Thursday, March 12, 2020

ESBL- and AmpC-producing Enterobacteriaceae , including Carbapenem-resistant Enterobacteriaceae (CRE)


Summary of positive and negative aspects and dosing of potentially useful drugs in the treatment of infections with ESBL- and AmpC-producing Enterobacteriaceae:

Drug
Positive aspects
Negative aspects
Dosing (for adults with normal renal function)
and comments
Meropenem, imipenem, doripenem
Reference drugs, usually active
Ecological impact; less experience with doripenem
Standard dosing is recommended
Ertapenem
Not active against P. aeruginosa; usually
active; convenient for outpatient therapy
and deescalation from other carbapenems
Ecological impact if CPE endemicity / outbreak; doubts in
cases of septic shock (insufficient dosing?); anecdotal failures described with development of resistance (porin loss)
1 g/day in most situations; for septic shock or high-inoculum infections with borderline MIC isolates, use other alternatives or increase
dose to 2 g/day
Amoxicillin-clavulanic acid
No inoculum effect; probably noninferior to
carbapenems in UTI and biliary tract
infections; not active against P. aeruginosa; convenient for oral switch
Not available for i.v. use in many countries;
heterogeneous resistance rates, usually >40% among
ESBL producers; AmpC producers are resistant
Intravenous, 2.2 g/8 h; oral, at least 1.250 g/8h for UTI
Ceftolozane-tazobactam
Areas with large proportions of susceptible isolates
Reserve drug for MDR P. aeruginosa infection; scarce
experience so far; 10-30% resistance rates among ESBL producers, lower rates in AmpC producers
1.5 g/8h; approved for cUTI and cIAI (with
metronidazole); consider 3 g/8 h for
pneumonia
Ceftazidime-avibactam
Large proportion of susceptible isolates
Reserve drug for KPC- or OXA-48-producing
Enterobacteriaceae
2.5 g/8 h; approved for cUTI and cIAI (with
metronidazole); in Europe, also approved for HAP in case of limited options
Cefotaxime, ceftriaxone, ceftazidime,
cefepime
Some ESBL-E may be susceptible; cefepime
is usually active against AmpC producers
Most isolates are resistant (except to cefepime in the
case of AmpC producers); inoculum effect; ecological
impact; clinical data are scarce and contradictory
If used, high doses are recommended
(cefotaxime, 1 g/6 h to 2 g/8 h; ceftazidime
or cefepime, 2 g/8 h)
Cefoxitin, cefotetan, cefmetazole,
moxalactam, flomoxef
Not active against P. aeruginosa; areas with
large proportions of susceptible isolates
(ESBL producers); probably useful against
UTI for stable patients
AmpC producers are resistant; inoculum effect;
observational studies with contradictory results;
anecdotally described development of resistance
during therapy
High doses; close follow-up needed
Temocillin
Active against ESBL and AmpC producers;
not active against P. aeruginosa
Not available in many countries; comparative studies are lacking


Probably 2 g every 8 h
Gentamicin, tobramycin, amikacin
Active against many ESBL and AmpC producers; useful for UTI
Nephrotoxicity; less efficacious in non-UTI infections; heterogeneous resistance rates
Standard dosing; may be considered empirically as carbapenem sparing
agents (in monotherapy or in
combination with a lower-spectrum beta-
lactam) until microbiological data are available
Tigecycline
Active against most ESBL and AmpC producers; not active against P. aeruginosa
FDA and EMA warnings for use only if other options
are unavailable/unsuitable; probably not a good
option for UTI or HAP
100-mg loading dose, 50 mg/12 h; may be an
alternative in cIAI

Fosfomycin (i.v.)
Noninferior to piperacillin-tazobactam in
cUTI (pending publication of data)
Not available in many countries; scant experience; risk of emergence of resistant subpopulations with monotherapy
4 g/6 h to 6–8 g/8 h
Ciprofloxacin, levofloxacin
Potentially useful for fully susceptible isolates; convenient for oral switch
Ecological impact; most isolates are resistant; failures for isolates with MICs of 0.5–1 mg/liter have been described
For i.v. ciprofloxacin, 400 mg/8–12 h; for oral ciprofloxacin, 500–700 mg/12 h; for
levofloxacin (i.v., oral), 750 mg/24 h
Trimethoprim-sulfamethoxazole
( Bactrim / Co-trimoxazole )
Convenient for oral switch
Most isolates are resistant; scant published experience
i.v. or oral, 160/800 mg/8–12 h

·         CPE: carbapenemase-producing Enterobacteriaceae
·         cUTI: complicated urinary tract infection
·         cIAI: complicated intrabadominal infection


Recommended dosing for the most frequently used drugs against carbapenem-resistant Enterobacteriaceae (CRE) for patients with normal renal function:



Drug
Usual/standard dose(s)
Dosing for CRE and comments
Meropenem
1 g/8 h
2 g/8 h by EI (isolates with MICs of 2–8 mg/liter; for isolates with higher MICs, it is probably not efficacious)
Ertapenem
1 g/24 h
Consider 2 g/day for double-carbapenem regimens
Colistin (a)
From the EMA, loading dose, 6–9 MU, and then 9 MU/day in 2–3 doses; from the FDA, 2.5–5 mg of colistin base activity/kg/day
EMA dose is recommended for severe CRE infections; the need for a loading dose and high continuation dose in patients without severe infection/shock is controversial
Polymyxin B (b)
From the FDA, 1.5–2.5 mg/kg/day in 2 doses
For mild infections and isolates with MICs of ≤1 mg/liter, the FDA dose is probably appropriate; for severe infections and isolates with MICs of up to 4 mg/liter, a loading dose of 2–2.5 mg/kg followed by 3 mg/kg/day in 2 doses is recommended (controversially)
Tigecycline
100-mg loading dose and then 50 mg/12 h
For HAP, cUTI, BSI, or shock, consider a 200-mg loading dose and then 100 mg/12 h
Gentamicin, tobramycin
5–7 mg/kg/day
For HAP or shock without other options, higher doses (10–15 mg/kg) might be considered, but the risk of toxicity is high; TDM is recommended
Amikacin
15–20 mg/kg/day
For HAP or shock without other options, higher doses (25–30 mg/kg) might be considered, but the risk of toxicity is high; TDM is recommended
Fosfomycin
4 g/6 h to 8 g/8 h
Use in combination; high sodium concn
Temocillin
2 g/8–12 h
KPC producers are occasionally susceptible; continuous infusion improves PK-PD target attainment
Aztreonam
1–2 g/8 h
MBL producers are susceptible if they are not ESBL or AmpC producers
Ceftazidime
1–2 g/8 h
OXA-48 producers are susceptible if they are not ESBL or AmpC producers
Ceftazidime-avibactam
2.5 g/8 h
KPC and OXA-48 producers are frequently susceptible
Meropenem-vaborbactam
2/2 g/8 h
KPC producers are frequently susceptible
Please refer to the text for explanations and references. EI, extended infusion; EMA, European Medicines Agency; FDA, U.S. Food and Drug Administration; HAP, hospital-acquired pneumonia; cUTI, complicated urinary tract infection; BSI, bloodstream infection; MU, million units; TDM, therapeutic drug monitoring; MBL, metallo-β-lactamase.

a = One million units of colistimethate sodium = 80 mg colistimethate sodium = 34 mg of colistin base activity.
b = One million units of polymyxin B = 100 mg of colistin base activity.


Multidrug-resistant A. baumannii and P. aeruginosa
For multidrug-resistant A. baumannii and P. aeruginosa, the polymyxins (ie, colistin and polymyxin B) are usually the cornerstones for therapy. Combination therapy is also advised when polymyxins are used to treat multidrug-resistant A. baumannii and P. aeruginosa.

Most multidrug-resistant A. baumannii and P. aeruginosa retain susceptibility for the polymyxins. Aminoglycosides may be useful, particularly for urinary tract infections, assuming susceptibility is retained for one of these antibiotics. Otherwise, there are a limited number agents with potential activity. Carbapenem-resistant A. baumannii and P. aeruginosa are typically resistant to all beta-lactams and fluoroquinolones. The intrinsic resistance of these organisms further limits antibiotic options. Although sulbactam has been used to treat some infections due to A. baumannii, most multidrug-resistant isolates of A. baumannii have reduced susceptibility to this agent.


Acinetobacter Infection
In the setting of resistance to first line agents, therapeutic options are generally limited to polymyxins (colistin [polymyxin E] and polymyxin B), minocycline, and tigecycline. We generally use polymyxins, for which there is the most clinical experience in treating extensively drug-resistant Acinetobacter. Furthermore, tigecycline may not reach adequate levels in the serum, urinary tract, or CNS to successfully treat infections in these compartments. Susceptibility testing for these agents should be performed as well prior to their use given the possibility of resistance.

We generally favor using a second agent, such as a carbapenem, minocycline, tigecycline, or rifampin, in addition to polymyxins for serious infections (eg, bacteremia, pneumonia, critical illness) with resistant isolates. There are no definitive clinical data that demonstrate improved outcomes with combination versus monotherapy, and some randomized trials have suggested that certain combinations (colistin and rifampin or colistin and meropenem) resulted in comparable clinical outcomes as monotherapy with colistin. Nevertheless, infections with multidrug-resistant Acinetobacter are associated with high mortality rates, and we are concerned that the use of a single agent is not adequate, particularly since resistance can develop during therapy, leaving no therapeutic alternatives.

Inhaled colistin may be beneficial in select patients, although not all studies suggest a benefit. We favor use of inhaled colistin among patients with severe pneumonia due to Acinetobacter that is resistant to beta-lactams and carbapenems (ie, sensitive to colistin only), since intravenous colistin yields low lung concentration.


Pseudomonas aeruginosa infection
A polymyxin (colistin or polymyxin B) is the only therapeutic option for some strains of multidrug-resistant P. aeruginosa. Thus colistin is being increasingly used despite its well-known propensity for causing nephrotoxicity and ototoxicity


References:
  1. ·         Rodríguez-Baño et al. Treatment of Infections Caused by Extended-Spectrum-Beta-Lactamase-, AmpC-, and Carbapenemase-Producing Enterobacteriaceae. Clinical Microbiology Reviews Feb 2018, 31 (2) e00079-17
  2. ·         UptoDate: Overview of carbapenemase-producing gram-negative bacilli
  3. ·         UptoDate: Acinetobacter infection: Treatment and prevention
  4. ·         UptoDate: Principles of antimicrobial therapy of Pseudomonas aeruginosa infections
All information accessed on 24 Feb 2020

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