Acinetobacter baumannii: Epidemiology, Antimicrobial Resistance, and Treatment Options

Abstract

Multidrug-resistant Acinetobacter baumannii is recognized to be among the most difficult antimicrobial-resistant gram-negative bacilli to control and treat. Increasing antimicrobial resistance among Acinetobacter isolates has been documented, although definitions of multidrug resistance vary in the literature. A. baumannii survives for prolonged periods under a wide range of environmental conditions. The organism causes outbreaks of infection and health care–associated infections, including bacteremia, pneumonia, meningitis, urinary tract infection, and wound infection. Antimicrobial resistance greatly limits the therapeutic options for patients who are infected with this organism, especially if isolates are resistant to the carbapenem class of antimicrobial agents. Because therapeutic options are limited for multidrug-resistant Acinetobacter infection, the development or discovery of new therapies, well-controlled clinical trials of existing antimicrobial regimens and combinations, and greater emphasis on the prevention of health care–associated transmission of multidrug-resistant Acinetobacter infection are essential. Visit to: acinetobacterbaumannii.com

Epidemiology

Risk factors for colonization or infection with multidrug-resistant Acinetobacter species include prolonged length of hospital stay, exposure to an intensive care unit (ICU), receipt of mechanical ventilation, colonization pressure, exposure to antimicrobial agents, recent surgery, invasive procedures, and underlying severity of illness [1, 3]. Widespread environmental contamination is often demonstrated, and outbreaks of infection have been traced to respiratory care equipment, wound care procedures, humidifiers, and patient care items [4–13]. Wilks et al. [8] reported a recent outbreak of multidrug-resistant Acinetobacter infection, with environmental contamination found on curtains, laryngoscope blades, patient lifting equipment, door handles, mops, and keyboards. Medical equipment has been implicated, emphasizing the need for special attention to disinfection of shared items and extra caution with respiratory care and wound care procedures [4, 5, 7]. One or more epidemic Acinetobacter clones often coexist with endemic strains, making it difficult to detect and control transmission. https://academic.oup.com/cid/article/46/8/1254/362279

Symptoms of Acinetobacter infection

Acinetobacter causes a variety of diseases, ranging from pneumonia to serious blood or wound infections, and the symptoms vary depending on the disease. Acinetobacter may also “colonize” or live in a patient without causing infection or symptoms, especially in tracheostomy sites or open wounds.

Transmission of Acinetobacter infection

Acinetobacter poses very little risk to healthy people. However, people who have weakened immune systems, chronic lung disease, or diabetes may be more susceptible to infections with Acinetobacter. Hospitalized patients, especially very ill patients on a ventilator, those with a prolonged hospital stay, those who have open wounds, or any person with invasive devices like urinary catheters are also at greater risk for Acinetobacter infection. Acinetobacter can be spread to susceptible persons by person-to-person contact or contact with contaminated surfaces.

Prevention of Acinetobacter infection

Acinetobacter can live on the skin and may survive in the environment for several days. Careful attention to infection control procedures, such as hand hygiene and environmental cleaning, can reduce the risk of transmission.

Treatment

Carbapenems. Increasing antimicrobial resistance leaves few therapeutic options, and there are no well-designed clinical trials to compare treatment regimens for multidrug-resistant Acinetobacter infection. Available data are from in vitro, animal, and observational studies. Carbapenems remain the treatment of choice if isolates retain susceptibility to this antimicrobial class. The Meropenem Yearly Susceptibility Test Information Collection (MYSTIC) surveillance program has documented discordance that favors imipenem as the more potent agent, compared with meropenem, for treatment of multidrug-resistant Acinetobacter infection [78, 79]. The converse result was reported in Greece [80]. Efflux pumps may affect meropenem to a greater degree, whereas specific ²-lactamases hydrolyze imipenem more efficiently [80]. Susceptibility testing of imipenem does not predict susceptibility to meropenem or vice versa [78]. Unfortunately, carbapenem-resistant Acinetobacter isolates are increasingly reported worldwide.

²-Lactamase inhibitors. ²-Lactamase inhibitors, particularly sulbactam, have intrinsic activity against many Acinetobacter strains. The presence of a ²-lactam agent (e.g., ampicillin) in combination with the ²-lactamase inhibitor does not appear to contribute activity or synergy [81, 82]. Monotherapy with sulbactam is not recommended for severe Acinetobacter infection. However, Wood et al. [83] reported successful use of sulbactam to treat 14 patients with multidrug-resistant Acinetobacter ventilator-associated pneumonia, finding no difference in clinical outcomes between sulbactam-treated patients and 63 patients who received imipenem. Levin et al. [84] reported a cure rate of 67% using ampicillin-sulbactam to treat carbapenem-resistant Acinetobacter infection, but good patient outcomes were associated with lower severity of illness. The results of antimicrobial susceptibility tests (e.g., with agar dilution or the Etest) of ²–lactam/²-lactamase combinations at fixed concentrations must be interpreted with caution, because they may indicate susceptibility when an isolate is actually resistant [82].

Tigecycline. Tigecycline, a relatively new glycylcycline agent, has bacteriostatic activity against multidrug-resistant Acinetobacter species [85, 86]. High-level resistance to tigecycline has been detected among some multidrug-resistant Acinetobacter isolates, and there is concern that the organism can rapidly evade this antimicrobial agent by upregulating chromosomally mediated efflux pumps [68, 87–91]. Peleg et al. [89] reported 2 cases of multidrug-resistant Acinetobacter bacteremia that occurred while patients were receiving tigecycline for another indication. Two recent studies documented overexpression of a multidrug efflux pump in Acinetobacter isolates with decreased susceptibility to tigecycline [92, 93]. Given these findings and concern about whether adequate peak serum concentrations can be achieved, tigecycline is best reserved for salvage therapy, with administration determined in consultation with an infectious diseases specialist [89].

Aminoglycosides. Aminoglycoside agents, such as tobramycin and amikacin, are therapeutic options for infection with multidrug-resistant Acinetobacter isolates that retain susceptibility. These agents are usually used in conjunction with another active antimicrobial agent. Many multidrug-resistant Acinetobacter isolates retain intermediate susceptibility to amikacin or tobramycin; resistance to this class of agents is increasingly associated with aminoglycoside-modifying enzymes or efflux pump mechanisms.

Polymyxin therapy. Given limited therapeutic options, clinicians have returned to the use of polymyxin B or polymyxin E (colistin) for the most drug-resistant Acinetobacter infections [94, 95]. Colistin acts by disturbing the bacterial cell membrane, thus increasing permeability, leading to cell death [94]. Colistin is bactericidal against Acinetobacter species, and its effect is concentration dependent [95]. Resistance to polymyxins has been reported, possibly as a result of outer cell membrane alterations or an efflux pump mechanism [65, 66, 94, 95]. Observational studies have reported rates of cure or improvement for colistin of 57%–77% among severely ill patients with multidrug-resistant Acinetobacter infections, including pneumonia, bacteremia, sepsis, intra-abdominal infection, and CNS infection [96–99]. Although high-quality pharmacokinetic data are lacking, colistin is reported to have relatively poor lung and CSF distribution, and clinical outcomes vary for different types of infections [96]. Despite an overall “good outcome” rate of 67%, Levin et al. [96] found a lower response rate of 25% for patients with pneumonia due to multidrug-resistant, gram-negative bacilli who were treated with parenteral colistin. Other studies have reported more favorable clinical response rates (56%–61%) for parenteral colistin treatment of multidrug-resistant Acinetobacter ventilator-associated pneumonia [100–103].

There are case reports of successful treatment of multidrug-resistant Acinetobacter meningitis with parenteral colistin, but its efficacy for this condition remains unclear [104, 105]. Several case reports and case series report the use of intraventricular or intrathecal polymyxin therapy, with or without parenteral therapy, for the treatment of gram-negative bacterial meningitis [104, 106–108]. A recent review of 31 reports involving 64 episodes of gram-negative bacterial meningitis found a cure rate of 80%, including cure for 10 (91%) of 11 patients with Acinetobacter meningitis [109]. The majority of patients received systemic antimicrobial therapy in addition to local administration of polymyxin. Neurologic toxicity occurred primarily in reports published before 1970, and the most common manifestation was meningeal irritation, which was apparently dose-dependent and reversible [109]. Overall, there is insufficient evidence to draw conclusions regarding the efficacy, safety, or pharmacokinetic properties of colistin for treatment of CNS infection, although it remains an important option for salvage therapy [104].

Data are lacking on the pharmacokinetics, pharmacodynamics, and toxicodynamics of colistin. Earlier methods of measuring serum concentrations of the drug were unable to adequately distinguish concentrations of colistimethate, the nonactive prodrug, from concentrations of colistin [95]. There are inconsistencies among manufacturers regarding the recommended dosing of colistin and the units of measurement employed [95]. Data suggest that current recommended dosing regimens may lead to serum levels of colistin that are less than the MIC for Acinetobacter infection [95]. These problems highlight the need for careful pharmacologic studies and the importance of attention to formulation and dosing in clinical care and research studies.

Synergy and combination therapy. A lack of controlled clinical trials makes it difficult to evaluate the role of synergy or combination therapy for multidrug-resistant Acinetobacter infection. Most available data are from uncontrolled case series, animal models, or in vitro studies. The studies summarized in table 2 investigated various combinations of rifampin, sulbactam, aminoglycoside agents, colistin, carbapenems, and other agents against multidrug-resistant Acinetobacter infection [102, 110–123].