Effect of Surotomycin,a Novel Cyclic Lipopeptide Antibiotic,on Intestinal Colonization with Vancomycin-Resistant Enterococci and Klebsiella pneumoniae in Mice

Surotomycin (formerly called CB-183,315) is a novel, orally administered cyclic lipopeptide antibacterial in development for the treatment of Clostridium difficile infection (CDI) that has potent activity against vancomycin-resistant enterococci (VRE) but limited activity against Gram-negative bacilli, including Bacteroides spp. We used a mouse model to investigate the impact of surotomycin exposure on the microbiome, and to test the consequences of the disruption on colonization by vancomycin-resistant enterococci (VRE) and extended-spectrum β-lactamase-producing Klebsiella pneumoniae (ESBL-KP), in comparison with the effects of oral vancomycin and metronidazole. Mice (8 per group) received saline, vancomycin, metronidazole, or surotomycin through an orogastric tube daily for 5 days and were challenged with 10⁵ CFU of VRE or ESBL-KP administered through an orogastric tube on day 2 of treatment. The concentrations of the pathogens in stool were determined during and after treatment by plating on selective media. A second experiment was conducted to determine if the antibiotics would inhibit established VRE colonization. In comparison to controls, oral vancomycin promoted VRE and ESBL-KP overgrowth in stool (8 log₁₀ to 10 log₁₀ CFU/g; P < 0.001), whereas metronidazole did not (<4 log₁₀ CFU/g; P > 0.5). Surotomycin promoted ESBL-KP overgrowth (>8 log₁₀ CFU/g; P, <0.001 for comparison with saline controls) but not VRE overgrowth. Surotomycin suppressed preexisting VRE colonization, whereas metronidazole and vancomycin did not. These results suggest that treatment of CDI with surotomycin could reduce levels of VRE acquisition and overgrowth from those with agents such as vancomycin and metronidazole. However, surotomycin and vancomycin may promote colonization by antibiotic-resistant Gram-negative bacilli.     

In vitro activity of tigecycline in combination with gentamicin against biofilm-forming Staphylococcus aureus

We investigated the activity of tigecycline in combination with gentamicin for the treatment of biofilm-forming methicillin-resistant and sensitive Staphylococcus aureus in an in vitro pharmacodynamic model. Tigecycline monotherapy demonstrated bacteriostatic activity throughout 48 h (−0.24 ± 0.17 log₁₀ CFU/mL), whereas tigecycline in combination with gentamicin demonstrated significant (P < 0.002) kill (−3.66 ± 0.26 log₁₀ CFU/mL) at 48 h. The addition of gentamicin to tigecycline significantly improved the killing activity of tigecycline in biofilm-forming S. aureus.     

Lysostaphin Treatment of Experimental Methicillin-Resistant Staphylococcus aureus Aortic Valve Endocarditis

The emergence of clinical isolates of methicillin-resistant Staphylococcus aureus with reduced susceptibility to vancomycin has prompted a search for new and novel therapeutic agents active against S. aureus. Lysostaphin, a peptidase produced by Staphylococcus simulans, specifically cleaves the glycine-glycine bonds unique to the interpeptide cross-bridge of the S. aureus cell wall. The effectiveness of various regimens of dosing with intravenous lysostaphin was compared to that of vancomycin in the rabbit model of aortic valve endocarditis caused by a clinical methicillin-resistant S. aureus isolate. All animals were treated for a total of 3 days. The most active regimen, lysostaphin given three times daily, produced sterile vegetations in 10 of 11 treated rabbits, with a mean reduction in vegetation bacterial counts of 8.5 log₁₀ CFU/g compared to the counts in the untreated controls. In contrast, vancomycin given twice daily sterilized no vegetations and reduced vegetation bacterial counts by only 4.8 log₁₀ CFU/g. Lysostaphin given once daily was less effective, reducing mean vegetation bacterial counts by only 3.6 log₁₀ CFU/g, but the combination of lysostaphin once daily and vancomycin twice daily reduced the mean vegetation bacterial density by 7.5 log₁₀ CFU/g, a result that was significantly better than that for either regimen alone (P < 0.05). Lysostaphin was well tolerated by the rabbits, with no evidence of immunological reactions following up to 9 weeks of intravenous administration. We conclude that lysostaphin given alone or in combination with vancomycin is more effective in the treatment of experimental methicillin-resistant S. aureus aortic valve endocarditis than vancomycin alone.     

In Vitro Pharmacodynamics of Human Simulated Exposures of Telavancin against Methicillin-Susceptible and -Resistant Staphylococcus aureus with and without Prior Vancomycin Exposure

Telavancin is a lipoglycopeptide with potent activity against methicillin-resistant Staphylococcus aureus (MRSA) and methicillin-susceptible S. aureus (MSSA). The activity of telavancin against MRSA and MSSA after prior vancomycin exposure was studied in an in vitro pharmacodynamic model. Two clinical MRSA and two MSSA isolates, all with vancomycin MICs of 2 μg/ml, were subjected to humanized free drug exposures of vancomycin at 1 g every 12 h (q12h) for 96 h, telavancin at 750 mg q24h for 96 h, and vancomycin at 1 g q12h for 72 h followed by telavancin at 750 mg q24h for 48 h (120 h total). The microbiological responses were measured by changes from 0 h in log₁₀ CFU/ml at the end of experiments and area under the bacterial killing and regrowth curves over 96 h (AUBC₀₋₉₆). The control isolates grew to 8.8 ± 0.3 log₁₀ CFU/ml. Initially, all regimens caused −4.5 ± 0.9 reductions in log₁₀ CFU/ml by 48 h followed by slight regrowth over the following 48 to 72 h. After 96 h, vancomycin and telavancin achieved −3.7 ± 0.9 and −3.8 ± 0.8 log₁₀ CFU/ml changes from baseline, respectively (P = 0.74). Sequential exposure to telavancin after vancomycin did not result in additional CFU reductions or increases, with ultimate log₁₀ CFU/ml reductions of −4.3 ± 1.1 at 96 h and −4.2 ± 1.3 at 120 h (P > 0.05 for all comparisons at 96 h). The AUBC_0–96 was significantly smaller for the regimen of telavancin for 96 h than for the regimens of vancomycin for 96 h and vancomycin followed by telavancin (P ≤ 0.04). No resistance was observed throughout the experiment. Against these MRSA and MSSA isolates with vancomycin MICs of 2 μg/ml, telavancin was comparable with vancomycin and its activity was unaffected by prior vancomycin exposure.     

In Vitro Pharmacodynamics of Human Simulated Exposures of Ceftaroline and Daptomycin against MRSA,hVISA, and VISA with and without Prior Vancomycin Exposure

The effects of prior vancomycin exposure on ceftaroline and daptomycin therapy against methicillin-resistant Staphylococcus aureus (MRSA) have not been widely studied. Humanized free-drug exposures of vancomycin at 1 g every 12 h (q12h), ceftaroline at 600 mg q12h, and daptomycin at 10 mg/kg of body weight q24h were simulated in a 96-h in vitro pharmacodynamic model against three MRSA isolates, including one heteroresistant vancomycin-intermediate S. aureus (hVISA) isolate and one VISA isolate. A total of five regimens were tested: vancomycin, ceftaroline, and daptomycin alone for the entire 96 h, and then sequential therapy with vancomycin for 48 h followed by ceftaroline or daptomycin for 48 h. Microbiological responses were measured by the changes in log₁₀ CFU during 96 h from baseline. Control isolates grew to 9.16 ± 0.32, 9.13 ± 0.14, and 8.69 ± 0.28 log₁₀ CFU for MRSA, hVISA, and VISA, respectively. Vancomycin initially achieved ≥3 log₁₀ CFU reductions against the MRSA and hVISA isolates, followed by regrowth beginning at 48 h; minimal activity was observed against VISA. The change in 96-h log₁₀ CFU was largest for sequential therapy with vancomycin followed by ceftaroline (−5.22 ± 1.2, P = 0.010 versus ceftaroline) and for sequential therapy with vancomycin followed by ceftaroline (−3.60 ± 0.6, P = 0.037 versus daptomycin), compared with daptomycin (−2.24 ± 1.0), vancomycin (−1.40 ± 1.8), and sequential therapy with vancomycin followed by daptomycin (−1.32 ± 1.0, P > 0.5 for the last three regimens). Prior exposure of vancomycin at 1 g q12h reduced the initial microbiological response of daptomycin, particularly for hVISA and VISA isolates, but did not affect the response of ceftaroline. In the scenario of poor vancomycin response for high-inoculum MRSA infection, a ceftaroline-containing regimen may be preferred.     

High Activity of Fosfomycin and Rifampin against Methicillin-Resistant Staphylococcus aureus Biofilm In Vitro and in an Experimental Foreign-Body Infection Model

Increasing antimicrobial resistance reduces treatment options for implant-associated infections caused by methicillin-resistant Staphylococcus aureus (MRSA). We evaluated the activity of fosfomycin alone and in combination with vancomycin, daptomycin, rifampin, and tigecycline against MRSA (ATCC 43300) in a foreign-body (implantable cage) infection model. The MICs of the individual agents were as follows: fosfomycin, 1 μg/ml; daptomycin, 0.125 μg/ml; vancomycin, 1 μg/ml; rifampin, 0.04 μg/ml; and tigecycline, 0.125 μg/ml. Microcalorimetry showed synergistic activity of fosfomycin and rifampin at subinhibitory concentrations against planktonic and biofilm MRSA. In time-kill curves, fosfomycin exhibited time-dependent activity against MRSA with a reduction of 2.5 log₁₀ CFU/ml at 128 × the MIC. In the animal model, planktonic bacteria in cage fluid were reduced by <1 log₁₀ CFU/ml with fosfomycin and tigecycline, 1.7 log₁₀ with daptomycin, 2.2 log₁₀ with fosfomycin-tigecycline and fosfomycin-vancomycin, 3.8 log₁₀ with fosfomycin-daptomycin, and >6.0 log₁₀ with daptomycin-rifampin and fosfomycin-rifampin. Daptomycin-rifampin cured 67% of cage-associated infections and fosfomycin-rifampin cured 83%, whereas all single drugs (fosfomycin, daptomycin, and tigecycline) and rifampin-free fosfomycin combinations showed no cure of MRSA cage-associated infections. No emergence of fosfomycin resistance was observed in animals; however, a 4-fold increase in fosfomycin MIC (from 2 to 16 μg/ml) occurred in the fosfomycin-vancomycin group. In summary, the highest eradication of MRSA cage-associated infections was achieved with fosfomycin in combination with rifampin (83%). Fosfomycin may be used in combination with rifampin against MRSA implant-associated infections, but it cannot replace rifampin as an antibiofilm agent.     

In Vitro Activity of Human-Simulated Epithelial Lining Fluid Exposures of Ceftaroline,Ceftriaxone, and Vancomycin against Methicillin-Susceptible and -Resistant Staphylococcus aureus

Staphylococcus aureus, including methicillin-susceptible (MSSA) and -resistant (MRSA) strains, is an important pathogen of bacterial pneumonia. As antibiotic concentrations at the site of infection are responsible for killing, we investigated the activity of human-simulated epithelial lining fluid (ELF) exposures of three antibiotics (ceftaroline, ceftriaxone, and vancomycin) commonly used for treatment of S. aureus pneumonia. An in vitro pharmacodynamic model was used to simulate ELF exposures of vancomycin (1 g every 12 h [q12h]), ceftaroline (600 mg q12h and q8h), and ceftriaxone (2 g q24h and q12h). Four S. aureus isolates (2 MSSA and 2 MRSA) were evaluated over 72 h with a starting inoculum of ∼10⁶ CFU/ml. Time-kill curves were constructed, and microbiological response (change in log₁₀ CFU/ml from 0 h and the area under the bacterial killing and regrowth curve [AUBC]) was assessed in duplicate. The change in 72-h log₁₀ CFU/ml was largest for ceftaroline q8h (reductions of >3 log₁₀ CFU/ml against all strains). This regimen also achieved the lowest AUBC against all organisms (P < 0.05). Vancomycin produced reliable bacterial reductions of 0.9 to 3.3 log₁₀ CFU/ml, while the activity of ceftaroline q12h was more variable (reductions of 0.2 to 2.3 log₁₀ CFU/ml against 3 of 4 strains). Both regimens of ceftriaxone were poorly active against MSSA tested (0.1 reduction to a 1.8-log₁₀ CFU/ml increase). Against these S. aureus isolates, ELF exposures of ceftaroline 600 mg q8h exhibited improved antibacterial activity compared with ceftaroline 600 mg q12h and vancomycin, and therefore, this q8h regimen deserves further evaluation for the treatment of bacterial pneumonia. These data also suggest that ceftriaxone should be avoided for S. aureus pneumonia.     

Effect of administering a multi-species probiotic mixture on the changes in fecal microbiota and symptoms of irritable bowel syndrome: a randomized,double-blind,placebo-controlled trial

We assessed the effect of multi-species probiotic mixture on the changes in fecal microbiota and irritable bowel syndrome (IBS) symptoms. Eighty-one IBS patients were randomly assigned to receive either probiotic mixture (n = 39; containing Lactobacillus acidophilus, L. rhamnosus, Bifidobacterium breve, B. actis, B. longum, and Streptococcus thermophilus) or placebo (n = 42) for 4 weeks. A questionnaire regarding general symptom relief was administered. The change in total symptom scores (sum of 10 IBS symptoms) and subtotal scores in 4 domains (pain, constipation, diarrhea, and bloating/gas) were evaluated. The change in fecal flora was determined by quantitative real-time PCR. The concentration of probiotic strains significantly increased after ingestion in probiotics group (B. bifidum, p = 0.043; B. lactis, p<0.001; L. acidophilus, p = 0.016; L. rhamnosus, p<0.001). The proportion of patients with adequate symptom relief was higher in probiotics group than in placebo group (74.4% vs 61.9%, p = 0.230). The decrease in total symptom score over time was not significantly different between the groups (p = 0.703). Among subtotal scores of 4 IBS symptom domains, the time effect was significantly different for diarrhea-symptom score between the groups (p = 0.017). A 4-week administration of multi-species probiotic mixture significantly increased the fecal concentration of most probiotic strains and improved diarrhea-symptom scores in IBS patients.     

Evaluation of the Sensitivity of an in vitro High Frequency Ultrasound Device to Monitor the Coagulation Process: Study of the Effects of Heparin Treatment in a Murine Model

This study evaluates the sensitivity of a new in vitro high frequency ultrasound test of the whole blood coagulation process. A rat model of anticoagulant treatment is reported. Many recent studies of the role of red blood cells in the whole blood coagulation process have revealed an increasing demand for global tests of the coagulation process performed on whole blood instead of plasma samples. In contrast to existing optical tests, high frequency ultrasound presents the advantages of characterizing the mechanical properties of whole blood clotting. Ultrasound longitudinal wave velocity and integrated attenuation coefficient (IAC) were simultaneously assessed in a 10 to 30 MHz frequency range during the whole blood coagulation process in vitro in rats under anticoagulant therapy. Differences between humans and rats were also clearly emphasized in non-clotting blood and in clotting blood using specific criteria deduced from acoustic parameters (ultrasound velocity for non-clotting blood: = 1574 ± 2 m/s for rats and 1583 ± 3 m/s for humans and IAC = 2.25 ± 0.14 dB/cm for rats and 1.5 ± 0.23 dB/cm for humans). We also measured the coagulation time t₀ from the acoustic velocity (t₀ = 11.15 ± 7 min for control rat blood and 43.3 ± 11.4 min for human blood). Different doses of heparin were administered to rats. The sensitivity of the ultrasound device to the effects of heparin was evaluated. Differences between non-treated rats and chronically and acutely treated rats were recorded and quantified. We particularly noted that the slope S and the amplitude I of the variations in acoustic velocity were linked to clot retraction, which is a good indicator of the platelet function. The amplitude of the variations in S was between (20 ± 8) × 10^–3 m/s² for control group rats, and (0.92 ± 0.35) × 10^–3 m/s² for chronic heparin-treated group rats. The values of I were 15 times higher for control group rats than for chronic heparin-treated group rats. (E-mail: rachel.libgot@univ-tours.fr)     

Branched-chain amino acids may improve recovery from a vegetative or minimally conscious state in patients with traumatic brain injury: a pilot study

Aquilani R, Boselli M, Boschi F, Viglio S, Iadarola P, Dossena M, Pastoris O, Verri M. Branched-chain amino acids may improve recovery from a vegetative or minimally conscious state in patients with traumatic brain injury: a pilot study.

Objective

To investigate whether supplementation with branched-chain amino acids (BCAAs) may improve recovery of patients with a posttraumatic vegetative or minimally conscious state.

Design

Patients were randomly assigned to 15 days of intravenous BCAA supplementation (n=22; 19.6g/d) or an isonitrogenous placebo (n=19).

Setting

Tertiary care rehabilitation setting.

Participants

Patients (N=41; 29 men, 12 women; mean age, 49.5±21y) with a posttraumatic vegetative or minimally conscious state, 47±24 days after the index traumatic event.

Intervention

Supplementation with BCAAs.

Main Outcome Measure

Disability Rating Scale (DRS) as log₁₀DRS.

Results

Fifteen days after admission to the rehabilitation department, the log₁₀DRS score improved significantly only in patients who had received BCAAs (log₁₀DRS score, 1.365±0.08 to 1.294±0.05; P<.001), while the log₁₀DRS score in the placebo recipients remained virtually unchanged (log₁₀DRS score, 1.373±0.03 to 1.37±0.03; P not significant). The difference in improvement of log₁₀DRS score between the 2 groups was highly significant (P<.000). Moreover, 68.2% (n=15) of treated patients achieved a log₁₀DRS point score of .477 or higher (3 as geometric mean) that allowed them to exit the vegetative or minimally conscious state.

Conclusions

Supplemented BCAAs may improve the recovery from a vegetative or minimally conscious state in patients with posttraumatic vegetative or minimally conscious state.     

Activity of fixed direct electrical current in experimental Staphylococcus aureus foreign-body osteomyelitis

Fixed DC was compared to ceftriaxone, ceftriaxone with 200?μA fixed DC, or no treatment in a rat model of methicillin-susceptible Staphylococcus aureus foreign-body osteomyelitis. After 3?weeks, fewer bacteria were present in bones of the ceftriaxone group (5.71 log₁₀cfu/g [P = 0.0004]) and the ceftriaxone/DC group (3.53 log₁₀cfu/g [P = 0.0002]) than untreated controls (6.70 log₁₀cfu/g). Fewer bacteria were present in the ceftriaxone/DC group than in the ceftriaxone-alone and DC-alone groups (P = 0.0012 and 0.0008, respectively). There were also fewer bacteria on the implanted wires in the groups treated with ceftriaxone (5.47 log₁₀cfu/cm²) or ceftriaxone/DC (2.82 log₁₀cfu/cm²) than in the untreated controls (6.44 log₁₀cfu/cm² [P = 0.0003 and 0.0002, respectively]). There were fewer bacteria in the ceftriaxone/DC rats than in the ceftriaxone-alone– and fixed DC-alone–treated rats (P = 0.0017 and 0.0016, respectively). Fixed DC with an antibiotic may be useful for treating foreign-body infections caused by S. aureus.     

Supplementation with probiotics modifies gut flora and attenuates liver fat accumulation in rat nonalcoholic fatty liver disease model

This study aimed to evaluate the relationship between gut probiotic flora and nonalcoholic fatty liver disease in a diet-induced rat model, and to compare the effects of two different probiotic strains on nonalcoholic fatty liver disease. Forty male Sprague-Dawley rats were randomized into 4 groups for 12 weeks: control (standard rat chow), model (fat-rich diet), Lactobacillus (fat-rich diet plus Lactobacillus acidophilus), and Bifidobacterium (fat-rich diet plus Bifidobacterium longum) groups. Probiotics were provided to rats in drinking water (10¹⁰/ml). Gut bifidobacteria and lactobacilli were obviously lower at weeks 8 and 10, respectively, in the model group compared with the control group. Supplementation with Bifidobacterium significantly attenuated hepatic fat accumulation (0.10 ± 0.03 g/g liver tissue) compared with the model group (0.16 ± 0.03 g/g liver tissue). However, there was no improvement in intestinal permeability in either the Lactobacillus or the Bifidobacterium group compared with the model group. In all 40 rats, the hepatic total lipid content was negatively correlated with gut Lactobacillus (r = −0.623, p = 0.004) and Bifidobacterium (r = −0.591, p = 0.008). Oral supplementation with probiotics attenuates hepatic fat accumulation. Further, Bifidobacterium longum is superior in terms of attenuating liver fat accumulation than is Lactobacillus acidophilus.     

Inhaled Microparticles Containing Clofazimine Are Efficacious in Treatment of Experimental Tuberculosis in Mice

Inhalable clofazimine-containing dry powder microparticles (CFM-DPI) and native clofazimine (CFM) were evaluated for activity against Mycobacterium tuberculosis in human monocyte-derived macrophage cultures and in mice infected with a low-dose aerosol. Both formulations resulted in 99% killing at 2.5 μg/ml in vitro. In mice, 480 μg and 720 μg CFM-DPI inhaled twice per week over 4 weeks reduced numbers of CFU in the lung by as much as log₁₀ 2.6; 500 μg oral CFM achieved a log₁₀ 0.7 reduction.     

Effects of arterial oxygen content on oxidative stress during resuscitation in a rat hemorrhagic shock model

Objective

To examine whether reactive oxygen species (ROS) production is affected by arterial oxygen content (CaO₂) in attempted resuscitation to restore blood pressure from hemorrhagic shock (HS) or not.

Methods

Under light anesthesia and spontaneous beating, 16 rats underwent HS for 80 min, during which 3.0 mL/100 g of blood was withdrawn, followed by resuscitation attempt for 70 min. At 80 min, rats were randomized into a high-CaO₂ group (Group 1, transfusion under fractional inspired oxygen (F_IO₂) of 1.0, n = 8) or a low-CaO₂ group (Group 2, fluid administration under F_IO₂ of 0.21, n = 8). In each group, either blood or lactate Ringer's (LR) solution was infused to maintain mean arterial pressure ≥75 mmHg under each F_IO₂ concentration. CaO₂, O₂ utilization coefficient (UC) and plasma %CoQ9 were compared between groups.

Results

Mean infused volume for attempted resuscitation was 7.6 ± 1.0 mL of blood in Group 1, and 31.4 ± 5.5 mL of LR solution in Group 2. At the end of resuscitation, CaO₂ was 18.5 ± 1.2 vol% in Group 1, almost double the 9.1 ± 0.8 vol% in Group 2 (P < 0.01). O₂ UC and %CoQ9 in all rats increased from baselines of 0.25 ± 0.12 and 7.6 ± 1.8% to 0.44 ± 0.13 and 9.7 ± 1.8% after resuscitation, respectively (P < 0.05 vs. baseline for each), but did not differ significantly between the groups.

Conclusion

In a rat HS model, attempted resuscitation to restore blood pressure increased O₂ UC as well as %CoQ9. However, the magnitude of %CoQ9 increase that represents ROS production is not affected by CaO₂ during resuscitation from HS.     

Clinically plausible hyperventilation does not exert adverse hemodynamic effects during CPR but markedly reduces end-tidal PCO₂

Aims

Ventilation at high respiratory rates is considered detrimental during CPR because it may increase intrathoracic pressure limiting venous return and forward blood flow generation. We examined whether ventilation at high, yet clinically plausible, tidal volumes could also be detrimental, and further examined effects on end-tidal pCO₂ (P_ETCO₂).

Methods

Sixteen domestic pigs were randomized to one of four ventilatory patterns representing two levels of respiratory rate (min⁻¹) and two levels of tidal volume (ml/kg); i.e., 10/6, 10/18, 33/6, and 33/18 during chest compression after 8 min of untreated VF.

Results

Data (mmHg, mean ± SD) are presented in the order listed above. Ventilation at 33/18 prompted higher airway pressures (p < 0.05) and persistent expiratory airway flow (p < 0.05) before breath delivery demonstrating air trapping. The right atrial pressure during chest decompression showed a statistically insignificant increase with increasing minute-volume (7 ± 4, 10 ± 3, 12 ± 1, and 13 ± 3; p = 0.055); however, neither the coronary perfusion pressure (23 ± 1, 17 ± 6, 18 ± 6, and 21 ± 2; NS) nor the cerebral perfusion pressure (32 ± 3, 23 ± 8, 30 ± 12, and 31 ± 3; NS) was statistically different. Yet, increasing minute-volume reduced the P_ETCO₂ demonstrating a high dependency on tidal volumes delivered at currently recommended respiratory rates.

Conclusions

Increasing respiratory rate and tidal volume up to a minute-volume 10-fold higher than currently recommended had no adverse hemodynamic effects during CPR but reduced P_ETCO₂ suggesting that ventilation at controlled rate and volume could enhance the precision with which P_ETCO₂ reflects CPR quality, predicts return of circulation, and serve to guide optimization of resuscitation interventions.     

Efficacies of Ceftazidime-Avibactam and Ceftazidime against Pseudomonas aeruginosa in a Murine Lung Infection Model

This study aimed to determine the efficacy of human-simulated plasma exposures of 2 g ceftazidime plus 0.5 g avibactam every 8 h administered as a 2-h infusion or a ceftazidime regimen that produced a specific epithelial lining fluid (ELF) percentage of the dosing interval in which serum free drug concentrations remain above the MIC (fT>MIC) against 28 Pseudomonas aeruginosa isolates within a neutropenic murine pneumonia model and to assess the impact of host infection on pulmonary pharmacokinetics. The fT>MIC was calculated as the mean and upper end of the 95% confidence limit. Against the 28 P. aeruginosa strains used, the ceftazidime-avibactam MICs were 4 to 64 μg/ml, and those of ceftazidime were 8 to >128 μg/ml. The change in log₁₀ CFU after 24 h of treatment was analyzed relative to that of 0-h controls. Pharmacokinetic studies in serum and ELF were conducted using ceftazidime-avibactam in infected and uninfected mice. Humanized ceftazidime-avibactam doses resulted in significant exposures in the lung, producing reductions of >1 log₁₀ CFU against P. aeruginosa with ceftazidime-avibactam MICs of ≤32 μg/ml (ELF upper 95% confidence limit for fT>MIC [ELF fT>MIC] of ≥19%), except for one isolate with a ceftazidime-avibactam MIC of 16 μg/ml. No efficacy was observed against the isolate with a ceftazidime-avibactam MIC of 64 μg/ml (ELF fT>MIC of 0%). Bacterial reductions were observed with ceftazidime against isolates with ceftazidime MICs of 32 μg/ml (ELF fT>MIC of ≥12%), variable efficacy at ceftazidime MICs of 64 μg/ml (ELF fT>MIC of ≥0%), and no activity at a ceftazidime MIC of 128 μg/ml, where the ELF fT>MIC was 0%. ELF fT>MICs were similar between infected and uninfected mice. Ceftazidime-avibactam was effective against P. aeruginosa, with MICs of up to 32 μg/ml with an ELF fT>MIC of ≥19%. The data suggest the potential utility of ceftazidime-avibactam for treatment of lung infections caused by P. aeruginosa.     

Rapid cooling of the heart with total liquid ventilation prevents transmural myocardial infarction following prolonged ischemia in rabbits

Study aim

Total liquid ventilation (TLV) with cooled perfluorocarbons has been demonstrated to induce an ultrafast cardioprotective cooling in rabbits. However, it remains unknown whether this technically challenging strategy would be actually more potent than a conventional external cooling after a prolonged ischemia inducing transmural myocardial infarction.

Methods

Anesthetized rabbits were randomly submitted to 60 min of coronary artery occlusion (CAO) under normothermic conditions (Control group, n = 7) or with cooling started at the 5th min of CAO (target left atrial temperature: 32 °C). Cooling procedures were either external cooling using cold blankets (EC group, n = 7) or ultrafast cooling initiated by 20 min of TLV (TLV group, n = 6). An additional group underwent a similar ultrafast cooling protocol started at the 20th min of CAO (TLV_delayed group, n = 6). After reperfusion, all hypothermic animals were rewarmed and infarct size was assessed after 4 h.

Results

In the EC group, the target temperature was reached only at 60 min of CAO whereas this time-interval was dramatically reduced to 15 and 25 min of CAO in TLV and TLV_delayed, respectively. Infarct sizes were significantly reduced in TLV and TLV_delayed but not in EC groups as compared to Control (45 ± 18%, 58 ± 5%, 78 ± 10% and 82 ± 7% of the risk zone, respectively). Similar significant differences were observed for the sizes of the no-reflow zones (15 ± 9%, 23 ± 8%, 49 ± 11% and 58 ± 13% of the risk zone, respectively).

Conclusion

Cooling induced by TLV afforded a potent cardioprotection and prevented transmural infarction following prolonged and severe ischemia, even when started later than a surface cooling in rabbits.     

Intensive,prolonged exercise seemingly causes gut dysbiosis in female endurance runners

Intensive, prolonged exercise is known to induce gastrointestinal disorders such as diarrhea, with gut dysbiosis suggested as being one of the causatives. In the present study, we wanted to investigate the relationship between intensive exercise and the gut microbiota status. To that end, the microbiota, the moisture content and the bacterial metabolites (e.g., organic acids) of female endurance runners (n = 15) and those of non-athletic but healthy, age-matching female controls (n = 14) were compared. The analysis of the gut microbiota analysis showed that, unlike control subjects, female endurance runners had distinct microbiotas, with some bacteria found in higher abundances likely being involved in gut inflammation. The concentration of succinate, a gut bacterial metabolite regarded as undesirable when accumulated in the lumen, was significantly (p<0.05) higher in the female endurance runners. Faecalibacterium, that was significantly (p<0.05) abundant in female endurance runners, can produce succinate in certain environments and hence may contribute to succinate accumulation, at least partly. The present work suggested that the gut microbiotas of female endurance runners are seemingly dysbiotic when compared with those of control subjects. Further investigation of the mechanism by which intensive, prolonged exercise affects the gut microbiota is recommended.     

Positive correlation between pregnancy-associated plasma protein-A level and OX40 ligand expression in patients with acute coronary syndromes

Objective

Increasing evidence show that serum pregnancy-associated plasma protein-A (PAPP-A) and OX40 ligand (OX40L) expression have been implicated in acute coronary syndromes (ACS). We investigated the relationship between PAPP-A level and OX40L in serum and membrane-bound OX40L in patients with ACS.

Methods

The present study included normal controls (n = 30), patients with stable angina (SA) (n = 60) and patients with ACS, including unstable angina (UA) (n = 50) and acute myocardial infarction (AMI) (n = 30). Serum concentrations of PAPP-A and soluble OX40L (sOX40L) were determined with Elisa, whereas the expression of OX40L on monocytes were analyzed with flow cytometry.

Results

The expression of OX40L in peripheral monocytes in patients with UA [25.6 ± 5.5 mean fluorescence intensity (MFI)] and AMI (29.4 ± 6.3 MFI) were significantly higher than those in patients with SA (10.6 ± 2.8 MFI) and controls (11.1 ± 3.5 MFI). Both sOX40L and PAPP-A in patients with UA (15.7 ± 4.9 ng/mL, 25.4 ± 6.8 μg/mL, respectively) and AMI (17.1 ± 5.3 ng/mL, 26.3 ± 5.6 μg/mL, respectively) were significantly higher than those in patients with SA (3.4 ± 1.4 ng/mL, 9.6 ± 2.1 μg/mL, respectively) and controls (3.9 ± 1.3 ng/mL, 8.5 ± 2.8 μg/mL, respectively) (P < 0.001). Interestingly, a positive correlation was found between sOX40L, membrane-bound OX40L and serum PAPP-A levels (r₁ = 0.54, r₂ = 0.51; P < 0.0001). Both serum and membrane-bound OX40L and PAPP-A levels significantly correlated with complex coronary stenosis (r₁ = 0.56, r₂ = 0.55, r₃ = 0.40; P < 0.001).

Conclusion

PAPP-A level was significantly related to soluble and membrane-bound OX40L in patients with ACS. Enhanced level of serum PAPP-A and sOX40L might represent a prognostic marker for coronary disease activity.