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Difficult to Treat Bacterial Infections: Have We Reached a “Dead End”?

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Difficult to Treat Bacterial Infections: Have We Reached a “Dead End”? 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 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 Bugs versus Drugs (and Humans) • The human body has 1013 human cells and 1014 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 Search for a Magic bullet • Paul Ehrlich (1854 – 1915) • German bacteriologist • Father of Chemotherapy • Powerful weapon • Precise target • Selective destruction Discovery of Penicillin - 1928 • Penicillium notatum 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” Antibiotic Resistance & Evolution PRP VRE VISA MRSA ESBL MBL VRSA 1961 1967 1983 1986 1988 1996 2002 Vancomycin Penicillin Vancomycin and teicoplanin 3rd gen Vancomycin β-lactams Carbapenem cephalosporin and teicoplanin Emergence → Spread Lechuguilla caves, New Mexico: National Geographic, April 2012 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 • 0.125 million years old: Homo sapiens • 70 years old: antibiotics 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 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 Evaluation continued • Repeat CSF analysis: – WBC: 690 (P90, L6, M4) – Glucose: 19mg/dl, protein: 178mg/dl – Culture: no growth MDR Gram Negatives • ESBL – E coli – Klebsiella spp. • Carbapenem resistance – Klebsiella spp. – P aeruginosa – Acinetobacter baumannii MDR Gram Negatives & Clinical Outcome • Limited treatment options • Higher mortality rate • Longer hospital stay • Increased cost Carbapenemases Classification Enzyme Most Common Bacteria Group A KPC, SME, Enterobacteriaceae IMI, NMC, GES Group B NDM 1 Enterobacteriaceae (metallo-β- IMP, VIM, P. aeruginosa lactamse) GIM, SPM Acinetobacter spp. Group D OXA Acinetobacter spp. Klbsiella pneumoniae Drugs potentially active against Carbapenamase producers • Colistin • Tigecycline • Fosfomycin • Combination therapy 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 Tigecycline • First glycylcycline • 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 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 PB2 1. Kasiakao SK et al. ANTIMICROBIAL AGENTS AND CHEMOTHERAPY, Aug. 2005, p. 3136–3146 2. Pankey GA et al. Diagnos3c Microbiology and Infec3ous Disease 63 (2009) 228–232 Combination Therapy for MDR-Gram Negatives Reference Regimen N Pathogens Outcome Kontopido etal Monotherapy (Colistin, 127 Klebsiella KPC Mortality colistin 23.1%; aminoglycoside Clin Micr Inf aminoglycoside, (ICU) 22.7%; tigecycline 31.3%; 2014 tigecycline) vs. tigecycline+aminoglycosides, combinations 18.1% ; colistin+aminoglycosides, 11.7% ; colistin+tigecycline, 44.4% Qureshi etal Monotherapy vs. combinations 41 Klebsiella KPC Mortality 57.8% vs. 13.3% Clin Micr Inf (colistin or tigecycline + 2012 carbapenem) Tumberello et Monotherapy vs combinations 125 Klebsiella KPC Mortality 54.3% vs. 34.1% CID 2012 Zarkotou etal Monotherapy vs. combinations 53 Klebsiella KPC Mortality 47 vs 0% CMID 2012 (colistin + tigecycline or tigecycline + gentamicin) Batirel etal Colistin monotherapy (N=36) 250 XDR A. Mortality 72 vs. 52% microbiological EJCMID 2014 vs. combination (N=214) baumannii eradication 56 vs. 80% Daikos etal Colistin monotherapy (N=37) 67 Klebsiella MBL Mortality 27 vs. 8.3% AAAC 2009 vs. combination with carbapenem or aminoglycosides (N=12) D-Mangoni Colistin monotherapy vs. 210 XDR A. Microbiological eradication 45 vs. 61% CID 2013 colistin + rifampin Baumannii New Antibiotics for MDR Gram Negatives Antimicrobial Compound Carbapenemase Indications class activity Aminoglycoside Plazomicin Yes IAIs and UTIs Beta-lactam + beta- Ceftozolane/tazobactam No (anti-Pseudomonal) UTIs, IAIs, HAP, VAP lactamase inhibitor Ceftazidime/avibactam Possible(KPC,OXA) cIAIs, cUTIs, HAP and VAP Ceftaroline/avibactam Possible (KPC) cUTIs Aztreonam/avibactam Yes (NDM1, KPC) Phase I Relebactam/imipenem Possible (KPC, Amp-C) cIAIs and cUTIs RPX7009/meropenem Yes cUTIs Carbapenem Biopenem No RTIs, UTIs Doripenem No UTIs, IAIs, HAP, VAP Panipenem No HAP, UTIs Razupenem No SSSI Tebipenem No RTIs Tomopenem No SSSI and HAP Cephalosporin Ceftobiprole No SSTI, HAP, CAP Ceftaroline No SSSI, CAP Quinolone Delafloxacin No SSSI Finafloxacin No CAP Tetracycline Eravacycline Yes (Acinitobacter) IAIs and UTIs Omadacycline No SSSTI 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 50 P = 0.001 45 42.6 40 35 30 23.7 25 20 17.0 Mortality % Mortality 15 10 5 0 De-escalated No Change Escalated (n=88) (n=245) (n=61) Kollef MH et al. Chest 2006;129:1210-1218 The Clinician’s Dilemma Avoid emergence of multidrug-resistant micro-organisms Immediate treatment of patients with serious sepsis Objective 1 Objective 2 Difficult to Treat Bacterial Infections: Have we reached a Dead End? 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 Thank you .
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