Efficacy of Rifampin and Its Combinations with Imipenem, Sulbactam, and Colistin in Experimental Models of Infection Caused by Imipenem-Resistant Acinetobacter baumannii

ABSTRACT There are currently no defined optimal therapies available for multidrug-resistant (MDR) Acinetobacter baumannii infections. We evaluated the efficacy of rifampin, imipenem, sulbactam, colistin, and their combinations against MDR A. baumannii in experimental pneumonia and meningitis models. The bactericidal in vitro activities of rifampin, imipenem, sulbactam, colistin, and their combinations were tested using time-kill curves. Murine pneumonia and rabbit meningitis models were evaluated using the A. baummnnii strain Ab1327 (with MICs for rifampin, imipenem, sulbactam, and colistin of 4, 32, 32, and 0.5 mg/liter, respectively). Mice were treated with the four antimicrobials and their combinations. For the meningitis model, the efficacies of colistin, rifampin and its combinations with imipenem, sulbactam, or colistin, and of imipenem plus sulbactam were assayed. In the pneumonia model, compared to the control group, (i) rifampin alone, (ii) rifampin along with imipenem, sulbactam, or colistin, (iii) colistin, or (iv) imipenem plus sulbactam significantly reduced lung bacterial concentrations (10.6 ± 0.27 [controls] versus 3.05 ± 1.91, 2.07 ± 1.82, 2.41 ± 1.37, 3.4 ± 3.07, 6.82 ± 3.4, and 4.22 ± 2.72 log10 CFU/g, respectively [means ± standard deviations]), increased sterile blood cultures (0% versus 78.6%, 100%, 93.3%, 93.8%, 73.3%, and 50%), and improved survival (0% versus 71.4%, 60%, 46.7%, 43.8%, 40%, and 85.7%). In the meningitis model rifampin alone or rifampin plus colistin reduced cerebrospinal fluid bacterial counts (−2.6 and −4.4 log10 CFU/ml). Rifampin in monotherapy or with imipenem, sulbactam, or colistin showed efficacy against MDR A. baumannii in experimental models of pneumonia and meningitis. Imipenem or sulbactam may be appropriate for combined treatment when using rifampin.

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In Vitro Activity and In Vivo Efficacy of Clavulanic Acid against Acinetobacter baumannii

Antimicrobial Agents and Chemotherapy ◽

10.1128/aac.00320-09 ◽

2009 ◽

Vol 53 (10) ◽

pp. 4298-4304 ◽

Cited By ~ 7

Author(s):

Alejandro Beceiro ◽

Rafael López-Rojas ◽

Juan Domínguez-Herrera ◽

Fernando Docobo-Pérez ◽

Germán Bou ◽

...

Keyword(s):

Acinetobacter Baumannii ◽

Clavulanic Acid ◽

Control Group ◽

In Vitro Activity ◽

Untreated Control Group ◽

Time Kill ◽

First Time ◽

Bacterial Concentrations

ABSTRACT Clavulanic acid (CLA) exhibits low MICs against some Acinetobacter baumannii strains. The present study evaluates the efficacy of CLA in a murine model of A. baumannii pneumonia. For this purpose, two clinical strains, Ab11 and Ab51, were used; CLA MICs for these strains were 2 and 4 mg/liter, respectively, and the imipenem (IPM) MIC was 0.5 mg/liter for both. A pneumonia model in C57BL/6 mice was used. The CLA dosage (13 mg/kg of body weight given intraperitoneally) was chosen to reach a maximum concentration of the drug in serum similar to that in humans and a time during which the serum CLA concentration remained above the MIC equivalent to 40% of the interval between doses. Six groups (n = 15) were inoculated with Ab11 or Ab51 and were allocated to IPM or CLA therapy or to the untreated control group. In time-kill experiments, CLA was bactericidal only against Ab11 whereas IPM was bactericidal against both strains. CLA and IPM both decreased bacterial concentrations in lungs, 1.78 and 2.47 log10 CFU/g (P ≤ 0.001), respectively, in the experiments with Ab11 and 2.42 and 2.28 log10 CFU/g (P ≤ 0.001), respectively, with Ab51. IPM significantly increased the sterility of blood cultures over that for the controls with both strains (P ≤ 0.005); CLA had the same effect with Ab51 (P < 0.005) but not with Ab11 (P = 0.07). For the first time, we suggest that CLA may be used for the treatment of experimental severe A. baumannii infections.

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In VitroandIn VivoActivities of E-101 Solution against Acinetobacter baumannii Isolates from U.S. Military Personnel

Antimicrobial Agents and Chemotherapy ◽

10.1128/aac.01606-10 ◽

2011 ◽

Vol 55 (7) ◽

pp. 3603-3608 ◽

Cited By ~ 4

Author(s):

G. A. Denys ◽

J. C. Davis ◽

P. D. O'Hanley ◽

J. T. Stephens

Keyword(s):

Acinetobacter Baumannii ◽

Bactericidal Activity ◽

Military Personnel ◽

Multidrug Resistant ◽

Full Thickness ◽

Content Type ◽

Full Thickness Excision ◽

Time Kill

ABSTRACTWe evaluated thein vitroandin vivoactivity of a novel topical myeloperoxidase-mediated antimicrobial, E-101 solution, against 5 multidrug-resistantAcinetobacter baumanniiisolates recovered from wounded American soldiers. Time-kill studies demonstrated rapid bactericidal activity against allA. baumanniistrains tested in the presence of 3% blood. Thein vitrobactericidal activity of E-101 solution againstA. baumanniistrains was confirmed in a full-thickness excision rat model. Additionalin vivostudies appear warranted.

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In Vitro Antibacterial Activity of Cefiderocol against Multidrug-Resistant Acinetobacter baumannii

Antimicrobial Agents and Chemotherapy ◽

10.1128/aac.02646-20 ◽

2021 ◽

Author(s):

Jacinda C. Abdul-Mutakabbir ◽

Logan Nguyen ◽

Philip T. Maassen ◽

Kyle C. Stamper ◽

Razieh Kebriaei ◽

...

Keyword(s):

Acinetobacter Baumannii ◽

Susceptibility Testing ◽

Inhibitory Concentration ◽

Multidrug Resistant ◽

Synergistic Activity ◽

Strong Activity ◽

Gram Negative ◽

In Vitro Antibacterial Activity ◽

Time Kill

Cefiderocol (CFDC), a novel siderophore cephalosporin, demonstrates strong activity against multidrug-resistant (MDR) Acinetobacter baumannii. Limited studies have evaluated CFDC alone and in combination with other Gram-negative antibiotics against MDR A. baumannii isolates. Susceptibility testing revealed lower CFDC minimum inhibitory concentration (MIC) values than the comparator Gram-negative agents (87% of MICs ≤ 4mg/L). Six isolates, with elevated CFDC MICs (16-32 mg/L), were selected for further experiments. Time-kill analyses presented with synergistic activity and beta-lactamase inhibitors increased CFDC susceptibility in each of the isolates.

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Colistin and Fusidic Acid, a Novel Potent Synergistic Combination for Treatment of Multidrug-Resistant Acinetobacter baumannii Infections

Antimicrobial Agents and Chemotherapy ◽

10.1128/aac.00753-15 ◽

2015 ◽

Vol 59 (8) ◽

pp. 4544-4550 ◽

Cited By ~ 18

Author(s):

Lynette M. Phee ◽

Jonathan W. Betts ◽

Binutha Bharathan ◽

David W. Wareham

Keyword(s):

Acinetobacter Baumannii ◽

Fusidic Acid ◽

Multidrug Resistant ◽

Content Type ◽

Low Concentrations ◽

Resistant Strains ◽

Time Kill ◽

Susceptibility Breakpoint ◽

Selection Of

ABSTRACTThe spread of multidrug-resistantAcinetobacter baumannii(MDRAB) has led to the renaissance of colistin (COL), often the only agent to which MDRAB remains susceptible. Effective therapy with COL is beset with problems due to unpredictable pharmacokinetics, toxicity, and the rapid selection of resistance. Here, we describe a potent synergistic interaction when COL was combined with fusidic acid (FD) againstA. baumannii. Synergyin vitrowas assessed against 11 MDRAB isolates using disc diffusion, checkerboard methodology (fractional inhibitory concentration index [FICI] of ≤ 0.5, susceptibility breakpoint index [SBPI] of >2), and time-kill methodology (≥2 log10CFU/ml reduction). The ability of FD to limit the emergence of COL resistance was assessed in the presence and absence of each drug alone and in combination. Synergy was demonstrated against all strains, with an average FICI and SBPI of 0.064 and 78.85, respectively. In time-kill assays, COL-FD was synergistic and rapidly bactericidal, including against COL-resistant strains. Fusidic acid prevented the emergence of COL resistance, which was readily selected with COL alone. This is the first description of a novel COL-FD regimen for the treatment of MDRAB. The combination was effective at low concentrations, which should be therapeutically achievable while limiting toxicity. Further studies are warranted to determine the mechanism underlying the interaction and the suitability of COL-FD as an unorthodox therapy for the treatment of multidrug-resistant Gram-negative infections.

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Effect of Hypoxia on the Pathogenesis of Acinetobacter baumannii and Pseudomonas aeruginosa In Vitro and in Murine Experimental Models of Infection

Infection and Immunity ◽

10.1128/iai.00543-18 ◽

2018 ◽

Vol 86 (10) ◽

Cited By ~ 7

Author(s):

María Luisa Gil-Marqués ◽

María Eugenía Pachón-Ibáñez ◽

Jerónimo Pachón ◽

Younes Smani

Keyword(s):

Pseudomonas Aeruginosa ◽

Epithelial Cells ◽

Acinetobacter Baumannii ◽

Experimental Models ◽

Host Cells ◽

Content Type ◽

Bactericidal Activities ◽

Bacterial Concentrations

ABSTRACT Hypoxia modulates bacterial virulence and the inflammation response through hypoxia-inducible factor 1α (HIF-1α). Here we study the influence of hypoxia on Acinetobacter baumannii and Pseudomonas aeruginosa infections. In vitro, hypoxia increases the bactericidal activities of epithelial cells against A. baumannii and P. aeruginosa, reducing extracellular bacterial concentrations to 50.5% ± 7.5% and 90.8% ± 13.9%, respectively, at 2 h postinfection. The same phenomenon occurs in macrophages (67.6% ± 18.2% for A. baumannii at 2 h and 50.3% ± 10.9% for P. aeruginosa at 24 h). Hypoxia decreases the adherence of A. baumannii to epithelial cells (42.87% ± 8.16% at 2 h) and macrophages (52.0% ± 18.7% at 24 h), as well as that of P. aeruginosa (24.9% ± 4.5% in epithelial cells and 65.7% ± 5.5% in macrophages at 2 h). Moreover, hypoxia decreases the invasion of epithelial cells (48.6% ± 3.8%) and macrophages (8.7% ± 6.9%) by A. baumannii at 24 h postinfection and by P. aeruginosa at 2 h postinfection (75.0% ± 16.3% and 63.4% ± 5.4%, respectively). In vivo, hypoxia diminishes bacterial loads in fluids and tissues in animal models of infection by both pathogens. In contrast, mouse survival time was shorter under hypoxia (23.92 versus 36.42 h) with A. baumannii infection. No differences in the production of cytokines or HIF-1α were found between hypoxia and normoxia in vitro or in vivo. We conclude that hypoxia increases the bactericidal activities of host cells against both pathogens and reduces the interaction of pathogens with host cells. Moreover, hypoxia accelerates the rate at which animals die despite the lower bacterial concentrations in vivo.

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In Vitro Activity of Tigecycline against Multidrug-Resistant Acinetobacter baumannii and Selection of Tigecycline-Amikacin Synergy

Antimicrobial Agents and Chemotherapy ◽

10.1128/aac.01581-07 ◽

2008 ◽

Vol 52 (8) ◽

pp. 2940-2942 ◽

Cited By ~ 27

Author(s):

Ellen S. Moland ◽

David W. Craft ◽

Seong-geun Hong ◽

Soo-young Kim ◽

Lucas Hachmeister ◽

...

Keyword(s):

Acinetobacter Baumannii ◽

Polymyxin B ◽

Multidrug Resistant ◽

Vitro Activity ◽

Resistant Isolate ◽

In Vitro Activity ◽

Bactericidal Activities ◽

Time Kill ◽

Selection Of

ABSTRACT Polymyxin B, minocycline, and tigecycline were the most potent of 10 antibiotics against 170 isolates of multidrug-resistant Acinetobacter baumannii. In time-kill studies, the exposure of a highly tigecycline-resistant isolate to tigecycline resulted in enhanced susceptibility to amikacin and synergistic bactericidal activities of the two drugs.

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In Vitro Evaluation of Antimicrobial Peptide Tridecaptin M in Combination with Other Antibiotics against Multidrug Resistant Acinetobacter baumannii

Molecules ◽

10.3390/molecules25143255 ◽

2020 ◽

Vol 25 (14) ◽

pp. 3255

Author(s):

Manoj Jangra ◽

Vrushali Raka ◽

Hemraj Nandanwar

Keyword(s):

Antimicrobial Peptide ◽

Acinetobacter Baumannii ◽

Ex Vivo ◽

Combined Treatment ◽

Antimicrobial Effect ◽

Concomitant Administration ◽

Multidrug Resistant ◽

Infection Model ◽

Permeability Barrier

The rapid emergence of antimicrobial resistance in Acinetobacter baumannii coupled with the dried pipeline of novel treatments has driven the search for new therapeutic modalities. Gram-negative bacteria have an extra outer membrane that serves as a permeability barrier for various hydrophobic and/or large compounds. One of the popular approaches to tackle this penetration barrier is use of potentiators or adjuvants in combination with traditional antibiotics. This study reports the in vitro potential of an antimicrobial peptide tridecaptin M in combination with other antibiotics against different strains of A. baumannii. Tridecaptin M sensitized the bacteria to rifampicin, vancomycin, and ceftazidime. Further, we observed that a tridecaptin M and rifampicin combination killed the bacteria completely in 4 h in an ex vivo blood infection model and was superior to rifampicin monotherapy. The study also found that concomitant administration of both compounds is not necessary to achieve the antimicrobial effect. Bacteria pre-treated with tridecaptin M (for 2–4 h) followed by exposure to rifampicin showed similar killing as obtained for combined treatment. Additionally, this combination hampered the survival of persister development in comparison to rifampicin alone. These findings encourage the future investigation of this combination to treat severe infections caused by extremely drug-resistant A. baumannii.

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In VitroSynergy of Colistin Combinations against Colistin-Resistant Acinetobacter baumannii, Pseudomonas aeruginosa, and Klebsiella pneumoniae Isolates

Antimicrobial Agents and Chemotherapy ◽

10.1128/aac.05996-11 ◽

2012 ◽

Vol 56 (9) ◽

pp. 4856-4861 ◽

Cited By ~ 72

Author(s):

Céline Vidaillac ◽

Lothaire Benichou ◽

Raphaël E. Duval

Keyword(s):

Pseudomonas Aeruginosa ◽

Klebsiella Pneumoniae ◽

Acinetobacter Baumannii ◽

Population Analysis ◽

Multidrug Resistant ◽

Colistin Resistance ◽

Content Type ◽

Checkerboard Assay ◽

Time Kill

ABSTRACTColistin resistance, although uncommon, is increasingly being reported among Gram-negative clinical pathogens, and an understanding of its impact on the activity of antimicrobials is now evolving. We evaluated the potential for synergy of colistin plus trimethoprim, trimethoprim-sulfamethoxazole (1/19 ratio), or vancomycin against 12 isolates ofAcinetobacter baumannii(n= 4),Pseudomonas aeruginosa(n= 4), andKlebsiella pneumoniae(n= 4). The strains included six multidrug-resistant clinical isolates,K. pneumoniaeATCC 700603,A. baumanniiATCC 19606,P. aeruginosaATCC 27853, and their colistin-resistant derivatives (KPm1, ABm1, and PAm1, respectively). Antimicrobial susceptibilities were assessed by broth microdilution and population analysis profiles. The potential for synergy of colistin combinations was evaluated using a checkerboard assay, as well as static time-kill experiments at 0.5× and 0.25× MIC. The MIC ranges of vancomycin, trimethoprim, and trimethoprim-sulfamethoxazole (1/19) were ≥128, 4 to ≥128, and 2/38 to >128/2,432 μg/ml, respectively. Colistin resistance demonstrated little impact on vancomycin, trimethoprim, or trimethoprim-sulfamethoxazole MIC values. Isolates with subpopulations heterogeneously resistant to colistin were observed to various degrees in all tested isolates. In time-kill assays, all tested combinations were synergistic against KPm1 at 0.25× MIC and 0.5× MIC and ABm1 and PAm1 at 0.5× MIC. In contrast, none of the tested combinations demonstrated synergy against any colistin-susceptibleP. aeruginosaisolates and clinical strains ofK. pneumoniaeisolates. Only colistin plus trimethoprim or trimethoprim-sulfamethoxazole was synergistic and bactericidal at 0.5× MIC againstK. pneumoniaeATCC 700603. Colistin resistance seems to promote thein vitroactivity of unconventional colistin combinations. Additional experiments are warranted to understand the clinical significance of these observations.

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In Vitro Double and Triple Synergistic Activities of Polymyxin B, Imipenem, and Rifampin against Multidrug-Resistant Acinetobacter baumannii

Antimicrobial Agents and Chemotherapy ◽

10.1128/aac.48.3.753-757.2004 ◽

2004 ◽

Vol 48 (3) ◽

pp. 753-757 ◽

Cited By ~ 98

Author(s):

Jimmy Yoon ◽

Carl Urban ◽

Christian Terzian ◽

Noriel Mariano ◽

James J. Rahal

Keyword(s):

Acinetobacter Baumannii ◽

Clinical Studies ◽

Three Dimensional ◽

Polymyxin B ◽

Microtiter Plate ◽

Multidrug Resistant ◽

Lethal Infection ◽

Effective Option ◽

Time Kill

ABSTRACT Eight unrelated clinical Acinetobacter baumannii isolates resistant to all commonly used antibiotics were subjected to three-dimensional checkerboard microtiter plate dilution and time-kill studies at one-fourth of their MICs of polymyxin B, imipenem, and rifampin. Synergy was demonstrated with combinations of polymyxin B and imipenem, polymyxin B and rifampin, and polymyxin B, imipenem, and rifampin. Double combinations of polymyxin B and imipenem and of polymyxin B and rifampin were bactericidal for seven of eight isolates, and triple combinations were bactericidal for all isolates within 24 h. Future clinical studies using double and triple therapy with these antibacterials may provide an effective option against potentially lethal infection due to multiresistant Acinetobacter baumannii.

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Anamnestic factors that shape reproductive health of women with repeated unsuccessful popygamy in vitro fertilization

HEALTH OF WOMAN ◽

10.15574/hw.2016.114.140 ◽

2016 ◽

pp. 140-143

Author(s):

N.V. Cotsabin ◽

◽

O.M. Makarchuk ◽

Keyword(s):

High Risk ◽

Risk Group ◽

Polycystic Ovary ◽

High Risk Group ◽

Stress Factors ◽

Control Group ◽

Fertilization In Vitro ◽

Infertile Women ◽

Group I

The proportion of patients with multiple unsuccessful attempts of assisted reproductive technology (ART) is about 30% of all patients treated with the use of ART. Women with history of unsuccessful ART attempts - a special category of patients who require emergency attention and a thorough examination at the stage of preparation for superovulation stimulation,the selection of embryos and endometrium preparation for embryo transfer. The objective: to distinguish high-risk group of unsuccessful attempts based on a detailed analysis of anamnestic and clinical data of infertile women with repeated unsuccessful ART attempts that requires more in-depth study of hormonal features, ovarian reserve and condition of the endometrium. Materials and methods. For better understanding of the problem of repeated unsuccessful ART attempts and сreation of efficient infertility treatment algorithms for these couples we conducted a thorough analysis of anamnestic data of three groups of infertile women (105 patients), which were distributed by age: group I – younger than 35, the II group – from 35 to 40, the III group - over 40 years. These groups of patients were compared with each other and with the control group of healthy women (30 persons). Results. Leading stress factors in the percentage three times prevailed in the group of infertile women and had a direct connection with the fact of procedure «fertilization in vitro» and chronic stressors caused by prolonged infertility. Primary infertility was observed significantly more frequent in patients younger than 35 years (p <0.05), secondary infertility - mostly in the second and third experimental groups (p <0.05). Noteworthy significant percentage of wellknown causes of infertility and idiopathic factor in all groups, and the prevalence of tubal-peritoneal factor in the second and third experimental groups, and endocrine dysfunction in the I experimental group. The most common disorder among this category of woman was polycystic ovary syndrome. Frequency of usual miscarriage among patients of I ana II groups was two times higher than in the third group (p <0.05). Among the experimental groups the leading place belongs urinary tract infection, respiratory tract diseases, pathologies of the cardiovascular system. Data of the stratified analysis show an increase likelihood of repeated unsuccessful ART attempts under the influence of constant chronic stress (odds ratio OR=2.06; 95% CI: 0.95–3.17; p<0.05). Conclusions. Among infertile patients with repeated unsuccessful ART attempts must be separated a high risk group of failures. The identity depends on the duration of infertility, female age and leading combination of factors. Key words: repeated unsuccessful ART attempts, anamnesis, infertility, high risk.

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