infectious disease · doripenem 500mg q8h monobactam aztreonam 2g iv q8h amikacin 8 mg/kg then 7.5...

INFECTIOUS DISEASEANTIMICROBIAL REVIEW

Michelle Aguirre

Janel Liane Cala

PGY1 Pharmacy Practice Residents

Medical Center Hospital

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

INTRODUCTION

Bacterial Morphology

https://www.slideshare.net/drsameh16/bacterial-staining-42157535

Gram Staining

http://ib.bioninja.com.au/options/untitled/b1-michttp://ib.bioninja.com.au/options/untitled/b1-microbiology-organisms/gram-staining.htmlologyorganisms/gram-staining.html

ANTIBIOGRAM,MIC INTERPRETATION

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

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

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?

PATHOGEN DIRECTED RX

Pop Quiz

• Is it MSSA or MRSA?

Methicillin Sensitive Staph Aureus (MSSA)

• Coagulase (+)

• Catalase (+)

• Oxacillin sensitive

• SSTI, PNA, Meningitis, Endocarditis, Osteomyelitis

• 1st Line: • Penicillinase-resistant Penicillin (Nafcillin, Oxacillin)

• 1st Generation Cephalosporins (Cefadroxil, Cefazolin, Cephalexin)

• Alternatives:• Clindamycin, Vancomycin, Tetracycline, Sulfamethoxazole-trimethoprim

Methicillin Resistant Staph Aureus (MRSA)

• Coagulase (+)

• Catalase (+)

• Oxacillin resistant

• SSTI, PNA, Meningitis, Endocarditis, Osteomyelitis

• 1st line: Vancomycin (MIC ≥2 switch agent)

• Alternatives• Daptomycin (not for PNA)

• Linezolid (for SSTI, PNA)

• Tigecycline (not for bacteremia)

• Ceftaroline

Table 1. MRSA Treatment Options

*for Community Acquired MRSA (CA-MRSA)

ᵃSalvage therapy

Oral Treatment IV Treatment

TMP-SMX*Clindamycin*Doxycycline, minocycline*Linezolid

VancomycinLinezolidDaptomycinCeftarolineTigecyclineᵃQuinupristin-dalfopristinᵃDalbavancin, oritavancin

Methicillin Resistant Staph Aureus (MRSA)

Vancomycin, Daptomycin, and Linezolid

• All active against gram-positive cocci, including MRSA

Agent Adverse reactions Pearls

Vancomycin Infusion reactions, renal toxicity (not contraindicated in AKI), ototoxicity (rare)

MIC ≥ 2 associated with treatment failureDo not use in MSSA infections (unless penicillin allergy)

Daptomycin CPK elevation (obtain baseline and monitor weekly)

Inactivated by pulmonary surfactant do not use for pneumonia

Linezolid Bone marrow suppression, peripheral neuropathy, optic neuritis, lactic acidosis

Long-term therapy increases risk of AE’sNot ideal in UTIs (~30% excreted in urine)

Table 2. Gram-Positive Drug Class Overview

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.

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)

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

• Vancomycin is the drug of choice for empiric coverage

• Ampicillin is the drug of choice for enterococcus if susceptible

E. faecalis E. faecium

More commonHighly virulentLess resistance

Less commonLess virulenceMore resistance VRE

Table 4. Usual treatment options based on species

*Active against E. faecium but not E. faecalis; salvage therapy

Vancomycin-Resistant Enterococcus

VRE (E. Faecalis) VRE (E. Faecium)

Pen G or ampicillinLinezolidDaptomycinTigecyclineFluoroquinolonesCystitis only: nitrofurantoin, fosfomycin, doxycycline

DaptomycinLinezolidQuinipristin/dalfopristin*TigecyclineCyctitis only: fosfomycin,doxycycline

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

Treatment Options for PseudomonasBetalactams Aminoglycosides Fluoroquinolones Polymyxin

PCN-Piperacillin/ Tazobactam

CephalosporinsCeftazidime 2g q8Cefepime 1-2g q8Ceftazidime/Avibactam 2.5g q8hCeftolozane/tazobactam 1.5g q8h

CarbapenemsImipenem/Cilastatin 1g q8hMeropenem 1g q8hDoripenem 500mg q8h

MonobactamAztreonam 2g IV q8h

Amikacin 8 mg/kg THEN7.5 mg/kg q12h

Gentamicin/ Tobramycin3 mg/kg THEN

2 mg/kg q8h

Ciprofloxacin 400 mg q8hLevofloxacin 750 mg q24

Colistin5mg/kg x1 THEN2.5mg/kg q12

Polymyxin B1.25 mg/kg q12

OTHER:Fosfomycin 3g PO x 1

Pop Quiz

A. Piperacillin/tazobactam

B. Aztreonam

C. Cefepime

D. Meropenem

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?

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

Acinetobacter treatment

• Imipenem 0.5-1gm IV q6h

• Meropenem 0.5-2 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

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

STENOTROPHOMONAS MALTOPHILIA

Trimethoprim/sulfamethoxazole 15mg/kg/day divided in 2 to 3

doses

Ticarcillin/clavulanate

Ampicillin/ sulbactam

3.1 g q6h IV

3 g q6h IV

Ceftazidime 2 g q8h IV

Ciprofloxacin 400 mg q8-12h IV

Levofloxacin 500-750 mg q24h IV

Moxifloxacin 400mg/day

Doxycycline 100 mg q12h IV

Colistin (MDR) + COMBI 2.5 mg/kg q12

ESBL (Extended Spectrum Betalactamase)

• 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

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

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 > 105 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

Carbapenem-Resistant Enterobacteriaceae

RISK FACTORS

Broad spectrum antibiotic useTraumaDiabetesIndwelling urinary/ venous cathetersMechanical ventilationImmunocompromised – malignancy, severe illness, organ transplant

• 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


Class A (KPC)

Klebsiellaproducing carbapenemase

Class B (NDM-1)

New Delhi Metalloproteases

Class D

OXA

Can be transmitted from Klebsiellato other genera

Most common in US

Dependence on Zinc for efficienthydrolysis of betalactams

Inhibited by EDTA

Very mobile genetic element

Hydrolyze oxacillin

Heterogenous class

6 subgroups produce carbapenemase

not susceptible to betalactam inhibitors

Variable response to betalactam inhibitor



PolymyxinsColistin-prodrug; slow conversion-renal dose adj

Polymyxin B -active drug-no renal dose adj-achieve higher peak concentrations

Most active agent in vitroPossible resistance development with monotherapy

ADV:Neurotoxicity***Nephrotoxicity (>40%)

TigecyclineIn vitro activityIncreased resistance developing Most effective when used in combination

Fosfomycin

I: uncomplicated UTI

Achieve high urinary concentration for prolonged time periodConcentration after single dose persist above MIC after 72hrs

AminoglycosidesI: uncomplicated UTI

Good clinical data in UTI but failed therapy with bloodstream infection

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



Colistin Polymyxin B

Form administered Prodrug Active drug

Time until maintenance dose

12-24 hours 12 hours

Maintenance dose Determined by CrClLower doses

Determined by MICHigher doses

Renal adjustment Yes No

Adverse Events Nephrotoxicity (50-60%)Neurotoxicity

Nephrotoxicity (20-40%)Neurotoxicity

Pearls Most studied for CREUTI use: achieves higher concentrations in urine

May be safer compared to colistin

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


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

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

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 intra-abdominal infections

• New pathways to be added:

• Clostridium difficile infections

• Meningitis

• Febrile neutropenia

• endocarditis

Antimicrobial Stewardship Resources

• Antimicrobial Stewardship SharePoint Site on MCH Intranet

• Navigate:• MCH Home Page > Employee Links (left hand side) > "Antimicrobial Stewardship“

• Follow Link:

• https://echdo365.sharepoint.com/department/AS/default.aspx?apr=1&wa=wsignin1.0

• 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

https://echdo365.sharepoint.com/department/AS/default.aspx?apr=1&wa=wsignin1.0

References

• Centers for Disease Control and Prevention. Antibiotic resistance threats in the United States. 2013 Atlanta, GA: CDC;2013.

• Huttner A. Antimicrobial resistance and infection control. Nov 18 2013;2(1):31.

• Arnold R et al. (2011). Emergence of Klebsiella pneumoniae Carbapenemase (KPC)-producing bacteria. South Med J, 104(1) 40-45. doi:10.1097/SMJ.0b013e3181fd7d5a.

• Rossolini G et al. (2005). Treatment and control of severe infections caused by multiresistant Pseudomonas aeruginosa. Clin Microbiol Infect, 11(4): 17-32.

• Morril H et al (2014). Treatment options for Carbapenem- Resistant Enterobacteriaceae infections. DOI: 10.1093/ofid/ofv050

• John Hopkins antibiotics guide. (2017). Unbound Medicin. [Mobile application software]. Retrieved from https://www.hopkinsguides.com/Hopkins.

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