Use of adjuvants in the treatment of Acinetobacter baumannii

ABSTRACT

The current antibiotic crisis to treat infections by Acinetobacter baumannii is linked with the increase of antimicrobial resistance and the lack of development of new antimicrobial drugs. For this reason, new alternatives for the treatment and control of infections by A. baumannii are necessary. Several studies have reported the effect of adjuvants to restore the efficacy of existing antimicrobial agents. Herein, we analyzed the main results on the development of adjuvant drugs, as monotherapy or in combination therapy with existing antimicrobial agents, which have shown promising results in vitro and in vivo. However, caution is needed and further extensive in vivo studies have to be performed to confirm the potential use of these adjuvants as true therapeutic alternatives.

KEYWORDS:

• Acinetobacter baumannii
• antimicrobial resistance
• adjuvant antibiotics

Acinetobacter baumannii is a Gram-negative bacillus with very high clinical relevance because of the high number of nosocomial infections caused by this bacterium, especially in intensive care units, and for being a paradigm of multi-drug antimicrobial resistance (MDR). The increase in infections by MDR A. baumannii is associated with prolonged hospital stays, increased mortality and higher costs.[1] A. baumannii is involved in a wide spectrum of infections, including pneumonia, bacteraemia, urinary tract infections, and skin and soft tissue infections, among others. A. baumannii is able to survive in the hospital environment for long periods, and several studies have emphasized the importance of environmental cleaning in controlling cross transmission infections for this bacterium.[2] All these reasons have made necessary the urgent search for new alternatives for the treatment and control of infections by A. baumannii; however, the development of new efficacious antimicrobials for these infections is lacking. Other approach would be to enhance the antibiotic activity in MDR A. baumannii infections administering antibiotics in conjunction with adjuvants, non-antibiotic compounds.[3] Thus, it is worthwhile to analyze the main results on the development of adjuvant therapeutics as monotherapy or in combination therapy in order to restore the efficacy of existing antibiotics.

1. Acinetobacter baumannii and the increasing challenge of antibiotic resistance

The multidrug-resistance in A. baumannii is a result of the combination of high level of genomic plasticity, mutation of endogenous genes, and acquisition of foreign genetic material. The principal antibiotic resistance mechanisms in A. baumannii are β-lactamases hydrolysis, penicillin-binding proteins modification, porins expression loss, efflux pump overexpression, aminoglycoside modifying enzymes activity mutations in genes codifying DNA gyrase and topoisomerase IV, and in the lpx and pmrA/B genes.[4]

A detailed analysis of the European Centre for Diseases Prevention and Control report in 2013 showed that seven European countries present a high rate (≥ 25%) of carbapenem-resistant A. baumannii.[5] In USA, 32.6% of isolates collected between 2005 and 2011 were resistant to carbapenems.[6] The high frequency of infections by MDR isolates has prompted an increase in the use of colistin. In this context, different studies showed a substantial increase in rate of A. baumannii colistin resistance. In a multicenter study conducted in Spain in 2010, the rates of colistin resistance rose to 3% from 0% in 2000; moreover, in other European and Asian countries including Greece and South Korea, the rate of colistin-resistant A. baumannii is much higher, reaching almost 28% in South Korea (as cited by Fernández-Cuenca et al. [7]). In addition, the use of other antimicrobials or the search for effective antibiotic combinations has not either reached optimal results in terms of clinical success.[3]

Therefore, antibiotic resistance is a ubiquitous and relentless clinical problem that is compounded by a dearth of new therapeutic agents. The retreat of the pharmaceutical sector from new antibiotics development has exacerbated the challenge of widespread resistance and signals a critical need for innovation. Not killing bacteria but avoiding the infection produced by A. baumannii, either immunizing the host or blocking the bacterial virulence factors, could be adjuvant approaches to reach new goals. These actions would be improved by combining the adjuvant treatment with the classical antimicrobial approach.

2. Adjuvants treatment in monotherapy

Some studies have been already performed in order to investigate the role of adjuvants as potential treatments against A. baumannii infections. Several of them have focused on the stimulation of the immune system by different approaches such the use of lysophosphatidylcholine (LPC), a major component of phospholipids in eukaryotic cells, which is involved in immune cell recruitment and modulation.[8] Preemptive therapy with LPC in murine peritoneal sepsis and pneumonia models by A. baumannii markedly enhanced spleen and lung bacterial clearance and reduced the positive blood cultures and mice mortality rates, possibly due to the reduction of proinflammatory cytokine production.[9] Other approaches are the use of small peptides or molecules with immunomodulatory properties in vitro and in vivo to control the infections caused by A. baumannii. Among them, E6k,D9k]hymenochirin-1B and Apolipoprotein E peptide [10,11] present high antibacterial activities and immunomodulatory properties in vitro, and c-di-GMP protects against murine intranasal A. baumannii infection by enhancing the neutrophil recruitment.[12] Furthermore, the inhibition of the bacterial synthesis of lipopolysaccharide (LPS), through the blocking of lpx genes, could be a potential adjuvant treatment approach.[13] LpxC inhibition blocks LPS biosynthesis, which has not effect on A. baumannii killing, but rather enhances phagocytosis and decreases inflammation, resulting in protection of mice from lethal infection.

3. Adjuvants treatment in combination therapy

Lately, an increasing number of studies address the combination of different adjuvants, in vitro and in vivo, to fight the antibiotic void alternatives to infections caused by A. baumannii. Most of these studies have tested the ability of new compounds to increase the activity of colistin.

A lipid II cell wall biosynthesis inhibitor (BAS00127538), for the first time, showed in vitro activity against MDR A. baumannii alone and synergy with colistin.[14]

Other study showed in vitro synergistic activity of piperazine derivates and sub-inhibitory concentrations of colistin against 13 clinical colistin-resistant A. baumannii strains.[15] In an in vitro study on 60 clinical carbapenem-resistant A. baumannii strains, CSA-13 ceragenin in combination with colistin, tobramycin, and ciprofloxacin demonstrated synergistic interactions, mostly with colistin but also with tobramycin.[16] Finally, in a murine peritoneal sepsis model by A. baumannii strains with different resistant phenotypes, LPC combined with colistin, tigecycline or imipenem improved the bacterial load, mice survival and bacteremia of the infection.[17]

Other studies have evaluated new adjuvant antibiotics on the activity of other classes of antimicrobials. Thus, a small-molecule (Antibiotic 301A1) showed in vitro synergy with rifampin and linezolid against Escherichia coli and A. baumannii, as an adjuvant capable of sensitizing Gram-negative bacteria to antibiotics to which they are ordinarily intrinsically resistant.[18] In an in vitro study, plant phenolics (ellagic and tannic acids) enhanced the susceptibility of MDR A. baumannii strains to a long variety of antibiotics, including aminoglycosides, β-lactams, fusidic acid, macrolides, rifampicin and tetracycline,[19] concluding that the use of such plant compounds as adjuvants could offer effective treatments in infections by A. baumannii.

Finally, Sahu et al. [20] showed the usefulness of disodium edetate, a potent class B metallo-β-lactamase (MBL) inhibitor, as an adjuvant antibiotic in combination with ceftriaxone plus sulbactam, which was active against 100% and 89% of ESBL and MBL producers MDR A. baumannii strains, respectively, concluding that this antibiotic adjuvant is effective restoring tie in vitro activity of some β-lactams .

4. Concluding remarks or future directions

Infections caused by MDR A. baumannii are a long-lasting and worldwide therapeutic challenge. While the development of new antibiotics remains one option in the fight against strains resistant to currently available ones, an attractive alternative is the development of adjuvant therapeutics to restore the efficacy of existing antibiotics. Different preliminary studies, in vitro and in vivo, have shown promising results with several adjuvant approaches. However, caution is needed and further extensive in vivo studies, such as toxicity and stability issues, and cross-resistance with drugs already in clinical use, have to be performed to elucidate the potential use of these adjuvants as true therapeutic alternatives.

Financial & competing interest disclosure

Younes Smani is supported by Plan Nacional de I+D+i and Instituto de Salud Carlos III, Subdirección General de Redes y Centros de Investigación Cooperativa, Ministerio de Economía y Competitividad, Spanish Network for Research in Infectious Diseases (REIPI RD12/0015/0001), co-financed by European Development Regional Fund “A way to achieve Europe” ERDF. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

Jerónimo Pachón

Clinical Unit of Infectious Diseases, microbiology, and Preventive Medicine, Institute of Biomedicine of Seville (IBiS), University Hospital Virgen del Rocío/CSIC/University of Seville, Seville, Spain

Younes Smani

Clinical Unit of Infectious Diseases, microbiology, and Preventive Medicine, Institute of Biomedicine of Seville (IBiS), University Hospital Virgen del Rocío/CSIC/University of Seville, Seville, Spain

CONTACT Younes smani [email protected], [email protected] Unidad Clínica de Enfermedades Infecciosas, Microbiología y Medicina Preventiva. Hospital Universitario Virgen del Rocío. Av. Manuel Siurot s/n. 41013 Seville, Spain.

María Eugenia Pachón-Ibáñez

Clinical Unit of Infectious Diseases, microbiology, and Preventive Medicine, Institute of Biomedicine of Seville (IBiS), University Hospital Virgen del Rocío/CSIC/University of Seville, Seville, Spain