Population Pharmacokinetic Analyses for Tebipenem after Oral Administration of Pro-Drug Tebipenem Pivoxil Hydrobromide.

Tebipenem pivoxil hydrobromide (TBP-PI-HBr) is an oral (PO) carbapenem pro-drug that is converted to the active moiety tebipenem in the enterocytes. Tebipenem has activity against multidrug-resistant Gram-negative pathogens, including extended-spectrum beta lactamase-producing Enterobacterales, and is being developed for the treatment of patients with complicated urinary tract infections (cUTI) and acute pyelonephritis (AP). The objectives of these analyses were to develop a population pharmacokinetic (PK) model for tebipenem using data from three phase 1 studies and one phase 3 study and to identify covariates that described the variability in tebipenem PK. Following construction of the base model, a covariate analysis was conducted. The model was then qualified by performing a prediction-corrected visual predictive check and evaluated by using a sampling-importance-resampling procedure. The final population PK data set was composed of data from 746 subjects who provided 3,448 plasma concentrations, including 650 patients (1,985 concentrations) with cUTI/AP. The final population PK model that best described tebipenem PK was found to be a two-compartment model with linear, first-order elimination and two transit compartments to describe the rate of drug absorption after PO administration of TBP-PI-HBr. The relationship between renal clearance (CLR) and creatinine clearance (CLcr), the most clinically significant covariate, was described using a sigmoidal Hill-type function. No dose adjustments are warranted on the basis of age, body size, or sex as none of these covariates were associated with substantial differences in tebipenem exposure in patients with cUTI/AP. The resultant population PK model is expected to be appropriate for model-based simulations and assessment of pharmacokinetic-pharmacodynamic relationships for tebipenem.

A Phase 1 First-in-Human Single-Ascending-Dose Trial With ESB1609, a Selective Agonist to the Sphingosine-1-Phosphate Receptor 5.

ESB1609 is a small-molecule sphingosine-1-phosphate-5 receptor-selective agonist designed to restore lipid homeostasis by promoting cytosolic egress of sphingosine-1-phosphate to reduce abnormal levels of ceramide and cholesterol in disease. A phase 1 study was conducted in healthy volunteers to determine the safety, tolerability, and pharmacokinetics of ESB1609. Following single oral doses, ESB1609 demonstrated linear pharmacokinetics in plasma and cerebrospinal fluid (CSF) for formulations containing sodium laurel sulfate. Plasma and CSF median time to maximum drug concentration (tmax ) were reached by 4-5 hours and 6-10 hours, respectively. The delay in achieving tmax in CSF relative to plasma, likely due to the high protein binding of ESB1609, was also observed in 2 rat studies. Continuous CSF collection via indwelling catheters confirmed that a highly protein-bound compound is measurable and established the kinetics of ESB1609 in human CSF. Mean plasma terminal elimination half-lives ranged from 20.2 to 26.8 hours. The effect of either a high-fat or standard meal increased maximum plasma concentration and area under the concentration-time curve from time 0 to infinity compared to the fasted state by 2.42-4.34-fold higher, but tmax and half-life remained the same irrespective of fed state. ESB1609 crosses the blood-brain barrier with CSF:plasma ratios ranging between 0.04% and 0.07% across dose levels. ESB1609 demonstrated a favorable safety and tolerability profile at exposures expected to be efficacious.

Evaluation of the Impact of Comorbidities on Omadacycline Pharmacokinetics.

Omadacycline is approved in the United States for the treatment of patients with community-acquired bacterial pneumonia or acute bacterial skin and skin structure infections. Analyses were undertaken to evaluate pharmacokinetic differences among subjects or patients stratified by comorbidities. Differences in clearance by smoking status, history of diabetes mellitus, chronic lung disease, hypertension, heart failure, or coronary artery disease were evaluated using a Welch two-sample t test. Smoking was the only significant comorbidity after correction for sex, with a clinically insignificant difference of 13%. Omadacycline dose adjustments based on these comorbidities do not appear to be warranted.

Antibacterial Drug Development: A New Approach Is Needed for the Field to Survive and Thrive.

It is often said that the marketplace for new antibiotics is broken. This notion is supported by the observation that many recently-approved antibiotics to treat drug-resistant bacteria have failed commercially in a spectacular fashion. Today, companies with peak market-cap values in excess of USD 500 million to 1 billion prior to product launch regularly sell for pennies on the dollar a few years after market introduction. It is possible, however, that the market is not as broken as we perceive. That is, in the collective mind of the clinician, recently-approved antibiotics may be too-poorly differentiated to justify their broad use and inordinate cost relative to those already existing. Perhaps we in the antibacterial drug development field must change our way of thinking if we are to survive and thrive. Rather than reflexively developing new ß-lactam-ß-lactamase inhibitor combinations for every new enzyme that evades our current inhibitors, we should focus discovery and development efforts on agents that revolutionize how we potentiate antibiotics. To this end, there has been renewed interest in phage therapies, virulence inhibitors, bacterial growth rate modulators, monoclonal antibodies, and other approaches to augment antibiotic effects. Herein, we suggest that the unmet medical need is less about adding poorly-differentiated antibiotics to our armamentarium and more about the need for innovation in how we augment antibiotic regimen effects.

Pharmacokinetic-Pharmacodynamic Target Attainment Analyses To Support Dose Selection for ME1100, an Arbekacin Inhalation Solution.

ME1100 (arbekacin inhalation solution) is an inhaled aminoglycoside that is being developed to treat patients with hospital-acquired and ventilator-associated bacterial pneumonia (HABP and VABP, respectively). Pharmacokinetic-pharmacodynamic (PK-PD) target attainment analyses were undertaken to evaluate ME1100 regimens for the treatment of patients with HABP/VABP. The data used included a population pharmacokinetic (PPK) 4-compartment model with 1st-order elimination, nonclinical PK-PD targets from one-compartment in vitro and/or in vivo infection models, and in vitro surveillance data. Using the PPK model, total-drug epithelial lining fluid (ELF) concentration-time profiles were generated for simulated patients with varying creatinine clearance (CLcr) (ml/min/1.73 m2) values. Percent probabilities of PK-PD target attainment by MIC were determined based on the ratio of total-drug ELF area under the concentration-time curve (AUC) to MIC (AUC/MIC ratio) targets associated with 1- and 2-log10 CFU reductions from baseline for Klebsiella pneumoniae, Pseudomonas aeruginosa, and Staphylococcus aureus Percent probabilities of PK-PD target attainment based on PK-PD targets for a 1-log10 CFU reduction from baseline at MIC values above the MIC90 value for K. pneumoniae (8 µg/ml), P. aeruginosa (4 µg/ml), and S. aureus (0.5 µg/ml) were ≥99.8% for ME1100 600 mg twice daily (BID) in simulated patients with CLcr values >80 to ≤120 ml/min/1.73 m2 ME1100 600 mg BID, 450 mg BID, and 600 mg once daily in simulated patients with CLcr values >50 to ≤80, >30 to ≤50, and 0 to ≤30 ml/min/1.73 m2, respectively, provided arbekacin exposures that best matched those for 600 mg BID in simulated patients with normal renal function. These data provide support for ME1100 as a treatment for patients with HABP/VABP.

Population Pharmacokinetic Analyses for Omadacycline Using Phase 1 and 3 Data.

Omadacycline, a novel aminomethylcycline antibiotic with activity against Gram-positive and -negative organisms, including tetracycline-resistant pathogens, received FDA approval in October 2018 for the treatment of patients with acute bacterial skin and skin structure infections (ABSSSI) and community-acquired bacterial pneumonia (CABP). A previously developed population pharmacokinetic (PK) model based on phase 1 intravenous and oral PK data was refined using data from infected patients. Data from 10 phase 1 studies used to develop the previous model were pooled with data from three additional phase 1 studies, a phase 1b uncomplicated urinary tract infection study, one phase 3 CABP study, and two phase 3 ABSSSI studies. The final population PK model was a three-compartment model with first-order absorption using transit compartments to account for absorption delay following oral dosing and first-order elimination. Epithelial lining fluid (ELF) concentrations were modeled as a subcompartment of the first peripheral compartment. A food effect on oral bioavailability was included in the model. Sex was the only significant covariate identified, with 15.6% lower clearance for females than males. Goodness-of-fit diagnostics indicated a precise and unbiased fit to the data. The final model, which was robust in its ability to predict plasma and ELF exposures following omadacycline administration, was also able to predict the central tendency and variability in concentration-time profiles using an external phase 3 ABSSSI data set. A population PK model, which described omadacycline PK in healthy subjects and infected patients, was developed and subsequently used to support pharmacokinetic-pharmacodynamic (PK-PD) and PK-PD target attainment assessments.

Triple combination antibiotic therapy for carbapenemase-producing Klebsiella pneumoniae: a systematic review.

BACKGROUND: The spread of carbapenemase-producing K. pneumoniae (CPKP) has become a significant problem worldwide. Combination therapy for CPKP is encouraging, but polymyxin resistance to many antibiotics is hampering effective treatment. Combination therapy with three or more antibiotics is being increasingly reported, therefore we performed a systematic review of triple combination cases in an effort to evaluate their clinical effectiveness for CPKP infections. METHODS: The PubMed database was searched to identify all published clinical outcomes of CPKP infections treated with triple combination therapy. Articles were stratified into two tiers depending on the level of clinical detail provided. A tier 1 study included: antibiotic regimen, regimen-specific outcome, patient status at onset of infection, and source of infection. Articles not reaching these criteria were considered tier 2. RESULTS: Thirty-three studies were eligible, 23 tier 1 and ten tier 2. Among tier 1 studies, 53 cases were included in this analysis. The most common infection was pneumonia (31%) followed by primary or catheter-related bacteremia (21%) and urinary tract infection (17%). Different combinations of antibiotic classes were utilized in triple combinations, the most common being a polymyxin (colistin or polymyxin B, 86.8%), tigecycline (73.6%), aminoglycoside (43.4%), or carbapenem (43.4%). Clinical and microbiological failure occurred in 14/39 patients (35.9%) and 22/42 patients (52.4%), respectively. Overall mortality for patients treated with triple combination therapy was 35.8% (19/53 patients). CONCLUSIONS: Triple combination therapy is being considered as a treatment option for CPKP. Polymyxin-based therapy is the backbone antibiotic in these regimens, but its effectiveness needs establishing in prospective clinical trials.

Validation of the American Association for the Surgery of Trauma organ injury severity scale for the kidney.

BACKGROUND: We queried an observational database of renal trauma patients to validate the organ injury severity scale (kidney) of the American Association for the Surgery of Trauma (AAST). METHODS: In a retrospective review of our renal trauma database (2,467 patients) with 58 clinical and radiographic patient variables, statistical "classification trees" were used to determine factors predicting need for surgical repair. RESULTS: Scales correlated with the need for surgery (grade I = 0%, grade II = 15%, grade III = 76%, grade IV = 78%, and grade V = 93%) and for nephrectomy (grade I = 0%, grade II = 0%, grade III = 3%, grade IV = 9%, and grade V = 86%). Classification tree analysis (confirmed in 83 additional patients) identified the AAST organ injury severity scale as the most important variable predicting the need for renal repair. CONCLUSION: In a retrospective review of more than 2,500 patients, we determined that the AAST organ injury severity scale correlates with the need for kidney repair or removal. Classification tree analysis confirmed the scale as the prime variable predicting need for surgical repair.

Dynamic half Fourier acquisition, single shot turbo spin-echo magnetic resonance imaging for evaluating the female pelvis.

PURPOSE: We assessed the merit of dynamic half Fourier acquisition, single shot turbo spin-echo sequence T2-weighted magnetic resonance imaging (MRI) for evaluating pelvic organ prolapse and all other female pelvic pathology by prospectively correlating clinical with imaging findings. MATERIALS AND METHODS: From September 1997 to April 1998, 100 consecutive women 23 to 88 years old with (65) and without (35) pelvic organ prolapse underwent half Fourier acquisition, single shot turbo spin-echo sequence dynamic pelvic T2-weighted MRI at our institution using a 1.5 Tesla magnet with phased array coils. Mid sagittal and parasagittal views with the patient supine, relaxed and straining were obtained using no pre-examination preparation or instrumentation. We evaluated the anterior vaginal wall, bladder, urethra, posterior vaginal wall, rectum, pelvic floor musculature, perineum, uterus, vaginal cuff, ovaries, ureters and intraperitoneal organs for all pathological conditions, including pelvic prolapse. Patients underwent a prospective physical examination performed by a female urologist, and an experienced radiologist blinded to pre-imaging clinical findings interpreted all studies. Physical examination, MRI and intraoperative findings were statistically correlated. RESULTS: Total image acquisition time was 2.5 minutes, room time 10 minutes and cost American $540. Half Fourier acquisition, single shot turbo spin-echo T2-weighted MRI revealed pathological entities other than pelvic prolapse in 55 cases, including uterine fibroids in 11, ovarian cysts in 9, bilateral ureteronephrosis in 3, nabothian cyst in 7, Bartholin's gland cyst in 4, urethral diverticulum in 3, polytetrafluoroethylene graft abscess in 3, bladder diverticulum in 2, sacral spinal abnormalities in 2, bladder tumor in 1, sigmoid diverticulosis in 1 and other in 9. Intraoperative findings were considered the gold standard against which physical examination and MRI were compared. Using these criteria the sensitivity, specificity and positive predictive value of MRI were 100%, 83% and 97% for cystocele; 100%, 75% and 94% for urethrocele; 100%, 54% and 33% for vaginal vault prolapse; 83%, 100% and 100% for uterine prolapse; 87%, 80% and 91% for enterocele; and 76%, 50% and 96% for rectocele. CONCLUSIONS: Dynamic half Fourier acquisition, single shot turbo spin-echo MRI appears to be an important adjunct in the comprehensive evaluation of the female pelvis. Except for rectocele, pelvic floor prolapse is accurately staged and pelvic organ pathology reliably detected. The technique is rapid, noninvasive and cost-effective, and it allows the clinician to visualize the whole pelvis using a single dynamic study that provides superb anatomical detail.

Life-threatening anaphylactoid reaction associated with indigo carmine intravenous injection.

Indigo carmine (sodium indigotindisulfonate), a blue dye, has been widely used by surgeons to identify and to examine the urinary tract and is considered biologically inert and extremely safe. We present a case of severe life-threatening anaphylactoid reaction followed by cardiac arrest associated with intravenous indigo carmine injection.

Developmental regression in autism: maternal perception.

Developmental regression among children with autism is a common phenomenon of unknown origin. The purpose of this study was to identify the differences between children with autism who reportedly regressed with those who did not regress. A representative group of 39 mothers were interviewed (40 children--1 pair of twin girls) about familial, pregnancy, perinatal, as well as medical history and developmental milestones. The study focused on mothers' perceptions of developmental regression. Nineteen children (47.5%) regressed in verbal and nonverbal communication and social but not in motor abilities. Mean age of regression was 24 months, with 11 children who regressed before and 8 after this age. No significant differences were reported by mothers of children who did or did not regress. More mothers of children who regressed, than those of children who did not, expressed guilt feelings regarding the development of autism, and almost all of them had an "explanation" for the possible mechanisms that might have influenced their children's developmental course. In conclusion, developmental regression in our population appears to be a typical event in the natural course of autism. There is little difference between those children who regressed and those who did not regress in maternal perceptions and reports of development, family, and medical history.

4-Defect repair of grade 4 cystocele.

PURPOSE: The 4-defect repair of grade 4 cystocele corrects discrete and severe deficiencies of vesicourethral support. We describe this technique used during pelvic reconstruction in 130 women. MATERIALS AND METHODS: During a 3-year period 130 patients (age range 35 to 96 years) underwent repair of grade 4 cystocele using the 4-defect repair technique. Cystocele repair had been performed in 60 patients (46%) and hysterectomy had been performed in 85 (65%). A "goalpost incision" is used in the vaginal wall to facilitate separation of the wall from underlying perivesical fascia, entry into the retropubic space, and exposure of the urethropelvic ligament, cardinal ligament and perivesical fascia. The 4 polypropylene sutures are used to provide an anterior vaginal wall sling which is modified to incorporate perivesical fascia and cardinal ligaments. Central defect repair is achieved by approximation of the cardinal ligaments and midline plication of the perivesical fascia over absorbable mesh. RESULTS: A total of 112 patients were available for followup which ranged from 6 to 42 months (mean 21). Repair of grade 4 cystocele was accompanied by other transvaginal repairs in 94 patients (83%), including rectocele repair in 81, hysterectomy in 22 and enterocele repair in 31. Of the patients 92% had excellent objective and subjective results for anatomical cystocele repair. Of the patients with preoperative stress urinary incontinence 90% had excellent or good subjective results. De novo urge incontinence was seen in 7% of patients. CONCLUSIONS: The 4-defect repair technique relies on anatomical restoration of 4 distinct deficiencies of pelvic support and is highly effective for relief of symptoms of grade 4 cystocele.

Diagnosis and management of trauma to the kidney.

Because trauma is an unplanned event, guidelines for managing patients sustaining upper urinary tract injury must already exist in the surgeon's mind before laying eyes on the injured patient. In order to simplify and standardize the evaluation and treatment of such patients, urologists have applied a system of staging paradigms and treatment algorithms, analogous to systems successfully used in the less chaotic arena of, for example, urologic oncology. Advancements in imaging modalities, improvements and renovations of surgical technique, and critical review of outcomes data have impacted on the management of genitourinary trauma and will be likely to influence the way we treat trauma patients in the future.

Acute adrenal insufficiency following unilateral radical nephrectomy: a case report.

Adrenal insufficiency following unilateral radical nephrectomy has not been previously described in medical literature. We present a 78-year-old male patient who experienced a difficult postoperative course with vague findings, and was ultimately diagnosed with acute adrenal insufficiency. Treatment with glucocorticoids and mineralocorticoids resulted in prompt control of the disease.

Psychopathology associated with sexual dysfunction.

The association between sexual disorders and psychological functioning was investigated in this study. Seventy-eight subjects who applied for sex therapy were divided into the following groups: Sexual Desire (SDD) and Erectile Disorder; Orgasm (ORG) and Premature ejaculation (PME) disorders. Fifty-six sexually functional subjects served as matched controls. The MMPI was administered to all subjects. The results indicated that the SDD and Erectile groups produced the most disturbed profiles, while the ORG and PME groups yielded profiles within normal limit (WNL). A good fit of individual to group profiles was found for SDD, but not for PME and ORG; thus, clinical interpretation was possible for the former only.

Sex, ethnic, and social differences in test anxiety among Israeli adolescents.

The effects of sex, ethnicity, and social class on levels of test anxiety were examined among a sample of 416 adolescent students in Israel. Significant sex differences in mean levels of test anxiety were found, with girls scoring consistently higher than boys across ethnic, social, and grade categories. Pupils of low socioeconomic status (SES) also scored consistently higher than pupils of high SES across grades. Nevertheless, this study provides little support for the commonly held view that sociocultural or sex group differences in school achievement are due, in any meaningful way, to differences in test anxiety. The group differences, though significant for SES and sex, were of negligible magnitude, and the correlation between test anxiety scores and grade point average was minimal for the group as a whole and nonsignificant for students of Eastern background, who have been purported to be particularly affected by high levels of test anxiety. The findings do support other cross-cultural studies, which have found only a modicum of shared variance between test anxiety and grades. It is concluded that test anxiety is not a particularly valid predictor of achievement or ability.