AMR 1: Management of Antimicrobial resistant gram negatives

AMR 1: Management of Antimicrobial resistant gram negatives. A Focus on Extended-Spectrum β-lactamase Producing Enterobacterales, Carbapenem-Resistant Enterobacterales, and Pseudomonas aeruginosa with Difficult-to-Treat Resistance

Scenario: You are seeing a 63 yo with CKD and admitted with septic shock. The patient is admitted to the ICU and started on piperacillin-tazobactam and vancomycin. Blood and urine cultures return with ESBL Klebsiella pneumoniae (R-ceftriaxone at MIC >2). It is suspected the cause of the septic shock is pyelonephritis. Within 12 hours the pressors are weened, but the patient continues to have fevers. Do you continue piperacillin-tazobactam or do you change to a carbapenem?

This is not an uncommon scenario. I have encountered many patients that are better(-ish) on an antibiotic that either the organism is resistant to or has a resistance gene that makes the antibiotic less then ideal. Until recently it was difficult to find data to help with management decisions and guide therapy in these situations. Faced with the question of pressing on since there is improvement (and risk worsening sepsis) or change to a carbapenem (and face potential expansion of resistance) is there any guidance or data?

Now there is both guidance and data.

The new IDSA Guidance paper, Infectious Diseases Society of America Antimicrobial Resistant Treatment Guidance: Gram-Negative Bacterial Infections.  

The recommendations in this paper are not earth shattering, but they do provide a nice guide for what to do in these vexing situations. The guidance reviews management of AMR in gram negatives, particularly ESBL-Enterobacteriaceae (E. coli, K. pneumoniae, K. oxytoca and P. mirabilis), Carbapenem resistant Enterobacteriaceae and Difficult to Treat (DTR) P aeruginosa. For each organism class there are multiple questions the group attempted to answer and provide some excellent guidance. I have summarized these recommendations in the tables below with some added information.

Empiric therapy: Consider 1) Previous organisms and associated susceptibility data for the last 6 months and 2) Antibiotic exposure in the last 30 days (e.g. if received piperacillin-tazobactam recently consider another class such as a carbapenem)

Duration of therapy: Prolonged treatment courses are not necessary. If the initial antibiotic is found to be inactive, this may change the duration of therapy. As an example, the patient receives 3 days of ceftriaxone, but the E coli is resistant. Days of therapy would start from when an effective therapy was started.

ESBL-Enterobacteriaceae: 

-ESBLs inactivate most penicillins, cephalosporins and aztreonam

-CTX-M is the most common ESBL in the United States

-If specific testing for an ESBL gene is not available a surrogate is ceftriaxone MIC >/=2

Treatment of ESBL Enterobacteriaceae
Disease	Preferred Treatment	Alternative/Notes
Cystitis	Nitrofurantoin TMP-SMX *piperacillin-tazobactam *cefepime	Amoxicillin-calvulanate Single dose aminoglycoside Fosfomycin** FQ (cipro/Levo)
Pyelonephritis@  Complicated UTI@	Ertapenem Meropenem FQ (cipro/levo) TMP-SMX
Infection outside the urinary tract (including blood stream infection)	Meropenem Imipenem ertapenem	Step Down:# -FQ -TMP-SMX

 

*If started on piperacillin-tazobactam or cefepime and found to be resistant and the patient is improved, no change needed. ONLY FOR CYSTITIS

**Fosfomycin is only recommended for E coli. Klebsiella, Proteus, Serratia and Pseudomonas all have the fosA gene which can hydrolyze Fosfomycin and lead to clinical failure. 

@If piperacillin-tazobacatm or cefepime where initiated and the is not susceptible, has proven ESBL or presumed EESBL (ceftriaxone resistance) change to a carbapenem. Do not use piperacillin-tazobactam or cefepime. See the MERINO Trial Harris et al JAMA 2018;320(10):984-994

#If susceptible can step down to oral therapy. Can change if 1)Susceptible to oral agent (FQ, TMP-SMX), 2) patient afebrile and hemodynamically stable 3) Appropriate source control 4) No issues with intestinal absorption.

Carbapenem Resistant Enterobacteriaceae 

-2 types of resistance 

1. Carbapenemase producers
   1. KPC most common in the United States
   2. Metallo-betalactamases: NDM-1, IMP, VIM
   3. Oxacillinases: OXA-48
2. Non-carbapenemase producers
   1. Rely on efflux pumps and porin channel alterations.-Tests: 1) Carbapenem inactivation test or CarbaNP Test

Treatment of Carbapenem Resistant Enterobacteriaceae
Disease	Preferred Treatment	Alternate/Notes
Cystitis	FQ (cipro, levo) Nitrofurantoin Single Dose AG	Meropenem* Ceftazidime-avibactam (CEF-AVI) Meropenem-vaborbactam (MER-VAB) Imipenem-relebactam (IMI-REL) Cefiderocol Colistin**
Pyelonephritis  Complicated UTI	CEF-AVI MER-VAB IMI-REL Cefiderocol	Meropenem* Once daily AG (if no concern for renal toxicity)
Infection outside the urinary tract:  Resistant to ertapenem, Susceptible to meropenem	Extended infusion meropenem CEF-AVI
Infection outside the urinary tract- Carbapenemase present (KPC)#	CEF-AVI MER-VAB$ IMI-REL$	Cefiderocol High-dose Tigecycline, eravacycline@
NDM-1, IMP, VIM  OXA-48$	CEF-AVI + aztreonam cefriderocol	High-dose Tigecycline, eravacycline@

*If R-ertapenem and S-meropenem, may represent a non-carbapenemase pathway. In these instances, meropenem will still work. For cystitis, standard dosing. For pyelonephritis, extended infusion needed

** Colistin is a last resort antibiotic. Should only be used for cystitis. Polymyxin B is NOT recommended for cystitis due to poor renal clearance.

# Majority of CRE in the US are carbapenemase producers and KPC. Rare to have other carbapenemases present. Meropenem or Imipenem will not work for these isolates

@ Tigecycline and eravacycline are ONLY indicated for intra-abdominal infection with source control. These agents have rapid tissue distribution after infusion and limited concentration in the urine and poor serum concentrations.

$ Meropenem-vaborbactam and imipenem-relebactam have very limited activity against OXA beta-lactamases and offer no added benefit and should be avoided. These agents also offer no added benefit in isolates that do not have a carbapenemase and are R ertapenem and S meropenem.

-Role of polymyxins: They should generally be avoided. Studies have demonstrated no added benefit and increased morbidity/toxicity.

–For UTI: Avoid Polymyxin B as this agent has poor urinary clearance. Colistin is preferred, if polymyxins are used.

Difficult to Treat Pseudomonas aeruginosa (DTR- P aeruginosa) 

-Multi-Drug resistant = resistance to at least one antibiotic in at least 3 different classes

–Difficult to Treat (DTR) = non-susceptible to all of the following: piperacillin-tazobactam, ceftazidime, cefepime, meropenem, imipenem, ciprofloxacin, levofloxacin

Difficult to Treat Pseudomonas aeruginosa (DTR- P aeruginosa)
Disease	Preferred Treatment	Alternate/Notes
Cystitis	Ceftolozane-tazobactam (CEFT-TAZ) CEF-AVI IMI-REL Cefiderocol Single dose AG	Colistin
Pyelonephritis  Complicated UTI	CEFT-TAZ CEF-AVI IMI-REL Cefiderocol	Once daily AG
Infection outside the urinary tract	CEFT-TAZ CEF-AVI IMI-REL

 

-Role of combination therapy: Combination therapy not required once susceptibilities are known

-Typically used as 1) Empiric therapy for a severe infection and 2) When DTR-Pa is resistant to most preferred agents and is used as salvage

Cefiderocol: See my prior post all about this siderophore (Trojan Horse) antibiotic. Not sure where I stand on this agent. There is proof that it works and susceptibility testing is difficult to perform. On the flip side (MAJOR) there is higher mortality in PNA and BSI, especially with Pseudomonas, which is a HUGE negative for this agent.

My major take away: 

-Mild infections (cystitis) there are alternate agents to a carbapenem or new Beta-Lactam.

-For more complicated infections a carbapenem or newer agent is preferred therapy

-For complicated infections change form piperacillin-tazobactam or cefepime to a preferred agent

-Once recovery has been documented you can use an oral FQ or TMP-SMX

-Treatment duration should not be affected by AMR

-We need more and better therapies for Pseudomonas. And this does not even discuss treatment of Acinetobacter, Achromobacter and Stenotrophomonas.

References:

https://www.idsociety.org/practice-guideline/amr-guidance/