Acinetobacter sp. (baumannii complex, pittii, nosocomialis)
Clinical Setting
- Acinetobacter baumannii complex causes a variety of local and systemic infections in both immunocompetent and immunocompromised patients
- Hospital-acquired opportunistic pathogen, frequent cause of ventilator-associated pneumonia
- Can cause a variety of other infections: e.g., soft tissue, wounds and bone; UTIs; meningitis; eye infections
- Any of the above can be associated with bacteremia.
- Resistance is a problem
- Acinetobacter sp. have among the largest number and variety of resistance mechanisms of all gram-negative bacilli
- Roughly 50% of Acinetobacter baumanii isolates demonstrate multi-drug resistance (MDR). In certain locations, substantive % of isolates demonstrate extensive drug resistance and even pan-drug resistance
- Resistance mechanisms, alone or in combination, include:
- Production of extended spectrum beta-lactamases (ESBLs)
- Production of AmpC cephalosporinases (rare)
- Production of serine-, metallo-, and OXA-carbapenemases
- Production of aminoglycoside-modifying enzymes
- Change in drug target binding sites, e.g., penicillin binding protein sites and DNA gyrase mutations
- Presence of efflux pumps
- Mutant porins proteins with subsequent decreased outer membrane permeability
- Roughly 50% of Acinetobacter baumanii isolates demonstrate multi-drug resistance (MDR). In certain locations, substantive % of isolates demonstrate extensive drug resistance and even pan-drug resistance
- Clinically, reliance is on phenotypic in vitro patterns of resistance. Outside of a research environment, it is not possible to identify which mechanism, or combination of mechanisms, is responsible for the lab's report of antibiotic resistance.
- For further discussion of drug resistance classes and mechanisms see Gram-negative Resistance, Overview. See Comments for other recent references on evolving treatment considerations and options.
- Acinetobacter sp. have among the largest number and variety of resistance mechanisms of all gram-negative bacilli
Classification
- Strictly aerobic non-fermentative coccobacillary gram negative bacillus
- Five Acinetobacter species are associated with human diseases:
- Acinetobacter baumannii is most important, responsible for 80% of infections
- A.pittii and A.nosocomialis also considered clinically important
- A. seifertii and A. dijkshoorniae also isolated from human clinical specimens
- Acinetobacter baumannii is most important, responsible for 80% of infections
- Acinetobacter calcoaceticus is considered a nonpathogenic environmental organism, rarely involved in causing disease
- Taxonomy reference: Future Sci OA. 2019. doi: 10.2144/fsoa-2018-0127
Primary Regimens
- Treatment options below are for therapy of moderately-severe, or severe infections in patients requiring systemic therapy
- Complicated UTI
- Ventilator associated Bacterial Pneumonia/ Hospital acquired bacterial pneumonia
- Bacteremia
- Meningitis: see Comments
Lab reports | Modifying Circumstances | Recommended Regimens | Comments |
Acinetobacter in sputum or sterile body site, antibiotic susceptibility results pending | Local rate of MDR <10-15%, not critically ill, monotherapy is reasonable |
Empiric therapy Cefepime 2 gm IV q8h OR |
No commercial source for sulbactam alone. High dose: (Eur J Pharm Sci 136:104940, 2019) |
Local rate of MDR >10-15% and/or patient is critically ill, consider combination therapy to increase odds of administering at least one active drug: |
Empiric therapy Ampicillin-sulbactam 9 gm ( 6gm amp/3 gm sulb) IV infused over 4 hrs and repeat q8h + Meropenem 2 gm IV infused over 3 hrs and repeat q8h + Polymyxin B 2.5 mg/kg loading dose IV infused over 2 hrs then, starting 12 hrs later, 1.5 mg/kg IV infused over 1 hr q12h |
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Susceptibility to multiple antibiotics | Monotherapy with Cefepime, Meropenem, or Ampicillin-sulbactam as above (see Comments) | ||
Resistance to all cephalosporins, aztreonam, and carbapenems; susceptibility to polymyxins |
Recommend infectious diseases consultation Cefiderocol 2 gm q8h IV over 3 hrs (see Comments: FDA approved for treatment of complicated UTIs and VABP/HABP) |
Another option: combination therapy with one or more of the following if susceptible in vitro (see Comments): Minocycline 200 mg IV x one dose then 100 mg IV q12 h ± Amikacin (more active than gentamicin; check renal function and monitor serum levels) ± Ampicillin-sulbactam 9 gm of sulbactam (6 gm Amp/ 3 gm sulbactam) IV over 4 hr and repeat q8h | |
Resistance to all antibiotics tested, including polymyxins | No known effective therapy: Recommend infectious diseases consultation Consider Cefiderocol 2 gm q8h IV over 3 hrs (FDA approved for treatment of complicated UTIs & VABP) |
See Comments |
Alternative Regimens
- Lab reports susceptibility to multiple antibiotics
- Some isolates may be susceptible to:
- Ciprofloxacin 400 mg IV q8h or Levofloxacin 750 mg IV q24h
- TMP-SMX 10 mg/kg/day (TMP component) IV divided q8h or q12h (Ann Pharmacother 2018; 52:120)
- Some isolates may be susceptible to:
- Lab reports MDR or extensive drug resistance
- Test for in vitro susceptibility to:
- Aminoglycosides:
- Amikacin more frequently active in vitro than gentamicin (Antimicrob Agents Chemother 2019; 63: e01154-19)
- Plazomicin: Aminoglycoside that is stable in presence of enzymes that inactivate gentamicin, tobramycin, and amikacin. Limited observational reports of success vs MDR pathogens.
- Eravacycline and Omadacycline: Next generation tetracyclines. Better pharmacokinetics than Tigecycline. Active in vitro vs Acinetobacter. No clinical data.
- Aminoglycosides:
- Test for in vitro susceptibility to:
Antimicrobial Stewardship
- Duration of therapy: Regardless of site of infection, duration of therapy is unclear and should be guided by clinical response.
Comments
- In hollow fiber in vitro model, pan-drug resistant strains of Acinetobacter were found susceptible to the combination of high concentrations of Ampicillin-sulbactam + Meropenem + Polymyxin B (Antimicrob Agents Chemother 2017;61:e01268-16).
- Cannot assume in vitro resistance of one carbapenem predicts resistance for another without testing.
- Acinetobacter is intrinsically resistant to Ertapenem.
- Susceptibility to Meropenem may not indicate susceptibility to Imipenem and vice versa
- Combination therapy with a Polymyxin + Meropenem no more efficacious than polymyxin alone (Lancet Infect Dis 2018; 18:391). Other trials found no benefit to combining a polymyxin with either Rifampin or Tigecycline
- Disease specific treatment considerations:
- Acinetobacter pneumonia:
- Based on current data, cannot recommend adjunctive inhaled/nebulized antibiotic therapy because of failure to show benefit in two prospective randomized clinical trials
- For Meningitis due to Acinetobacter species:
- If possible, remove CNS devices that may be a source
- If susceptible, Meropenem is the preferred carbapenem due to CNS penetration and lower risk of seizures as compared to other carbapenems
- If resistance to Meropenem, intraventricular or lumbar sac: Colistin; wide range of recommended doses: 0.75 mg to 7.5 mg of Colistin Base Activity per day
- For UTI:
- If carbapenem resistant and systemic therapy needed, use Colistin as Polymyxin B concentrations in the urine are very low
- If possible, remove Foley catheter
- Acinetobacter pneumonia:
- Combination therapy:
- Combination of Meropenem + polymyxin (either Polymyxin B or Colistin) not recommended:
- Based on a failed randomized controlled trial (Lancet Infect Dis 2018;18:391-400) of 406 patients with serious infections due to carbapenem-nonsusceptible Gram-negative bacteria, 77% of whom were infected with Acinetobacter baumannii.
- Rate of clinical failure (83% for Colistin and 81% for the combination) and the rate for mortality (46% for Colistin and 52% for the combination) were no better with the combination than with Colistin monotherapy.
- In subset analysis, patients infected with strains resistant to both carbapenems and colistin, mortality was less with colistin monotherapy despite the in vitro resistance (Clin Infect.Dis 2019;69:769)
- The results were no better in patients given early empiric therapy with colistin, with or without, meropenem (Clin Infect Dis 2018; 67:1815)
- The trial was under powered to compare efficacy vs carbapenem-resistant Klebsiella and Pseudomonas aeruginosa infections
- Rate of clinical failure (83% for Colistin and 81% for the combination) and the rate for mortality (46% for Colistin and 52% for the combination) were no better with the combination than with Colistin monotherapy.
- Based on a failed randomized controlled trial (Lancet Infect Dis 2018;18:391-400) of 406 patients with serious infections due to carbapenem-nonsusceptible Gram-negative bacteria, 77% of whom were infected with Acinetobacter baumannii.
- Combination of Meropenem + polymyxin (either Polymyxin B or Colistin) not recommended:
- Use of other agents
- Doripenem is not approved to treat any type of pneumonia and it is not approved for doses > 500 mg q8h.
- Tigecycline is not recommended due to sub-therapeutic serum concentrations in bacteremia plus increased risk of all cause mortality compared with other agents (Clin Infect Dis 2012 Jun;54(12):1699)
- Minocycline IV:
- Limited clinical experience (Infect Dis Ther 2017; 6:199)
- In vitro data (Antimicrob Agents Chemother 2019;63:e01154-19 ) indicates susceptibility of 67-86 % of clinical isolates
- In retrospective study of 76 patients, clinical cure and microbiologic eradication in 79% and 82% of those with monomicrobial infection (Antimicrob Agents Chemother 2019;63:e01154-19)
- Cefiderocol
- Broad range of antibacterial activity against Gram-negatives that produce ESBLs, AmpC cephalosporinases, oxacillinases, serine carbapenemases (KPCs), metallo-beta-lactamases (NDM, VIM)
- Inconclusive clinical trial results
- Cefiderocol vs. Best Available Therapy (BAT)
- Underpowered, randomized open label study of patients with nosocomial pneumonia, sepsis, complicated UTI, and bacteremia due to carbapenemase producing gram-negative bacilli: 28 day all cause mortality was 9/49 (18.4%) with BAT and 25/101 (24.8%) with cefiderocol therapy (not statistically significant): Lancet Infect Dis 2021; 21: 226
- Underpowered, randomized open label study of patients with nosocomial pneumonia, sepsis, complicated UTI, and bacteremia due to carbapenemase producing gram-negative bacilli: 28 day all cause mortality was 9/49 (18.4%) with BAT and 25/101 (24.8%) with cefiderocol therapy (not statistically significant): Lancet Infect Dis 2021; 21: 226
- Cefiderocol vs high dose meropenem for treatment of HABP/VABP due to resistant GNB in randomized double blind trial
- Cefiderocol 2 gm IV over 3 hr q8h was non-inferior to meropenem 2 gm IV over 3 hr q8h. In 16 patients with meropenem resistant Acinetobacter, day 14 all cause mortality was 0% in 5 patients treated with cefiderocol and 46% in 11 patients treated with meropenem (Lancet Infect Dis 2021; 21: 213)
- Cefiderocol vs. Best Available Therapy (BAT)
- References: Evolving treatment considerations and options
- IDSA treatment guidance (Clin Infect Dis 2022, 74:2089)
- Semin Respir Crit Care Med 2022, 43:97