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16S Ribosomal Methylation: Emerging Aminoglycoside Resistance

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16S Ribosomal Methylation: Emerging Aminoglycoside Resistance Yohei Doi, MD, PhD Division of Infectious Diseases University of Pittsburgh School of Medicine Background on aminoglycosides Resistance mechanisms New aminoglycosides Streptomycin, produced by a species of Streptomyces, was the first aminoglycoside discovered All subsequent aminoglycosides were derived from Streptomyces spp. (-mycin) or from Micromonospora spp. (-micin) Active against various groups of bacteria . Not active against anaerobes Mandell: Mandell, Douglas, and Bennett's Principles and Practice of Infectious Diseases, 7th ed. Amino-glycoside amino-containing or non- amino-containing sugars six-membered ring with amino group substituents = aminocyclitol kanamycin Generic Name Source Year Reported Streptomycin Streptomyces griseus 1944 Neomycin Streptomyces fradiae 1949 Kanamycin Streptomyces kanamyceticus 1957 Paromomycin Streptomyces fradiae 1959 Gentamicin Micromonospora purpurea and Micromonospora echinospora 1963 Tobramycin Streptomyces tenebrarius 1967 Amikacin Streptomyces kanamyceticus 1972 Netilmicin Micromonospora inyoensis 1975 Spectinomycin Streptomyces spectabilis 1961 Sisomicin Micromonospora inyoensis 1970 Dibekacin Streptomyces kanamyceticus 1971 Isepamicin Micromonospora purpurea 1978 Mandell: Mandell, Douglas, and Bennett's Principles and Practice of Infectious Diseases, 7th ed. Aminoglycosides are used for treatment of various conditions: . Streptomycin – tuberculosis . Paromomycin – cryptosporidiosis, amoebiasis, leishmaniasis . Spectinomycin – gonorrhea . Gentamicin/streptomycin – synergy with β-lactams for Enterococcus spp. Gram-negative bacilli (GNB), including Pseudomonas aeruginosa Toxicity: nephrotoxicity, ototoxicity Safer alternatives for GNB infections (β-lactams, fluoroquinolones) have limited the use of aminoglycosides Nonetheless, aminoglycosides continue to play an important role in the management of serious infections caused by GNBs: . In combination with broad-spectrum β-lactams for “empiric” therapy . For organisms resistant to all other antimicrobial agents Three aminoglycosides are used systemically worldwide: . Gentamicin . Tobramycin . Amikacin They are all “4,6-disubstituted deoxystreptamines” 4 6 4,6-disubstituted deoxystreptamines On the other hand, the use of “4,5-disubstituted deoxystreptamines” is limited due to higher toxicity . Neomycin . Paromomycin 4,5-disubstituted deoxystreptamines Aminoglycosides bind specifically to the aminoacyl site (A- site) of 16S ribosomal RNA within the prokaryotic 30S ribosomal subunits Interfere with protein synthesis by inducing mistranslation Yusupov MM, et al. Science 2001;292:883-96 Mutation of the 16S rRNA or ribosomal proteins Reduced permeability Export by efflux pumps Enzymatic inactivation . The most common Post-transcriptional methylation of 16S rRNA . The most broad-spectrum Ramirez MS, et al. Drug Resist Updat 2010;13:151-71 Enzymatic inactivation is mediated by 3 classes of aminoglycoside-modifying enzymes (AMEs): . Acetyltransferases (AACs) . Nucleotidyltransferases (ANTs or AADs) . Phosphotransferases (APHs) Ramirez MS, et al. Drug Resist Updat 2010;13:151-71 AMEs catalyze modification at −OH or −NH2 groups: Ramirez MS, et al. Drug Resist Updat 2010;13:151-71 Resistance phenotypes of AMEs are substrate-specific: Gm Siso Tob Amk Dbk Ntl Neo Sm Phospho- APH(3’)-Ia R S S S S S R S transferases (APHs) APH(3’)-VIa S S S S S S R S AAC(3)-Ia R R S S S S S S Acetyltransferases AAC(3)-IIa R R R S R R S S (AACs) AAC(6’)-Ib S R R R R R S S Nucleotidyl- ANT(2”)-Ia R R R S R S S S transferases (ANTs/AADs) ANT(3”)-Ia S S S S S S S R Shaw KJ, et al. Microbiol Rev 1993; 57:138–63 However, production of multiple AMEs may lead to resistance to all aminoglycosides Further modifications have been made to generate aminoglycosides resistant to the effect of multiple AMEs . Arbekacin . Plazomicin A derivative of dibekacin, first synthesized in 1973 Demonstrates a broad spectrum of activity against Gram- positives and Gram-negatives, including those resistant to existing aminoglycosides Approved for treatment of MRSA infection in Japan and several other countries Arbekacin is a derivative of dibekacin, which is a derivative of kanamycin B APH(3’) APH(2”) AAC(6’) Arbekacin has good activity against P. aeruginosa Fujimura S, et al. Japanese Journal of Chemotherapy, 2009 And A. baumannii Zapor MJ, et al. Antimicrob Agents Chemother 2010;54:3015-7 Adverse effects: . Nephrotoxicity . Ototoxicity Comparable to other intravenous aminoglycosides Currently in clinical trial at Walter Reed National Military Medical Center (NCT01659515) . Bacterial infection of the respiratory tract, bloodstream, skin, soft tissue, bone, or genitourinary tract . Caused by MDR, ESBL-producing, carbapenemase-producing, cephalosporin-resistant Gram-negative bacteria, or . Caused by MRSA, VRE, VISA/VRSA . Arbekacin MIC of ≤4 mg/L Also, a nebulized formulation is moving to Phase I for ventilator-associated and hospital-acquired bacterial pneumonia A derivative of sisomicin Demonstrates a broad spectrum of activity against Gram- positives and Gram-negatives Hydroxylethyl substituent Hydroxyl-aminobutyric acid substituent Armstrong ES and Miller GH. Curr Opin Microbiol 2010;13:565-73 Armstrong ES and Miller GH. Curr Opin Microbiol 2010;13:565-73 Armstrong ES and Miller GH. Curr Opin Microbiol 2010;13:565-73 Tobramycin Amikacin Plazomicin Gentamicin Endimiani A, et al. Antimicrob Agents Chemother 2009;53:4504--7 Phase I . Randomized, double-blind, placebo-controlled trials in healthy subjects . Pharmacokinetics, safety, tolerability . Linear and dose-proportional PK . AUC0-24 = 239 ± 45h*mg/L, Cmax = 113 ± 17 mg/L, t1/2 = 3 ± 0.3 h, Vss = 0.24 ± 0.04 L/kg at 15 mg/kg, day 5 dose . No evidence of nephrotoxicity or ototoxicity Cass RT, et al. Antimicrob Agents Chemothr 2011;55:5874-80 Phase I – lung penetration . Randomized, double-blind, placebo-controlled trial in healthy subjects . Once daily for 5 days; 10.7 mg/kg or 15 mg/kg . Lung penetration of plazomicin (the ratio of ELF to plasma AUC) was approximately 13% ECCMID 2013; abstract P1637 Phase II . Randomized, double-blind, comparator (levofloxacin)-controlled trial in complicated UTI and acute pyelonephritis patients . Safety, efficacy . Comparable clinical and microbiological efficacy . One plazomicin patient had mild unilateral permanent tinnitus; another plazomicin patient had prolonged elevation of serum creatinine ICAAC 2012; abstract L2-2118a Phase III . A multicenter, international, randomized, assessor-blinded, active comparator-controlled study . Bloodstream infections (BSI) and nosocomial pneumonia due to CRE . Superiority of a plazomicin-based regimen compared with a colistin- based regimen in all-cause 28-day mortality The activity of both arbekacin and plazomicin is lost when a strain produces an 16S ribosomal RNA methyltransferase (16S-RMTase) Wachino J, et al. Drug Resist Updat 2012;15:133-48 An example of disk testing result for E. coli producing RmtD . amikacin, tobramycin, gentamicin and arbekacin amikacin tobramycin arbekacin gentamicin 16S-RMTases now have global distribution: Wachino J, et al. Drug Resist Updat 2012;15:133-48 The combination of carbapenemase and 16S-RMTase is increasingly encountered Combinations that have been reported: . NDM-1 MBL + ArmA/RmtB/RmtC . OXA-23 carbapenemase + ArmA . VIM-1/2 MBL+ ArmA/RmtB . IMP-1 MBL + ArmA . KPC + ArmA/RmtD . SPM-1 MBL + RmtD Still rare among KPC-producing K. pneumoniae The use of aminoglycosides have been limited by resistance due to production of aminoglycoside modifying enzymes The new generation of aminoglycosides, designed to resist AMEs, hold promise as treatment options against highly-resistant Gram-negative infections . In combination with another agent . Bloodstream infections (BSI) and nosocomial pneumonia due to carbapenem-resistant Enterobacteriaceae University of Pittsburgh Funding agencies . Lee Harrison . National Institutes of Health . Jessica O’Hara . Agency for Healthcare Research . Jesabel Rivera and Quality . Pennsylvania Department of Instituto Adolfo Lutz Health . Doroti Oliveira de Garcia . Maria Fernanda Bueno . Gabriela Francisco Nagoya University . Yoshichika Arakawa . Jun-ichi Wachino .
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