Threat Level Urgent: Multidrug resistant Pseudomonas ...

9/30/2021

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Brad Taranto, PharmD

PGY1 Pharmacy Resident

The Christ Hospital

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MDR Acinetobacter and Pseudomonas isolates*

(September 2019 - September 2021)

* Data from The Christ Hospital Cincinnati, Ohio, 2021

COVID-19

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United States Centers for Disease Control (CDC) (2013)

Magiorakos, et al Clin Microbiol Inf (2012)

Multidrug-Resistant (MDR)

Resistant to ≥1 agent in 3

different antimicrobial categories

Extensively drug resistant (XDR)

Resistance to agents in

all but 2 antimicrobial categories

Pandrug-Resistant (PDR)

Resistant to all antimicrobial agents

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Enzymatic inactivation

Decreased permeability

Increased efflux Alteration of

drug target site

Overproduction of drug target

site

Britannica. Antibiotic resistance. 2009

Breijyeh, et al. Molecules (2020)

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Class A

• Penicillinases

• Carbapenemases

Class B

• Metallo-β-lactamases

Class C

• ampCβ-lactamases

Class D

• Oxacillinases

Ambler Classification of β-lactamases

Toussaint, et al. Ann Pharmacother (2015)

NSBLs

ESBLs

KPC

Hall, et al. J Antimicrob Chemo (2005)

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Mojica, et al. Curr Drug Targets (2016)

erratiaS

seudomonas/ ProteusP

cinetobacterA

itrobacterC

nterobacterEMoy, et al. Clin Ther (2017)

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Nordmann, et al. Emerg Inf Dis (2011)

Mo, et al. Diagn Microbiol Infect Dis (2019)

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drug target site


site


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drug target site


site


Resistant39%

Intermediate2%

Susceptible59%

Acinetobacter spp. (Sep. ‘19 – Sep. ‘21)

Meropenem susceptibility

Viehman, et al. Drugs (2014)

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0 0 0

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1 1

2 2

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# o

f c

as

es

Month

CARBAPENEM-RESISTANT ACINETOBACTER SPP.

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Antimicrobial

classProposed agents Notes

Carbapenems Meropenem, imipenem • Increasing resistance

Polymyxins Polymyxin B, Polymyxin E (Colistin)

• Most reliable susceptibility

• Limited by toxicities (nephro- and

neuro-)

Tetracyclines Tigecycline, eravacycline, omadacycline • Limited use in bacteremia, UTI

Aminoglycosides Amikacin, tobramycin, gentamicin • Increasing resistance

β-lactam/β-lactamase

inhibitorsAmpicillin/sulbactam

• Sulbactam has intrinsic activity vs.

Acinetobacter spp.

Cephalosporins Cefiderocol • Novel mechanism

Susceptibility (%)

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Susceptibility (%)

74

Susceptibility (%)

~90

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Reference Patients Intervention Outcomes Conclusion

Makris (2018)RCT including

39 patients with

VAP

IV ColistinClinical response: 16%

Mortality: 63%↑Microbiological

response with

combination

therapy, but no

mortality benefit

IV Colistin +

ampicillin/sulbactam

Clinical response: 70%

Mortality: 50%

Yilmaz (2015)

Retrospective

observational

study including

70 patients with

VAP

IV ColistinClinical response: 76%

28-day mortality: 41%

No difference in

terms of

microbiological

response or

mortality

IV Colistin + extended

infusion meropenem


28-day mortality: 48.5%

Balkan (2015)

Retrospective

cohort study

including 107

patients with

bacteremia

IV ColistinEradication: 69%

14-day mortality: 53%No difference in

terms of

microbiological

eradication or

mortality

Non-colistin-based

combination therapy

Eradication: 83%


Drug name (Brand) Formulary status

Minocycline (Minocin) Formulary

Tigecycline (Tygacil) Criteria for use*

Eravacycline (Xerava) Non-formulary

Omadacycline (Nuzyra) Non-formulary

*MDR gram-negative organism with known tigecycline susceptibility

(amongst other criteria)

Susceptibility (%)

~60

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Reference Patients Intervention Outcomes Conclusions

Shin (2012)

Retrospective

cohort study

including 27

patients with

various infections

(mainly VAP)

Tigecycline

monotherapyClinical success: 58.5%

14-day mortality: 5.9%No difference in

clinical success

(p=0.56) or 14-day

mortality (p=0.26)Tigecycline-based

combination therapyClinical success: 70%


Kim (2016)

Retrospective

cohort study

including 70

patients with

PNA

Tigecycline-based

therapy

Clinical success: 47%

30-day mortality: 33% No difference in

clinical success

(p=0.95) or 30-day

mortality (p=0.77)Colistin-based therapyClinical success: 48%


Ampicillin-sulbactam doses up to 12 g (2:1) described

High doses of ampicillin can cause seizures, electrolyte

derangements

Susceptibility (%)

~30

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Ye (2016)

Retrospective

cohort study

including 168

patients with

PNA

Sulbactam-based

therapy

Eradication: 63.5%

30-day mortality: 33.3%↑Microbiologic

eradication with

sulbactam-based

therapy (p<0.001)

No difference in 30-day

mortality (p=0.618)

Tigecycline-based

therapy

Eradication: 33.3%

30-day mortality: 29.8%

Yilmaz

(2015)

Retrospective

cohort study

including 70

patients with

VAP

IV Colistin +

carbapenem


28-day mortality: 48.5% No difference in clinical

response rate (p=0.53)

or 30-day mortality

(p=0.21)IV Colistin +

sulbactam



Susceptibility (%)

>90

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• Prospective, randomized, open-label phase III study

• 118 patients with carbapenem-resistant nosocomial PNA, BSI, cUTIDesign

• Cefiderocol vs. ‘Best available therapy’ (BAT)

• Most commonly colistin + tigecycline/amp-sulbactam/fosfomycinIntervention

• Clinical cure: Cefiderocol 66% vs. BAT 58% (not significant)

• Cefiderocol > BAT in BSI and cUTI, but not in PNA

Primary Outcomes

• 28-day mortality (A. baumannii only): Cefiderocol 50% vs. BAT 18%

• Cefiderocol associated with higher mortality overall in PNA/BSI, but had mortality benefit in cUTI

Safety Outcomes

Bassetti, et al. Lancet Inf Dis (2021)

Reference Patients Intervention Outcomes

Rattanaumpawan (2010)N=50 patients with

VAP

Nebulized colistin 2 MU q12h +IV

antibiotics↑ favorable

microbiological

outcome

No difference in

overall mortality

Nebulized NS +IV antibiotics

Betrosian (2008)N=28 patients with

VAP

IV colistin 3 MU q8h No difference in

microbiological

response or

overall mortalityIV amp/sulbactam 9 g q8h

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• Bayesian meta-analysis of 15 unique treatment regimensfrom 23 studies vs. MDR A. baumanii infections incritically ill patients

Design

• IV colistin monotherapy vs. alternative therapies

• Pairwise comparisons within studies

• Common-comparator comparisons across studiesIntervention

• 4 therapies improved survival compared to IV colistin

• (1) Sulbactam (2) IV colistin + IV fosfomycin(3) IV colistin + inhaled colistin (4) high-dose tigecycline

Outcomes

Jung, et al. Crit Care (2020)

Agents with potential activity include carbapenems, polymyxins, aminoglycosides, tigecycline, ampicillin-sulbactam, and cefiderocol

No single agent has emerged as the clear drug-of-choice

Regimen should be selected based on available susceptibility data

Combination therapy may be considered → Risk vs. benefit

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Aminoglycosides

Fluoroquinolones (except moxifloxacin)

4th generation cephalosporins (i.e. cefepime/ceftazidime)

Antipseudomonal penicillins (i.e. piperacillin, ticarcillin)

Carbapenems (except ertapenem)

Polymyxins

Monobactams




drug target site


site

Eichenberger, et al. Antibiotics (2019)

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drug target site


site

Eichenberger, et al. Antibiotics (2019)

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Tamma, et al. IDSA (2020)

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What is DTR and where does it fit?

Multidrug-Resistant (MDR)

Resistant to ≥1 agent in 3

different antimicrobial categories

Extensively drug resistant (XDR)

Resistance to agents in

all but 2 antimicrobial categories

Pandrug-Resistant (PDR)

Resistant to all antimicrobial agents

Resistance to all…

•β-lactams (including carbapenems)

•Fluoroquinolones

•Monobactams

Kadri, et al. Clin Infect Dis (2019)

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2014

2015

2017

2019

Ceftolozane-tazobactam(Zerbaxa®)

Ceftazidime-avibactam(Avycaz®)

Meropenem-vaborbactam(Vabomere®)

Imipenem-cilastatin-relebactam(Recarbrio®)

KPC OXA-48 NDM VIM IMP P. aeruginosa A. baumannii

Ceftolozane-

tazobactamZerbaxa® ⁺ Yes

Ceftazidime-

avibactamAvycaz® ⁺ ⁺ ⁺ Yes*

Meropenem-

vaborbactamVabomere® ⁺ No

Imipenem-

cilastatin-

relebactam

Recarbrio® ⁺ ⁺ No

Formulary?

Activity against B-lactam-

resistant isolates of:

*Ordering restricted to ID only

Drug Brand NameActivity against carbapenemases

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Infection source Preferred treatment Alternative treatment

Cystitis

Ceftolozane-tazobactam

Ceftazidime-avibactam

Imipenem-cilastatin-relebactam

Cefiderocol

Single-dose of an aminoglycoside

Colistin

Pyelonephritis or cUTI




Cefiderocol

Once-daily aminoglycosides

All other infections




Cefiderocol

Aminoglycosides (if bloodstream

infection and adequate source control)

IDSA MDR Guidance (2020)

Ceftolozane-tazobactam(Zerbaxa®)

Ceftazidime-avibactam(Avycaz®)

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Humphries

(2017)

309 P. aeruginosa

isolates resistant to

≥1 of the following:

cefepime, Pip/tazo,

meropenem

In vitro susceptibility

testing of isolates to

ceftolozane-

tazobactam (COT)

and ceftazidime-

avibactam (CZA)

COT

%Susceptible: 73%

CZA

%Susceptible: 62%


(COT, Zerbaxa®)

appears to have superior

activity against MDR P.

aeruginosa compared to

ceftazidime-avibactam

(CZA, Avycaz®)COT

%Susceptible: 52%

CZA

%Susceptible: 27%

105 P. aeruginosa

isolates resistant to

all 3 above ABX

Humphries, et al. Antimicrob Agents Chemother (2017)

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• Prospective, randomized, open-label phase III study

• 118 patients with carbapenem-resistant nosocomial PNA, BSI, cUTIDesign

• Cefiderocol vs. ‘Best available therapy’ (BAT)

• Most commonly colistin + tigecycline/amp-sulbactam/fosfomycinIntervention

• Clinical cure: Cefiderocol 66% vs. BAT 58% (not significant)

• Cefiderocol > BAT in BSI and cUTI, but not in PNA

Primary Outcomes

• 28-day mortality (A. baumannii only): Cefiderocol 50% vs. BAT 18%

• Cefiderocol associated with higher mortality overall in PNA/BSI, but had mortality benefit in cUTI

Safety Outcomes

Uncomplicated cystitis

• Ceftolozane-tazobactam, ceftazidime-avibactam, cefiderocol, or single-dose aminoglycoside

Complicated UTI or pyelonephritis

• Ceftolozane-tazobactam, ceftazidime-avibactam, cefiderocol

All other infections

• Ceftolozane-tazobactam, ceftazidime-avibactam

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Combination therapy is not routinely necessary

Anti-pseudomonal β-lactams and FQs have reliable activity

BL/BLIs and cefiderocol should be reserved for DTR isolates

Drug Indication DosingDose

adjustments

MeropenemUTI, BSI, HAP/VAP caused by

MDR GNRIV: 1 g q8h (extended infusion over 3 hr) Renal

Colistin (polymyxin E)BSI, HAP/VAP caused by MDR

GNR

Inhalation: 4.5 MU q8hRenal

IV: 9 MU x1, then 4.5 MU q12h

TigecyclineIAI, HAP/VAP, SSTI caused by

MDR GNR

Standard dose IV: 100 mg x1, then 50 mg

q12h

HepaticHigh dose (complicated infections caused

by MDR A. baumannii, P. aeruginosa) IV:

200 mg x1, then 100 mg q12h

Ampicillin-sulbactamBSI, HAP/VAP caused by MDR

GNRIV: 3 g q8h (extended infusion over 4 hr) Renal

CefiderocolUTI, HAP/VAP caused by MDR

GNRIV: 2 g q8h Renal


HAP/VAP caused by MDR GNR IV: 3 g q8h

RenalIAI, UTI, SSTI, BSI caused by

MDR GNRIV: 1.5 g q8h

Ceftazidime-avibactamIAI, UTI, HAP/VAP caused by

MDR GNRIV: 2.5 g q8h Renal

Abbreviations: Urinary tract infection (UTI), bloodstream infection (BSI), hospital-acquired pneumonia (HAP), ventilator-associated pneumonia (VAP), skin

and soft tissue infection (SSTI), multidrug resistant (MDR), gram-negative rods (GNR)

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Threat Level Urgent: Multidrug resistant Pseudomonas ...

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