Acinetobacter sp. (baumannii complex, pittii, nosocomialis)

by David N. Gilbert, M.D. last updated 2022-01-07 09:43:12.210552-05:00 © Antimicrobial Therapy, Inc.
Acinetobacter baumannii complex, A. pittii, A. 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
    • 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.

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 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

  • The following recommendations relate to Acinetobacter infections in hospitalized infections:
    • 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
Meropenem 2 gm IV infused over 3 hrs and repeat q8h (continuous infusion regimens in clinical trial) OR
Ampicillin-sulbactam 9 gm (6 gm amp/3 gm sulb)  IV over 4 hrs and repeat q8h

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

 
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
  • 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.

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
  • 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
  • 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:
    • 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
        • 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)