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

2011 ◽  
Vol 55 (7) ◽  
pp. 3603-3608 ◽  
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.

scholarly journals The Novel β-Lactam Enhancer Zidebactam Augments theIn VivoPharmacodynamic Activity of Cefepime in a Neutropenic Mouse LungAcinetobacter baumanniiInfection Model

2019 ◽  
Vol 63 (4) ◽  
Author(s):  
S. S. Bhagwat ◽  
H. Periasamy ◽  
S. S. Takalkar ◽  
S. R. Palwe ◽  
H. N. Khande ◽  
...  
Keyword(s):  
Bactericidal Effect ◽  
Multidrug Resistant ◽  
Mouse Lung ◽  
Infection Model ◽  
Bactericidal Action ◽  
Content Type ◽  
Time Kill ◽  
The Impact

ABSTRACTWCK 5222 is a combination of cefepime and the high-affinity PBP2-binding β-lactam enhancer zidebactam. The cefepime-zidebactam combination is active against multidrug-resistant Gram-negative bacteria, including carbapenemase-expressingAcinetobacter baumannii. The mechanism of action of the combination involves concurrent multiple penicillin binding protein inhibition, leading to the enhanced bactericidal action of cefepime. The aim of the present study was to assess the impact of the zidebactam-mediated enhancedin vitrobactericidal action in modulating the percentage of the time that the free drug concentration remains above the MIC (percentfT>MIC) for cefepime required for thein vivokilling ofA. baumannii. Cefepime and cefepime-zidebactam MICs were comparable and ranged from 2 to 16 mg/liter for theA. baumanniistrains (n = 5) employed in the study. Time-kill studies revealed the improved killing of these strains by the cefepime-zidebactam combination compared to that by the constituents alone. Employing a neutropenic mouse lung infection model, exposure-response analyses for all theA. baumanniistrains showed that the cefepimefT>MIC required for 1-log10kill was 38.9%. In the presence of a noneffective dose of zidebactam, the cefepimefT>MIC requirement dropped significantly to 15.5%, but it still rendered a 1-log10kill effect. Thus, zidebactam mediated the improvement in cefepime’s bactericidal effect observed in time-kill studies, manifestedin vivothrough the lowering of cefepime’s pharmacodynamic requirement. This is a first-ever study demonstrating a β-lactam enhancer role of zidebactam that helps augment thein vivoactivity of cefepime by reducing the magnitude of its pharmacodynamically relevant exposures againstA. baumannii.

scholarly journals Endocarditis Caused by Highly Penicillin-Resistant Viridans Group Streptococci: Still Room for Vancomycin-Based Regimens

2019 ◽  
Vol 63 (8) ◽  
Author(s):  
Juan M. Pericàs ◽  
Ruvandhi Nathavitharana ◽  
Cristina Garcia-de-la-Mària ◽  
Carles Falces ◽  
Juan Ambrosioni ◽  
...  
Keyword(s):  
Bactericidal Activity ◽  
Treatment Options ◽  
Content Type ◽  
High Level ◽  
Viridans Group Streptococci ◽  
Time Kill

ABSTRACT Optimal treatment options remain unknown for infective endocarditis (IE) caused by penicillin-resistant (PEN-R) viridans group streptococcal (VGS) strains. The aims of this study were to report two cases of highly PEN-R VGS IE, perform a literature review, and evaluate various antibiotic combinations in vitro and in vivo. The following combinations were tested by time-kill studies and in the rabbit experimental endocarditis (EE) model: PEN-gentamicin, ceftriaxone-gentamicin, vancomycin-gentamicin, daptomycin-gentamicin, and daptomycin-ampicillin. Case 1 was caused by Streptococcus parasanguinis (PEN MIC, 4 μg/ml) and was treated with vancomycin plus cardiac surgery. Case 2 was caused by Streptococcus mitis (PEN MIC, 8 μg/ml) and was treated with 4 weeks of vancomycin plus gentamicin, followed by 2 weeks of vancomycin alone. Both patients were alive and relapse-free after ≥6 months follow-up. For the in vitro studies, except for daptomycin-ampicillin, all combinations demonstrated both synergy and bactericidal activity against the S. parasanguinis isolate. Only PEN-gentamicin, daptomycin-gentamicin, and daptomycin-ampicillin demonstrated both synergy and bactericidal activity against the S. mitis strain. Both strains developed high-level daptomycin resistance (HLDR) during daptomycin in vitro passage. In the EE studies, PEN alone failed to clear S. mitis from vegetations, while ceftriaxone and vancomycin were significantly more effective (P < 0.001). The combination of gentamicin with PEN or vancomycin increased bacterial eradication compared to that with the respective monotherapies. In summary, two patients with highly PEN-R VGS IE were cured using vancomycin-based therapy. In vivo, regimens of gentamicin plus either β-lactams or vancomycin were more active than their respective monotherapies. Further clinical studies are needed to confirm the role of vancomycin-based regimens for highly PEN-R VGS IE. The emergence of HLDR among these strains warrants caution in the use of daptomycin therapy for VGS IE.

scholarly journals In VitroResponses of Acinetobacter baumannii to Two- and Three-Drug Combinations following Exposure to Colistin and Doripenem

2013 ◽  
Vol 58 (2) ◽  
pp. 1195-1199 ◽  
Author(s):  
Louise M. Oleksiuk ◽  
M. Hong Nguyen ◽  
Ellen G. Press ◽  
Cassaundra L. Updike ◽  
Jessica A. O'Hara ◽  
...  
Keyword(s):  
Acinetobacter Baumannii ◽  
Bactericidal Activity ◽  
Drug Combinations ◽  
Content Type ◽  
Before And After ◽  
Time Kill

ABSTRACTWe comparedin vitrokilling of colistin, doripenem, and sulbactam by time-kill methods againstAcinetobacter baumanniiisolates collected from patients before and after colistin-doripenem treatment (initial and recurrent isolates, respectively). Colistin-doripenem bactericidal activity against recurrent isolates was attenuated (mean log10kill, −5.74 versus −2.88;P= 0.01) but was restored by adding sulbactam. Doripenem MICs rather than colistin MICs correlated with the activity of colistin-doripenem. Among colistin-resistant isolates, colistin-doripenem-sulbactam combinations achieved greater killing than colistin-doripenem alone (−5.65 versus −2.43;P= 0.04).

scholarly journals In Vitro and In Vivo Activities of β-Lactams in Combination with the Novel β-Lactam Enhancers Zidebactam and WCK 5153 against Multidrug-Resistant Metallo-β-Lactamase-Producing Klebsiella pneumoniae

2019 ◽  
Vol 63 (5) ◽  
Author(s):  
Bartolome Moya ◽  
Isabel M. Barcelo ◽  
Gabriel Cabot ◽  
Gabriel Torrens ◽  
Snehal Palwe ◽  
...  
Keyword(s):  
Pseudomonas Aeruginosa ◽  
Klebsiella Pneumoniae ◽  
Molecular Targets ◽  
Multidrug Resistant ◽  
The Novel ◽  
Penicillin Binding Protein ◽  
Content Type ◽  
Time Kill

ABSTRACT Zidebactam and WCK 5153 are novel bicyclo-acyl hydrazide (BCH) agents that have previously been shown to act as β-lactam enhancer (BLE) antibiotics in Pseudomonas aeruginosa and Acinetobacter baumannii. The objectives of this work were to identify the molecular targets of these BCHs in Klebsiella pneumoniae and to investigate their potential BLE activity for cefepime and aztreonam against metallo-β-lactamase (MBL)-producing strains in vitro and in vivo. Penicillin binding protein (PBP) binding profiles were determined by Bocillin FL assay, and 50% inhibitory concentrations (IC50s) were determined using ImageQuant TL software. MICs and kill kinetics for zidebactam, WCK 5153, and cefepime or aztreonam, alone and in combination, were determined against clinical K. pneumoniae isolates producing MBLs VIM-1 or NDM-1 (plus ESBLs and class C β-lactamases) to assess the in vitro enhancer effect of BCH compounds in conjunction with β-lactams. Additionally, murine systemic and thigh infection studies were conducted to evaluate BLE effects in vivo. Zidebactam and WCK 5153 showed specific, high PBP2 affinity in K. pneumoniae. The MICs of BLEs were >64 μg/ml for all MBL-producing strains. Time-kill studies showed that a combination of these BLEs with either cefepime or aztreonam provided 1 to >3 log10 kill against MBL-producing K. pneumoniae strains. Furthermore, the bactericidal synergy observed for these BLE–β-lactam combinations translated well into in vivo efficacy even in the absence of MBL inhibition by BLEs, a characteristic feature of the β-lactam enhancer mechanism of action. Zidebactam and WCK 5153 are potent PBP2 inhibitors and display in vitro and in vivo BLE effects against multidrug-resistant (MDR) K. pneumoniae clinical isolates producing MBLs.

scholarly journals Activity of Cefiderocol Alone and in Combination with Levofloxacin, Minocycline, Polymyxin B, or Trimethoprim-Sulfamethoxazole against Multidrug-Resistant Stenotrophomonas maltophilia

2020 ◽  
Vol 64 (9) ◽  
Author(s):  
M. Biagi ◽  
A. Vialichka ◽  
M. Jurkovic ◽  
T. Wu ◽  
A. Shajee ◽  
...  
Keyword(s):  
Active Site ◽  
Stenotrophomonas Maltophilia ◽  
Polymyxin B ◽  
Multidrug Resistant ◽  
First Line ◽  
Content Type ◽  
Preclinical Data ◽  
Time Kill

ABSTRACT The production of an L1 metallo-β-lactamase and an L2 serine active-site β-lactamase precludes the use of β-lactams for the treatment of Stenotrophomonas maltophilia infections. Preclinical data suggest that cefiderocol is the first approved β-lactam with reliable activity against S. maltophilia, but data on strains resistant to current first-line agents are limited, and no studies have assessed cefiderocol-based combinations. The objective of this study was to evaluate and compare the in vitro activity of cefiderocol alone and in combination with levofloxacin, minocycline, polymyxin B, or trimethoprim-sulfamethoxazole (TMP-SMZ) against a collection of highly resistant clinical S. maltophilia isolates. For this purpose, the MICs of cefiderocol, ceftazidime, levofloxacin, minocycline, polymyxin B, and TMP-SMZ for 37 S. maltophilia isolates not susceptible to levofloxacin and/or TMP-SMZ were determined. Nine strains with various cefiderocol MICs were then tested in time-kill experiments with cefiderocol alone and in combination with comparators. The only agents for which susceptibility rates exceeded 40% were cefiderocol (100%) and minocycline (97.3%). Cefiderocol displayed the lowest MIC50 and MIC90 values (0.125 and 0.5 mg/liter, respectively). In time-kill experiments, synergy was observed when cefiderocol was combined with levofloxacin, minocycline, polymyxin B, or TMP-SMZ against 4/9 (44.4%), 6/9 (66.7%), 5/9 (55.5%), and 6/9 (66.7%) isolates, respectively. These data suggest that cefiderocol displays potent in vitro activity against S. maltophilia, including strains resistant to currently preferred agents. Future dynamic and in vivo studies of cefiderocol alone and in combination are warranted to further define cefiderocol’s synergistic capabilities and its place in therapy for S. maltophilia infections.

scholarly journals Pharmacokinetics and Pharmacodynamics of Minocycline against Acinetobacter baumannii in a Neutropenic Murine Pneumonia Model

2017 ◽  
Vol 61 (5) ◽  
Author(s):  
Jian Zhou ◽  
Kimberly R. Ledesma ◽  
Kai-Tai Chang ◽  
Henrietta Abodakpi ◽  
Song Gao ◽  
...  
Keyword(s):  
Acinetobacter Baumannii ◽  
Multidrug Resistant ◽  
Time Curve ◽  
Content Type ◽  
Concentration Time ◽  
Dose Linearity ◽  
Unit Reduction ◽  
The Relationship

ABSTRACT Multidrug-resistant (MDR) Acinetobacter baumannii is increasingly more prevalent in nosocomial infections. Although in vitro susceptibility of A. baumannii to minocycline is promising, the in vivo efficacy of minocycline has not been well established. In this study, the in vivo activity of minocycline was evaluated in a neutropenic murine pneumonia model. Specifically, we investigated the relationship between minocycline exposure and bactericidal activity using five A. baumannii isolates with a broad range of susceptibility (MIC ranged from 0.25 mg/liter to 16 mg/liter). The pharmacokinetics of minocycline (single dose of 25 mg/kg of body weight, 50 mg/kg, 100 mg/kg, and a humanized regimen, given intraperitoneally) in serum and epithelial lining fluid (ELF) were characterized. Dose linearity was observed for doses up to 50 mg/kg and pulmonary penetration ratios (area under the concentration-time curve in ELF from 0 to 24 h [AUCELF,0–24]/area under the concentration time curve in serum from 0 to 24 h [AUCserum,0–24]) ranged from 2.5 to 2.8. Pharmacokinetic-pharmacodynamics (PK-PD) index values in ELF for various dose regimens against different A. baumannii isolates were calculated. The maximum efficacy at 24 h was approximately 1.5-log-unit reduction of pulmonary bacterial burdens from baseline. The AUC/MIC ratio was the PK-PD index most closely correlating to the bacterial burden (r 2 = 0.81). The required AUCELF,0–24/MIC for maintaining stasis and achieving 1-log-unit reduction were 140 and 410, respectively. These findings could guide the treatment of infections caused by A. baumannii using minocycline in the future. Additional studies to examine resistance development during therapy are warranted.

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

2015 ◽  
Vol 59 (8) ◽  
pp. 4544-4550 ◽  
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.

scholarly journals Novel Phage Lysin Capable of Killing the Multidrug-Resistant Gram-Negative Bacterium Acinetobacter baumannii in a Mouse Bacteremia Model

2015 ◽  
Vol 59 (4) ◽  
pp. 1983-1991 ◽  
Author(s):  
Rolf Lood ◽  
Benjamin Y. Winer ◽  
Adam J. Pelzek ◽  
Roberto Diez-Martinez ◽  
Mya Thandar ◽  
...  
Keyword(s):  
Acinetobacter Baumannii ◽  
Genomic Library ◽  
Multidrug Resistant ◽  
Clinical Isolates ◽  
Gram Negative ◽  
Content Type ◽  
Highly Active ◽  
Genes Encoding

ABSTRACTAcinetobacter baumannii, a Gram-negative multidrug-resistant (MDR) bacterium, is now recognized as one of the more common nosocomial pathogens. Because most clinical isolates are found to be multidrug resistant, alternative therapies need to be developed to control this pathogen. We constructed a bacteriophage genomic library based on prophages induced from 13A. baumanniistrains and screened it for genes encoding bacteriolytic activity. Using this approach, we identified 21 distinct lysins with different activities and sequence diversity that were capable of killingA. baumannii. The lysin (PlyF307) displaying the greatest activity was further characterized and was shown to efficiently kill (>5-log-unit decrease) all testedA. baumanniiclinical isolates. Treatment with PlyF307 was able to significantly reduce planktonic and biofilmA. baumanniibothin vitroandin vivo. Finally, PlyF307 rescued mice from lethalA. baumanniibacteremia and as such represents the first highly active therapeutic lysin specific for Gram-negative organisms in an array of native lysins found inAcinetobacterphage.

scholarly journals Characterizing the Antimicrobial Activity of N2,N4-Disubstituted Quinazoline-2,4-Diamines toward Multidrug-Resistant Acinetobacter baumannii

2017 ◽  
Vol 61 (6) ◽  
Author(s):  
Renee Fleeman ◽  
Kurt S. Van Horn ◽  
Megan M. Barber ◽  
Whittney N. Burda ◽  
David L. Flanigan ◽  
...  
Keyword(s):  
Antibacterial Activity ◽  
Acinetobacter Baumannii ◽  
Alkyl Substituent ◽  
Fold Increase ◽  
Multidrug Resistant ◽  
Antibiofilm Activity ◽  
Gram Negative ◽  
Content Type

ABSTRACT We previously reported a series of N 2,N 4-disubstituted quinazoline-2,4-diamines as dihydrofolate reductase inhibitors with potent in vitro and in vivo antibacterial activity against methicillin-resistant Staphylococcus aureus (MRSA) strains. In this work, we extended our previous study to the Gram-negative pathogen Acinetobacter baumannii. We determined that optimized N 2,N 4-disubstituted quinazoline-2,4-diamines are strongly antibacterial against multidrug-resistant A. baumannii strains when the 6-position is replaced with a halide or an alkyl substituent. Such agents display potent antibacterial activity, with MICs as low as 0.5 μM, while proving to be strongly bactericidal. Interestingly, these compounds also possess the potential for antibiofilm activity, eradicating 90% of cells within a biofilm at or near MICs. Using serial passage assays, we observed a limited capacity for the development of resistance toward these molecules (4-fold increase in MIC) compared to existing folic acid synthesis inhibitors, such as trimethoprim (64-fold increase) and sulfamethoxazole (128-fold increase). We also identified limited toxicity toward human cells, with 50% lethal doses (LD50s) of ≤23 μM for lead agents 4 and 5. Finally, we demonstrated that our lead agents have excellent in vivo efficacy, with lead agent 5 proving more efficacious than tigecycline in a murine model of A. baumannii infection (90% survival versus 66%), despite being used at a lower dose (2 versus 30 mg kg−1). Together, our results demonstrate that N 2,N 4-disubstituted quinazoline-2,4-diamines have strong antimicrobial and antibiofilm activities against both Gram-positive organisms and Gram-negative pathogens, suggesting strong potential for their development as antibacterial agents.

scholarly journals In VitroandIn VivoSynergistic Effects of Cryptdin 2 and Ampicillin against Salmonella

2011 ◽  
Vol 55 (9) ◽  
pp. 4176-4182 ◽  
Author(s):  
Praveen Rishi ◽  
Simran Preet ◽  
Sushma Bharrhan ◽  
Indu Verma
Keyword(s):  
Ex Vivo ◽  
Paneth Cell ◽  
Synergetic Effect ◽  
Multidrug Resistant ◽  
Content Type ◽  
Serovar Typhimurium ◽  
Therapeutic Alternatives ◽  
Time Kill

ABSTRACTIn view of the emergence of multidrug-resistantSalmonellastrains, there is a need for therapeutic alternatives. To reduce the dose of antibiotic required in order to decrease the associated side effects, the present study was aimed at evaluating the synergism between cryptdin 2 (a Paneth cell antimicrobial peptide) and ampicillin (Amp) againstSalmonella entericaserovar Typhimurium. The synergy was evaluated in terms of the fractional bactericidal concentration (FBC) index, time-kill assay results (in vitro), macrophage functions, i.e., intracellular killing, lipid peroxidation, superoxide dismutase activity, and generation of nitrite (ex vivo), and decreases in CFU of salmonellae in livers, spleens, and small intestines of infected mice treated with cryptdin 2 and/or Amp (in vivo).In vitrosynergism between the two agents was observed on the basis of the FBC index and time-kill assays. When the agents were used in combination,ex vivostudies revealed an enhanced effect on macrophage functions, particularly exhibiting a synergetic effect in terms of SOD levels.In vivosynergy was indicated by larger log unit decreases in all target organs of mice treated with the combination than those for the drugs used alone. These results point toward the possible use of cryptdin 2 as an adjunct to ampicillin and may help in developing alternate strategies to combatSalmonellainfections.

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