2012 Bugs and Drugs Update

Transcription

1 Objectives 2012 Bugs and Drugs Update Lindsay Schray, PharmD NICU Clinical Specialist Nationwide Children s At the end of this presentation the audience member should be able to: List pathogenic bacteria seen with necrotizing enterocolitis (NEC) infections Review the antibiotic susceptibilities for common causative bacteria across various regions for NEC Describe current management, treatment and prophylactic regimens for NEC Plan of Attack Antimicrobial Resistance Overview of bacterial resistance Trends in bacterial resistance Antibiotic options: what s old is new again Focus on necrotizing enterocolitis Mechanisms of resistance Drug inactivation or modification β-lactamases Alteration of target site Changes to penicillin-binding proteins Alteration of metabolic pathways Reduced drug accumulation Decreased permeability Efflux pumps Peleg AY, Hooper DC. N Engl J Med. 2010;362: Antimicrobial Resistance Bacterial Resistance is on the Rise There is no SPACE to ESKAPE Serratia Pseudomonas Acinetobacter Citrobacter Enterobacter Enterococcus Staphylococcus (aureus) Klebsiella Acinetobacter Pseudomonas Enterobacter Boucher HW et al. CID. 2009;48(1):

2 S.P.A.C.E. Troublesome Beta-lactamases Emerging resistance during antimicrobial therapy Double antimicrobial coverage Can produce a beta-lactamase Mutants produce large quantities of beta-lactamase Mutants occur at a frequency 1 in in 10 8 Most micro labs detect at Resistant mutants may not be detected Enterobacteriaceae (GI bugs) Klebsiellaspp., Enterobacter spp., E.coli Extended-spectrum beta-lactamases (ESBLs) Hydrolyzes Penicillins Aztreonam Cephalosporins (1 st, 2 nd, 3 rd, and ~4 th generations) Cefoxitin (Cephamycins), carbapenems, beta-lactamase inhibitor combinations usually remain active Clavulanic acid, tazobactam, or sulbactam Perez F. Curr Opin Pharmcol. 2007;7(5): Troublesome Beta-lactamases Rates of Resistance in Moms Amp-C Hydrolyzes Penicillins Aztreonam Cephalosporins (1st, 2nd, 3 rd and ~4 th generations) Cefoxitin Beta-lactamase inhibitor combinations Carbapenems usually remain active Klebsiella pneumoniae carbapenemases (KPCs) Hydrolyze all above antimicrobial classes including carbapenems Jacoby GA. Clin Microbiol Rev. 2009;22(1): Anderson KF et al. J Clin Microbiol. 2007;45: Investigation of multi-resistant gram-negative bacteria occurrence in routine antenatal urine screens Wickramasinghe N, et al. Arch Dis Child Fetal Neonatal Ed. 2012;97(3):F234. Why does this matter to us? Antibiotic Options Birmingham (UK) team isolated gentamicin-resistant and ESBLproducing Enterobacteriaceae in 14 and 8 of 1277 neonatal admissions Case report of Amp-C E.coli meningitis in 33 weeker Antimicrobial stewardship to help reduce resistance rates Using knowledge of pharmacodynamics/kinetics to optimize drug concentrations Continuous infusions (Beta-lactams, vancomycin) Wickramasinghe N, et al. Arch Dis Child Fetal Neonatal Ed. 2012;97(3):F234. Fakioglu E, et al. J Perinatol. 2006;26(8): Patel AD, et al. Arch Dis Child 2012;97:e20. 2

3 Antibiotic Options Lack of new agents for gram-negative coverage ~5 th generation Cephalosporins Ceftaroline MRSA and broad gram-negative coverage (+/- Pseudomonas) Ceftobiprole MRSA and broad gram-negative coverage including Pseudomonas coverage No neonatal data yet Trials in recruitment phase May also be hydrolyzed by ESBLs Not for sole coverage Antibiotic Options Colistimethate Oldie but (not so?) goody Coly-Mycin M [US] colistimethate colistin methanesulfate colistin sulfomethate Colomycin [UK] Jajoo M, et al. Pediatr Infect Dis J Mar;30(3): Colistin Colistin Mechanism of Action Pro-drug Inactive Active Colistimethate (CMS) Colistin Colistin Mechanism of Action Colistin Mechanism of Action Ca 2+ Ca 2+ Ca 2+ Ca 2+ Ca 2+ Disrupted Cell Membrane Before Colistin After Colistin Indian J Crit Care Med2009;13:

4 Spectrum of Activity Pharmacokinetics/Dynamics Multi-drug resistant gram-negative bacilli SPACE bugs Pseudomonas [e.g. P. aeruginosa] Acinetobacter[e.g. A. baumannii] Citrobacter [e.g. C. freundii] Enterobacter[e.g. E. aerogenes] GI bugs E. coli K. pneumoniae Owen and Colleagues Possible post antibiotic effect Owen, et al. J Antimicrob Chemother 2007;59: FDA Approved Indications Adverse Effects Susceptible gram-negative infections in neonates, infants, children, adolescents and adults P. aeruginosa E. aerogenes E. coli K. pneumoniae Neonatal dosing IM, IV: 2.5-5mg/kg/DAY divided q8h Can be given by inhaled route in older patients 75mg INH q12h Adjust for renal impairment (both dose and frequency) Nephrotoxicity Dose/duration related Caution use in renal impairment Neurotoxicity Paresthesias, numbness of extremities Pruritus, vertigo, dizziness, slurred speech Respiratory depression, failure Ototoxicity Clin Microbiol Infect 2008;21(3): Hosp Pharm 2007;42(12): Arch Dis Child 2001;84: BMC Infect Dis 2005;5:1-8. Colistin Dosing Issues Haven t We Got Anything Better? Dosed based on estimate of ideal body weight IBW (kg) = [length 2 (in cm) x 1.65]/1000 American System for Coly-Mycin M Labeled as mg of colistin base activity 150 mg of colistin base per vial European System for Colomycin Labeled as international units of colistimethate (CMS) Makes literature sifting difficult Increased incidence of multi-drug resistant gram-negative infections Lack of new antimicrobial options for multi-drug resistant gram-negative infections Increasing critical drug shortages Amikacin Gentamicin Piperacillin/tazobactam (Zosyn ) Increased understanding of product stability, kinetics, and appropriate dosing Traub SL, Kichen L. Am J Hosp Pharm. 1983,40(1): Jajoo M, et al. Pediatr Infect Dis J Mar;30(3): Am J Health-Syst Pharm 2007;64:

5 Clinical Efficacy and Safety Eighteen critically sick neonates, 21 courses 10 term and 8 preterm (26-39 weeks GA) Multi-drug resistant A. baumannii, K. pneumoniae, P. aeruginosa, and Enterobacter spp. Doses ranged from 50,000 to 75,000 IU/kg/DAY divided q8h (4-6mg/kg/DAY colistin base) Pneumonia, bacteremia, meningitis Favorable clinical outcomes in 17 of 21 (76%) Increase in serum creatinine by > 0.5 mg/dl above baseline in 2 of 21 (9%) Jajoo M, et al. Pediatr Infect Dis J Mar;30(3): Pathophysiology Poorly understood and multiple factors involved Mucosal injury possibly due to: Immature motility and digestion Immature intestinal circulatory regulation Immature barrier function Inflammatory mediators Immature immunity Abnormal bacterial colonization Mortality rate up to 50% Risk factors Prematurity Perinatal asphyxia Respiratory distress syndrome Cyanotic heart disease Bacterial infection Enteral nutrition Vasconstricting medications (indomethacin) Berrington JE, et al. J Pediatr. 2012;160(1): Suspected bacterial pathogens Gram positive CONS Gram negative Escherichia coli Klebsiella pneumoniae Pseudomonas Anaerobes (if perforation?) Bacteroides fragilis Culture data in NEC Documented bacteremia in few cases < 20% in most reports Trends in neonatal bacteremia E.coli Group B Streptococcus (GBS) Staphylococcus aureus Klebsiella pneumoniae and other enterobacteriacea Pseudomonas Greenhow TL,et al. Pediatrics. 2012;129(3):e

6 Culture data in NEC Common treatments Medical Bowel rest (NPO) Nasogastric suction Systemic antibiotics IV fluids Surgical Peritoneal drain Exploratory laparotomy Bowel resection All Infants Infants < 1200 grams Coates EW, et al. Pediatrics 2005;116:e Common antimicrobial regimens to treat NEC Antibiotic soup Gentamicin + ampicillin Gentamicin + vancomycin Gentamicin + ampicillin +/- vancomycin Gentamicin + clindamycin +/- vancomycin Gentamicin + metronidazole +/- vancomycin Gentamicin + piperacillin-tazobactam +/- vancomycin Consider anaerobic coverage if pneumoperitoneum suspected or confirmed and if perforation or bowel necrosis is suspected Are these appropriate regimens given suspected organisms? Spectrum of Activity MRSA GBS CONS E.Coli K.pneumo Pseudomonas B.fragilis Ampicillin X X Gentamicin X X X Pip-tazobactam X X X X Clindamycin X X X X Metronidazole Vancomycin X X X Are these appropriate regimens given suspected organisms? Average OHIO NICU Microbial Sensitivities MRSA GBS CONS E.Coli K.pneumo Pseudomonas B.fragilis Ampicillin Gentamicin Pip-tazobactam Clindamycin Metronidazole 97 Vancomycin NEC prevention PREVENT prematurity Feeding strategies GI priming with trophic feeds Human milk 6-10 fold decrease in incidence versus formula fed Feeding protocols Established feeding protocols decreases incidence of NEC and improves time to full feeds and decreased hospitalization 6

7 New thoughts on NEC risks/treatment/prophylaxis Transfusion associated NEC (TANEC) New thoughts on NEC risks/treatment/prophylaxis Supplemental L-arginine Arginine is amino acid precursor to nitric oxide synthase ARIPI trial looking into risks of fresh versus older PRBCs Mohamed A, Shah PS. Pediatrics. 2012;129(3): Fergusson D, et al. Transfus Med Rev. 2009;23(1): Shah P, Shah V. Cochrane Database Syst Rev. 2007;18(3):CD New thoughts on NEC risks/treatment/prophylaxis Probiotics Non-pathogenic bacteria: Bifidobacterium Abnormal colonization of preterm infant with antibiotic resistant bacteria Hand washing, sterile environment Prophylactic antibiotic use Delayed enteral feeding, no human milk No direct breast feeding or maternal exposure C-sections Colonization of unit with pathogenic bacteria Probiotic Benefits: Maintain intestinal integrity Up regulate immunity Increase production of anti-inflammatory cytokines modulate intestinal inflammation Prevent overgrowth of pathogenic bacteria Probiotic Risks: Currently not FDA regulated Unknown optimal strain and dosing regimen Risk of invasive disease Jenke A, et al. Arch Dis Child Fetal Neonatal Ed. 2012;97(3):F Take home points Antimicrobial resistance in on the rise Methods to improve antimicrobial stewardship and responsible prescribing are necessary Lack of novel treatment options for multi-drug resistant organisms NEC continues to be a major cause of morbidity and mortality in the NICU population New treatment options/awareness of risk factors may show promise 2012 Bugs and Drugs Update Lindsay Schray, PharmD NICU Clinical Specialist Nationwide Children s Lindsay.Schray@NationwideChildrens.org 7