Abrar K. Thabit

Antimicrobial resistance: impact on clinical and economic outcomes and the need for new antimicrobials

Introduction: Antimicrobial resistance is a well-recognized global threat; thus, the development of strong infection control policies coupled with antimicrobial stewardship strategies and new therapies is required to reverse this process. In its 2013 report on antimicrobial resistance, the Centers for Disease Control and Prevention focused on this problem while presenting estimated annual rates of infections with antimicrobial-resistant organisms and their related mortality rates. Whereas some resistant pathogens were considered less threatening, others such as carbapenem-resistant Enterobacteriaceae were associated with higher mortality rates owing to limited treatment options. Areas covered: An overview of the most common antimicrobial-resistant pathogens, focusing on risk factors for acquisition, clinical and economic outcomes, as well as current treatment options. Strategies to optimize antimicrobial therapy with currently available agents, in addition to newly developed antimicrobials are also discussed. Expert opinion: The emergence of pathogens with a variety of resistance mechanisms has intensified the challenges associated with infection control and treatment strategies. Therefore, prudent use of currently available antimicrobial agents, as well as implementing measures to limit spread of resistance is paramount. Although several new antimicrobials have been recently approved or are in the pipeline showing promise in the battle against resistance, the appropriate use of these agents is required as the true benefits of these treatments are to be recognized in the clinical care setting.

Antibacterial Efficacy of Eravacycline In Vivo against Gram-Positive and Gram-Negative Organisms

ABSTRACT Members of the tetracycline class are frequently classified as bacteriostatic. However, recent findings have demonstrated an improved antibacterial killing profile, often achieving ≥3 log10 bacterial count reduction, when such antibiotics have been given for periods longer than 24 h. We aimed to study this effect with eravacycline, a novel fluorocycline, given in an immunocompetent murine thigh infection model over 72 h against two methicillin-resistant Staphylococcus aureus (MRSA) isolates (eravacycline MICs = 0.03 and 0.25 μg/ml) and three Enterobacteriaceae isolates (eravacycline MICs = 0.125 to 0.25 μg/ml). A humanized eravacycline regimen, 2.5 mg/kg of body weight given intravenously (i.v.) every 12 h (q12h), demonstrated progressively enhanced activity over the 72-h study period. A cumulative dose response in which bacterial density was reduced by more than 3 log10 CFU at 72 h was noted over the study period in the two Gram-positive isolates, and eravacycline performed similarly to comparator antibiotics (tigecycline, linezolid, and vancomycin). A cumulative dose response with eravacycline and comparators (tigecycline and meropenem) over the study period was also observed in the Gram-negative isolates, although more variability in bacterial killing was observed for all antibacterial agents. Overall, a bacterial count reduction of ≥3 log was achieved in one of the three isolates with both eravacycline and tigecycline, while meropenem achieved a similar endpoint against two of the three isolates. Bactericidal activity is typically defined in vitro over 24 h; however, extended regimen studies in vivo may demonstrate an improved correlation with clinical outcomes by better identification of antimicrobial effects.

Pharmacodynamic and pharmacokinetic profiling of delafloxacin in a murine lung model against community-acquired respiratory tract pathogens

Increasing antimicrobial resistance in community-acquired pneumonia (CAP) pathogens has contributed to infection-related morbidity and mortality. Delafloxacin is a novel fluoroquinolone with broad-spectrum activity against Gram-positive and -negative organisms, including Streptococcus pneumoniae and methicillin-resistant Staphylococcus aureus (MRSA). This study aimed to define the pharmacodynamic profile of delafloxacin against CAP pathogens using a neutropenic murine lung infection model. Five S. pneumoniae, 2 methicillin-susceptible S. aureus (MSSA), 2 MRSA and 2 Klebsiella pneumoniae isolates were studied. Delafloxacin doses varied from 0.5 mg/kg/day to 640 mg/kg/day and were given as once-daily to every 3 h regimens over the 24-h treatment period. Efficacy was measured as the change in log10 CFU at 24 h compared with 0-h controls. Plasma and bronchopulmonary pharmacokinetic studies were conducted. Delafloxacin demonstrated potent in vitro and in vivo activity. Delafloxacin demonstrated high penetration into the lung compartment, as epithelial lining fluid concentrations were substantially higher than free drug in plasma. The ratio of the area under the free drug concentration-time curve to the minimum inhibitory concentration of the infecting organism (fAUC/MIC) was the parameter that best correlated with the efficacy of the drug, and the magnitude required to achieve 1 log10 CFU reduction was 31.8, 24.7, 0.4 and 9.6 for S. pneumoniae, MRSA, MSSA and K. pneumoniae, respectively. The observed in vivo efficacy of delafloxacin was supported by the high pulmonary disposition of the compound. The results derived from this pre-clinical lung model support the continued investigation of delafloxacin for the treatment of community-acquired lower respiratory tract infections.

Eravacycline Pharmacokinetics and Challenges in Defining Humanized Exposure In Vivo

ABSTRACT We assessed the pharmacokinetic profile of eravacycline, a novel antibiotic of the tetracycline class, and determined the dose in an immunocompetent murine thigh infection model that would provide free-drug exposure similar to that observed in humans after the administration of 1 mg/kg intravenously (i.v.) every 12 h (q12h). Eravacycline demonstrated a nonlinear protein-binding profile. The 2.5-mg/kg i.v. q12h dose in mice resulted in an area under the concentration-time curve for the free, unbound fraction of the drug of 1.64 mg · h/liter, which closely resembles the human exposure level.

Effect of simvastatin and atorvastatin on serum vitamin d and bone mineral density in hypercholesterolemic patients: a cross-sectional study.

Background Besides lipid-lowering effect of statins, they have been shown to have nonlipid lowering effects, such as improving bone health. An improvement in bone mineral density (BMD) has been indicated in some studies after the use of statins, in addition to an increase in 25-hydroxyvitamin D (25OHD) level. The aim of this study is to explore the association between statins and bone health taking into consideration 25OHD level and BMD. Methods This is a randomized, cross-sectional comparative study. Subjects were divided into two groups, hypercholesterolemic participants taking simvastatin or atorvastatin as the study group and a matched control group not taking statins. All participants were assessed for serum 25OHD and BMD at lumbar spine and femoral neck. Results A total of 114 participants were included in the study, 57 participants in each group. Results of serum 25OHD showed no significant difference between study and control groups (P = 0.47), while BMD results of lumbar spine and femoral neck showed significant difference (P = 0.05 and 0.03, resp.). Conclusion Simvastatin and atorvastatin, at any dose for duration of more than one year, have no additive effect on 25OHD level but have a positive effect on the BMD.

Assessment of Clostridium difficile Burden in Patients Over Time With First Episode Infection Following Fidaxomicin or Vancomycin.

In patients with first episode Clostridium difficile infection treated with vancomycin or fidaxomicin, more patients receiving fidaxomicin achieved at least 2 log10 colony-forming units/g reduction in spores at the follow-up visit (P=.02). Similar to published literature, a higher proportion of patients receiving fidaxomicin demonstrated sustained clinical response.

Multidrug-Resistant Pseudomonas aeruginosa Infection in a Child with Cystic Fibrosis.

ABSTRACT We describe a pediatric cystic fibrosis patient who developed a pulmonary exacerbation due to two multidrug-resistant (MDR) Pseudomonas aeruginosa isolates. In addition to these MDR organisms, the case was further complicated by β-lactam allergy. Despite the MDR phenotype, both isolates were susceptible to an antimicrobial combination.

An exploratory study to evaluate Clostridium difficile polymerase chain reaction ribotypes and infection outcomes.

Background Clostridium difficile infection ranges from mild to severe prolonged diarrhea with systemic symptoms. Previous studies have assessed the correlation of some disease severity parameters to C. difficile ribotypes. However, certain clinical parameters of interest have not yet been evaluated. Aim We conducted an exploratory study to evaluate the correlation of C. difficile ribotypes to parameters not assessed previously, notably days to diarrhea resolution (in terms of days to formed stools and days to less than three stools per day), length of hospital stay, 30-day recurrence rates, and 30-day readmission rates. Additional severity parameters evaluated include leukocytosis, serum creatinine, fever, and nausea/vomiting. Methods Polymerase chain reaction ribotyping was performed on C. difficile isolates from baseline stool samples of 29 patients. A retrospective chart review was conducted to assess the parameters of interest. Results The most common ribotypes were 027 (38%), 014/020 (21%), and 106/174 (21%). Numerically, 027 ribotype patients required more days to less than three stools per day versus 014/020 and 106/174 ribotype patients (P=0.2). The three ribotypes were similar regarding time to formed stools, duration of hospitalization, and 30-day readmission rate (P=0.2, 0.6, and 0.8, respectively). Recurrence within 30 days occurred in two patients with 027 and two patients with 014/020 (P=0.6). Leukocytosis and fever were more prominent with 027 than with 014/020 and 106/174 (P=0.04 for both parameters), although the degree of nausea/vomiting did not differ between the three groups (P=0.3). A serum creatinine level ≥1.5 times the premorbid level was seen in only three patients, each infected with a different ribotype. Conclusion Although these data provide a baseline assessment of outcomes to aid in the design of future studies, the diversity of C. difficile ribotypes within the population must be considered, and additional work with other ribotypes may further explain the association with these outcomes.

Impact of vancomycin faecal concentrations on clinical and microbiological outcomes in Clostridium difficile infection

To assess the impact of faecal vancomycin concentrations on clinical and microbiological outcomes in patients with Clostridium difficile infection (CDI) and whether these concentrations vary with stool consistency and frequency, faecal concentrations of vancomycin were measured in stools collected at various times from patients initiated on 125mg every 6h (q6h) for 10 days. Stool consistency and frequency were determined over the course of therapy. Clinical and microbiological outcomes were assessed during therapy, at the end of therapy (EOT) and during a 19-38-day follow-up visit. Faecal vancomycin concentrations in 55 stool samples from 15 patients ranged from 175-6299μg/g at Days 3-5 of therapy (midpoint), 17-5277μg/g at EOT and 0-70μg/g at follow-up. Clinical cure or failure at EOT and at follow-up was not dependent on vancomycin concentrations measured at the midpoint (P=0.72) or at EOT (P=0.76). Likewise, concentrations at EOT and at follow-up did not predict colonisation at follow-up (P=0.85 and 0.71, respectively). Faecal vancomycin concentrations during the course of therapy (Days 3-5) did not differ with either stool consistency or frequency (P=0.94 and 0.16, respectively). However, after completion of therapy, patients with more frequent stools showed higher concentrations than patients with less frequent stools (P=0.04). Oral vancomycin 125mg q6h led to faecal concentrations that did not predict clinical outcomes of CDI in terms of cure or gut colonisation and did not vary with stool consistency and frequency.

Lack of Correlation between Bristol Stool Scale and Quantitative Bacterial Load in Clostridium difficile Infection

Decision to test for Clostridium difficile infection (CDI) is usually made when patients have loose stools with Bristol stool score of ≤5. We aimed to assess the relationship between bacterial load of C. difficile and Bristol stool scale, as well as stool frequency in stool samples collected from patients infected with the organism. Samples were collected at baseline, during therapy, and at the end of therapy. Spearman correlation test was used to evaluate these relationships. No correlation between Bristol stool scale and fecal load of C. difficile was found for both spores and vegetative cells at all time points as counts were persistently high (P = non-significant). Weak positive correlations were found between stool frequency and fecal load of C. difficile spores and vegetative cells (r s = 0.22 and 0.24, P = 0.04 and 0.03, respectively). These findings indicate that quantitative colony counts were sufficiently high to detect C. difficile, irrespective of stool consistency, and suggest that semiformed stool should be sought for the pathogen in symptomatic patients with frequent stools.