) 41 Klebsiella KPC Mortality 57.8% vs. 13.3% Tumberello et CID 2012 Zarkotou etal CMID 2012 Monotherapy vs combinations 125 Klebsiella KPC Mortality 54.3% vs. 34.1% Monotherapy vs. combinations (colistin + tigecycline or tigecycline + gentamicin) 53 Klebsiella KPC Mortality 47 vs 0% Batirel etal EJCMID 2014 Colistin monotherapy (N=36) vs. combination (N=214) 250 XDR A. baumannii Mortality 72 vs. 52% microbiological eradication 56 vs. 80% Daikos etal AAAC 2009 Colistin monotherapy (N=37) vs. combination with carbapenem or aminoglycosides (N=12) 67 Klebsiella MBL Mortality 27 vs. 8.3% D-Mangoni CID 2013 Colistin monotherapy vs. colistin + rifampin 210 XDR A. Baumannii Microbiological eradication 45 vs. 61%

24 New Antibiotics for MDR Gram Negatives Antimicrobial class Compound Carbapenemase activity Indications Aminoglycoside Plazomicin Yes IAIs and UTIs Beta-lactam + betalactamase inhibitor Ceftozolane/tazobactam Ceftazidime/avibactam Ceftaroline/avibactam Aztreonam/avibactam Relebactam/imipenem RPX7009/meropenem No (anti-pseudomonal) Possible(KPC,OXA) Possible (KPC) Yes (NDM1, KPC) Possible (KPC, Amp-C) Yes UTIs, IAIs, HAP, VAP ciais, cutis, HAP and VAP cutis Phase I ciais and cutis cutis Carbapenem Biopenem Doripenem Panipenem Razupenem Tebipenem Tomopenem No No No No No No RTIs, UTIs UTIs, IAIs, HAP, VAP HAP, UTIs SSSI RTIs SSSI and HAP Cephalosporin Ceftobiprole Ceftaroline No No SSTI, HAP, CAP SSSI, CAP Quinolone Delafloxacin Finafloxacin No No SSSI CAP Tetracycline Eravacycline Omadacycline Yes (Acinitobacter) No IAIs and UTIs SSSTI

25 De-escalation Starting with a broad-spectrum empiric therapy regimen (to avoid inappropriate therapy), combined with a commitment to: Change from broad- to narrow-spectrum therapy Reduce duration of therapy Stop therapy in selected patients, as dictated by the patient s clinical response & culture results Culture data are used to narrow, focus or even stop therapy

26 P = Mortality % De-escalated (n=88) No Change (n=245) Escalated (n=61) Kollef MH et al. Chest 2006;129:

27 The Clinician s Dilemma Avoid emergence of multidrug-resistant micro-organisms Immediate treatment of patients with serious sepsis Objective 1 Objective 2

28 Difficult to Treat Bacterial Infections: Have we reached a Dead End?

29 Take-home Messages Number of bacteria in the human body outnumber our own cells Bacteria have well evolved mechanisms to resist adverse conditions Establishing the diagnosis is crucial Important to follow the rational approach in management of gram negative infections Use antibiotics judiciously

30 Thank you