INFECTIOUS DISEASE ANTIMICROBIAL REVIEW. Michelle Aguirre Janel Liane Cala PGY1 Pharmacy Practice Residents Medical Center Hospital

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1 INFECTIOUS DISEASE ANTIMICROBIAL REVIEW Michelle Aguirre Janel Liane Cala PGY1 Pharmacy Practice Residents Medical Center Hospital

2 Objectives Review basic microbiology of organisms Implement MCH Antibiogram utilization Define minimum inhibitory concentration (MIC) Discuss resistant drug organisms and treatment Identify risk factors for common multi-drug resistant pathogens

3 INTRODUCTION

4 Bacterial Morphology

5 Gram Staining organisms/gram-staining.html

6

7 ANTIBIOGRAM, MIC INTERPRETATION

8 MCH Antibiogram Printed each year based on previous year s laboratory data for critical care and medical floors Provided by pharmacy department and the antimicrobial stewardship program Should be reviewed and used to determine proper empiric therapy based on most common organisms seen in different types of infections

9 MIC Interpretation MIC: minimum inhibitory concentration Lowest concentration of an antibiotic that inhibits the growth of a given strain of bacteria Susceptibility Interpretation S (sensitive): organism is inhibited by the serum concentration of the drug that is achieved using recommended dosage I (intermediate): isolates with MICs that approach usually attainable blood and tissue levels and for which response rates may be lower than for susceptible strains R (resistant): resistant to the usually achievable serum drug levels

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12 Case Question VE is a 44-year-old man who was admitted for an abscess. He was started on empiric therapy with pipercillin/tazobactam and vancomycin. Which de-escalation is appropriate based on the following susceptibilities?

13 PATHOGEN DIRECTED RX

14 Is it MSSA or MRSA? Pop Quiz

15 Methicillin Sensitive Staph Aureus (MSSA) Coagulase (+) Catalase (+) Oxacillin sensitive SSTI, PNA, Meningitis, Endocarditis, Osteomyelitis 1 st Line: Penicillinase-resistant Penicillin (Nafcillin, Oxacillin) 1 st Generation Cephalosporins (Cefadroxil, Cefazolin, Cephalexin) Alternatives: Clindamycin, Vancomycin, Tetracycline, Sulfamethoxazole-trimethoprim

16 Methicillin Resistant Staph Aureus (MRSA) Coagulase (+) Catalase (+) Oxacillin resistant SSTI, PNA, Meningitis, Endocarditis, Osteomyelitis 1 st line: Vancomycin (MIC 2 switch agent) Alternatives Daptomycin (not for PNA) Linezolid (for SSTI, PNA) Tigecycline (not for bacteremia) Ceftaroline

17 Methicillin Resistant Staph Aureus (MRSA) Table 1. MRSA Treatment Options Oral Treatment TMP-SMX* Clindamycin* Doxycycline, minocycline* Linezolid IV Treatment Vancomycin Linezolid Daptomycin Ceftaroline Tigecyclineᵃ Quinupristin-dalfopristinᵃ Dalbavancin, oritavancin *for Community Acquired MRSA (CA-MRSA) ᵃSalvage therapy

18 Vancomycin, Daptomycin, and Linezolid All active against gram-positive cocci, including MRSA Table 2. Gram-Positive Drug Class Overview Agent Adverse reactions Pearls Vancomycin Daptomycin Linezolid Infusion reactions, renal toxicity (not contraindicated in AKI), ototoxicity (rare) CPK elevation (obtain baseline and monitor weekly) Bone marrow suppression, peripheral neuropathy, optic neuritis, lactic acidosis MIC 2 associated with treatment failure Do not use in MSSA infections (unless penicillin allergy) Inactivated by pulmonary surfactant do not use for pneumonia Long-term therapy increases risk of AE s Not ideal in UTIs (~30% excreted in urine)

19 Case Question A 33-year-old obese man with a history of recurrent skin abscesses due to MRSA presents to the emergency department with a productive cough, pleuritic chest pain, and dyspnea. One week ago he had influenza. Chest radiography shows multilobar infiltrates and early cavitation. A sputum Gram stain shows numerous gram-positive cocci in clusters. The sputum culture grows S. aureus, which is resistant to oxacillin, has MIC of 6 to vancomycin, and greater than 4 to clindamycin and which are susceptible to daptomycin, linezolid, and quinupristin/dalfopristin.

20 Case Question (continued) Which one of the following antimicrobial regimens would be the best treatment for this patient s infection? a) Daptomycin 6 mg/kg intravenously once daily b) Linezolid 600 mg intravenously twice daily c) Vancomycin 1 g intravenously twice daily d) Ceftriaxone (1 g/d intravenously) plus azithromycin (500 mg/d intravenously) e) Vancomycin (15-20 mg/kg intravenously twice daily) to achieve a trough concentration of 10 to 15 µg/ml plus clindamycin (600 mg intravenously every 8 hours)

21 Enterococcus Gram-positive bacteria in short chains (may appear as streptococcus in pairs/chains in gram-stain report) Present in normal colonic flora, oropharyngeal and vaginal secretions Usually a nosocomial, opportunistic pathogen E. faecalis E. faecium More common Highly virulent Less resistance Less common Less virulence More resistance VRE Vancomycin is the drug of choice for empiric coverage Ampicillin is the drug of choice for enterococcus if susceptible

22 Vancomycin-Resistant Enterococcus Table 4. Usual treatment options based on species VRE (E. Faecalis) Pen G or ampicillin Linezolid Daptomycin Tigecycline Fluoroquinolones Cystitis only: nitrofurantoin, fosfomycin, doxycycline VRE (E. Faecium) Daptomycin Linezolid Quinipristin/dalfopristin* Tigecycline Cyctitis only: fosfomycin, doxycycline *Active against E. faecium but not E. faecalis; salvage therapy

23 Pseudomonas aeruginosa Gram-negative, non-fermenting rod Usually a nosocomial, opportunistic pathogen Usual infections Respiratory: pneumonia GU: UTI/pyelonephritis CV: endocarditis, bacteremia, sepsis Skin/bone: cellulitis, osteomyelitis Risk factors: Immunosuppression, diabetes mellitus, cystic fibrosis, neutropenia, AIDS

24 Treatment Options for Pseudomonas Betalactams Aminoglycosides Fluoroquinolones Polymyxin PCN -Piperacillin/ Tazobactam Cephalosporins Ceftazidime 2g q8 Cefepime 1-2g q8 Ceftazidime/Avibactam 2.5g q8h Ceftolozane/tazobactam 1.5g q8h Amikacin 8 mg/kg THEN 7.5 mg/kg q12h Gentamicin/ Tobramycin 3 mg/kg THEN 2 mg/kg q8h Ciprofloxacin 400 mg q8h Levofloxacin 750 mg q24 Colistin 5mg/kg x1 THEN 2.5mg/kg q12 Polymyxin B 1.25 mg/kg q12 Carbapenems Imipenem/Cilastatin 1g q8h Meropenem 1g q8h Doripenem 500mg q8h OTHER: Fosfomycin 3g PO x 1 Monobactam Aztreonam 2g IV q8h

25 Pop Quiz Patient on piperacillin/tazobactam for 4 days treating HAP and WBC 25, febrile, requiring pressors. Which intravenous antimicrobial agents would be appropriate for a patient with this susceptibility report? A. Piperacillin/tazobactam B. Aztreonam C. Cefepime D. Meropenem

26 Acinetobacter Gram negative, strictly aerobic, nonmotile, coccobacilli Commonly found in: soil, water, catheters, ventilation equipment Usual types of infection: PNA, Septicemia, Burn Wounds Risk factors: Immunosuppression Burns Medical devices (central line, catheter, ventilator, endoscopes, feeding tubes) Previous antibiotic exposure

27 Acinetobacter treatment Imipenem 0.5-1gm IV q6h Meropenem gm IV q 8h Ampicillin/Sulbactam 3g (2:1) q6h Tigecycline 100 mg IV, then 50 mg IV q 12 h Pan-resistant isolates: Colistin + any of the above Variable activity AMG, Cephalosporins, Minocycline, Rifampin, TMP/SMX

28 STENOTROPHOMONAS MALTOPHILIA Aerobic, gram negative bacillus with polar flagella Found mostly in aquatic environment, plants, soil; frequent colonizer of body fluids Nosocomial sources: dh2o, nebulizers, dialysates, contaminated disinfectants Low virulence mostly affects immunocompromised Risk factors: Foreign bodies (catheters) Neutropenia Broad spectrum abx CF

29 STENOTROPHOMONAS MALTOPHILIA Trimethoprim/sulfamethoxazole 15mg/kg/day divided in 2 to 3 doses Ticarcillin/clavulanate Ampicillin/ sulbactam Ceftazidime Ciprofloxacin Levofloxacin Moxifloxacin Doxycycline Colistin (MDR) + COMBI 3.1 g q6h IV 3 g q6h IV 2 g q8h IV 400 mg q8-12h IV mg q24h IV 400mg/day 100 mg q12h IV 2.5 mg/kg q12

30 ESBL (Extended Spectrum Betalactamase)

31 ESBL (Extended Spectrum Betalactamase)

32 Carbapenems- similar outcomes and mortality within class Ceftolozane- Tazobactam** RENAL IAI 1.5g q8h 4-14d + Metronidazole cuti 1.5g q8h x 7days (at least**) Ceftazidime-avibactam** RENAL IAI 2.5g q8h 5-14d + Metronidazole cuti 2.5g q8h x 7days (at least**)- 14d Cefepime 2g q8h variable; not suggested; inferior to carbapenem Piperacillin- Tazobactam- variable; not recommended Fluoroquinolones- Cipro Uncomplicated UTI- Fosfomycin, Nitrofurantoin, Bactrim

33 Pop Quiz JW is a patient who is being seen for an intra-abdominal ESBL infection. In addition, he has a history of poorly controlled seizures for which he takes several antiepileptic drugs. Which of the following carbapenems would you avoid the most in this patient? a) Ertapenem b) Meropenem c) Imipenem/cilastin d) Doripenem

34 Case Question OC is a 42 year-old female with PMH of HTN presenting for complaints of increased urinary frequency and 4/10 suprapubic pain. No fevers and PE is normal. UA shows WBC 17, (+)leukocyte esterases and urine culture shows > 10 5 cfu/ml ESBL E. coli in the urine. PMH: Afib (on Warfarin, Amiodarone) Which outpatient treatment agent could you consider for this patient? a) Meropenem b) Levofloxacin c) Fosfomycin d) Bactrim e) No treatment indicated

35 Carbapenem-Resistant Enterobacteriaceae RISK FACTORS Broad spectrum antibiotic use Trauma Diabetes Indwelling urinary/ venous catheters Mechanical ventilation Immunocompromised malignancy, severe illness, organ transplant

36 Carbapenem-Resistant Enterobacteriaceae includes 70 different genera from Enterobacteriaceae with various mechanisms to become resistant to carbapenems Usual type of infections: VAP, UTI, IAI Exhibit resistance to most beta-lactam antibiotics Optimal treatment is largely unknown

37 Carbapenem-Resistant Enterobacteriaceae Class A (KPC) Klebsiella producing carbapenemase Can be transmitted from Klebsiella to other genera Most common in US Class B (NDM-1) New Delhi Metalloproteases Dependence on Zinc for efficient hydrolysis of betalactams Inhibited by EDTA Very mobile genetic element Class D OXA Hydrolyze oxacillin Heterogenous class 6 subgroups produce carbapenemase not susceptible to betalactam inhibitors Variable response to betalactam inhibitor

38 Carbapenem-Resistant Enterobacteriaceae Polymyxins Colistin -prodrug; slow conversion -renal dose adj Polymyxin B -active drug -no renal dose adj -achieve higher peak concentrations Tigecycline Fosfomycin I: uncomplicated UTI Aminoglycosides I: uncomplicated UTI Most active agent in vitro Possible resistance development with monotherapy ADV: Neurotoxicity*** Nephrotoxicity (>40%) In vitro activity Increased resistance developing Most effective when used in combination Achieve high urinary concentration for prolonged time period Concentration after single dose persist above MIC after 72hrs Good clinical data in UTI but failed therapy with bloodstream infection

39 Carbapenem-Resistant Enterobacteriaceae Combination: Colistin+ Tigecycline + Meropenem extended infusion (2g q8h over 3hrs) Lower mortality rate than monotherapy (27% VS 38%) Advantage: Reduction of initial inappropriate therapy potential synergistic effects suppression of emerging resistance Disadvantage Increased adverse effects Development of Clostridium difficile infection

40 Carbapenem-Resistant Enterobacteriaceae Colistin Polymyxin B Form administered Prodrug Active drug Time until maintenance dose Maintenance dose hours 12 hours Determined by CrCl Lower doses Renal adjustment Yes No Adverse Events Nephrotoxicity (50-60%) Neurotoxicity Pearls Most studied for CRE UTI use: achieves higher concentrations in urine Determined by MIC Higher doses Nephrotoxicity (20-40%) Neurotoxicity May be safer compared to colistin

41 Carbapenem-Resistant Enterobacteriaceae Promising Drug: Ceftazidime- Avibactam possible activity against class A, Class B, class D Betalactamase Avibactam activity against KPCs and OXA, but no activity on NDM1 ADV: N/V/ constipation, anxiety

42 ANTIMICROBIAL STEWARDSHIP Having an antimicrobial stewardship program (with certain components) is required by the Joint Commission MCH antimicrobial stewardship program supported by administration and the members include: Infectious disease physician: Dr. Mocherla Pharmacy leader: Erica Wilson, Lindsay Rumold Pharmacists, laboratory personnel, nurses, physicians, and infection control staff

43 Antimicrobial Stewardship What we do Infectious disease rounds (Tuesdays and Thursdays) with Dr. Mocherla Monitor and report resistance patterns and antibiotic use Projects to improve use of antibiotics Collect data and report stewardship activities to appropriate committees

44 Antimicrobial Stewardship Resources Antimicrobial Stewardship Pocket Guide Completed, printed and distributed, and printed as posters Can also be found on intranet SharePoint site Includes Antibiogram and Antibiotic Use Algorithms CAP, HAP, VAP, aspiration PNA, acute bacterial skin and skin structure infections, UTIs, complicated intra-abdominal infections, complicated intraabdominal infections New pathways to be added: Clostridium difficile infections Meningitis Febrile neutropenia endocarditis

45 Antimicrobial Stewardship Resources Antimicrobial Stewardship SharePoint Site on MCH Intranet Navigate: MCH Home Page > Employee Links (left hand side) > "Antimicrobial Stewardship Follow Link: signin1.0 The following resources will be available on the site: Infectious Disease Guidelines and Resources, MCH Antibiogram, MCH Empiric Antibiotic Use Algorithms, Antibiotic Dosing, Educational Presentations, Infection Control Committee Reports, and Policies & Procedures

46

47 References Centers for Disease Control and Prevention. Antibiotic resistance threats in the United States Atlanta, GA: CDC;2013. Huttner A. Antimicrobial resistance and infection control. Nov ;2(1):31. Arnold R et al. (2011). Emergence of Klebsiella pneumoniae Carbapenemase (KPC)- producing bacteria. South Med J, 104(1) doi: /smj.0b013e3181fd7d5a. Rossolini G et al. (2005). Treatment and control of severe infections caused by multiresistant Pseudomonas aeruginosa. Clin Microbiol Infect, 11(4): Morril H et al (2014). Treatment options for Carbapenem- Resistant Enterobacteriaceae infections. DOI: /ofid/ofv050 John Hopkins antibiotics guide. (2017). Unbound Medicin. [Mobile application software]. Retrieved from

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