Pharmacodynamics of vancomycin for CoNS infection: experimental basis for optimal use of vancomycin in neonates.

OBJECTIVES: CoNS are the most common cause of neonatal late-onset sepsis. Information on the vancomycin pharmacokinetics/pharmacodynamics against CoNS is limited. The aim of this study was to characterize vancomycin pharmacokinetic/pharmacodynamic relationships for CoNS and investigate neonatal optimal dosage regimens. METHODS: A hollow fibre and a novel rabbit model of neonatal central line-associated bloodstream CoNS infections were developed. The results were then bridged to neonates by use of population pharmacokinetic techniques and Monte Carlo simulations. RESULTS: There was a dose-dependent reduction in the total bacterial population and C-reactive protein levels. The AUC/MIC and Cmax/MIC ratios were strongly linked with total and mutant resistant cell kill. Maximal amplification of resistance was observed in vitro at an fAUC/MIC of 200 mg ·â€Šh/L. Simulations predicted that neonates <29 weeks post-menstrual age are underdosed with standard regimens with respect to older age groups. CONCLUSIONS: The AUC/MIC and Cmax/MIC ratios are the pharmacodynamic indices that best explain total and resistant cell kill in CoNS infection. This suggests that less-fractionated regimens are appropriate for clinical use and continuous infusions may be associated with increased risk of emergence of antimicrobial resistance. This study has provided the pharmacodynamic evidence to inform an optimized neonatal dosage regimen to take into a randomized controlled trial.

An invertebrate model to evaluate virulence in Aspergillus fumigatus: the role of azole resistance.

The impact of different mutations in the Aspergillus fumigatus ergosterol biosynthesis pathway on pathogenesis has been evaluated using a simple invertebrate mini host, the caterpillar Galleria mellonella. A set of strains that includes clinical isolates and isogenic mutants with mutations at the cyp51A gene conferring azole resistance were studied. All strains demonstrated a similar in vitro growth pattern and are equally virulent against the insect larvae. These results suggest that in A. fumigatus acquisition of this particular azole-resistance mechanism would not imply any significant change in virulence. G. mellonella may provide a convenient and inexpensive model for the in vivo prescreening of mutants of A. fumigatus, contributing to the generation of a hypotheses that can be further tested in refined experiments in mammalian models.

Impact of Bolus dosing versus continuous infusion of Piperacillin and Tazobactam on the development of antimicrobial resistance in Pseudomonas aeruginosa.

Management of nosocomial pneumonia is frequently complicated by bacterial resistance. Extended infusions of beta-lactams are increasingly being used to improve clinical outcomes. However, the impact of this strategy on the emergence of antimicrobial resistance is not known. A hollow-fiber infection model with Pseudomonas aeruginosa (PAO1) was used. Pharmacokinetic (PK) profiles of piperacillin-tazobactam similar to those in humans were simulated over 5 days. Three dosages of piperacillin-tazobactam were administered over 0.5 h or 4 h, with redosing every 8 h. Two initial bacterial densities were investigated (∼10(4) CFU/ml and ∼10(7) CFU/ml). The time courses of the total bacterial population and the resistant subpopulation were determined. All data were described using a mathematical model, which was then used to define the relationship between drug concentrations, bacterial killing, and emergence of piperacillin resistance. There was logarithmic growth in controls in the initial 24 h, reaching a plateau of ∼9 log10 CFU/ml. Bacterial killing following administration of piperacillin via bolus dosing and that after extended infusions were similar. For the lower initial bacterial density, trough total plasma piperacillin concentration/MIC ratios of 3.4 and 10.4 for bolus and extended-infusion regimens, respectively, were able to suppress the emergence of piperacillin resistance. For the higher initial bacterial density, all regimens were associated with progressive growth of a resistant subpopulation. A stratified approach, according to bacterial density, is required to treat patients with nosocomial pneumonia. Antimicrobial monotherapy may be sufficient for some patients. However, for patients with a high bacterial burden, alternative therapeutic strategies are required to maximize bacterial killing and prevent antimicrobial resistance.

Pharmacokinetics and pharmacodynamics of anidulafungin for experimental Candida endophthalmitis: insights into the utility of echinocandins for treatment of a potentially sight-threatening infection.

Candida chorioretinitis and endophthalmitis are relatively common manifestations of disseminated candidiasis. Anidulafungin is increasingly used for the treatment of disseminated candidiasis, but its efficacy for Candida endophthalmitis is not known. A nonneutropenic model of hematogenous Candida endophthalmitis was used. Anidulafungin at 5, 10, and 20 mg/kg was initiated at 48 h postinoculation. The fungal densities in the kidney and vitreous humor were determined. Anidulafungin concentrations in the plasma and vitreous humor were measured using high-performance liquid chromatography (HPLC). A pharmacokinetic-pharmacodynamic model was used to link anidulafungin concentrations with the observed antifungal effect. The area under the concentration-time curve (AUC) associated with stasis was determined in the both the kidney and the vitreous humor. The results were bridged to humans to identify likely dosages that are associated with significant antifungal activity within the eye. Inoculation of Candida albicans resulted in logarithmic growth in both the vitreous humor and the kidney. The pharmacokinetics of anidulafungin were linear. There was dose-dependent penetration of the anidulafungin into the vitreous humor. The exposure-response relationships in the kidney and vitreous were completely discordant. AUCs of 270 and 100 were required for stasis in the eye and kidney, respectively. The currently licensed regimen results in an AUC for an average patient that is associated with stasis in the kidney but minimal antifungal activity in the eye. We conclude that anidulafungin penetrates the eye in a dose-dependent manner and that dosages higher than those currently licensed are required to achieve significant antifungal activity in the eye.

The functional role of cardiac activity in perception and action.

SKORA, L.I., J.J.A. LIVERMORE and K. Roelofs. The functional role of cardiac activity in perception and action. NEUROSCI BIOBEHAV REV X(X) XXX-XXX, 2022. Patterns of cardiac activity continuously vary with environmental demands, accelerating or decelerating depending on circumstances. Simultaneously, cardiac cycle affects a host of higher-order processes, where systolic baroreceptor activation largely impairs processing. However, a unified functional perspective on the role of cardiac signal in perception and action has been lacking. Here, we combine the existing strands of literature and use threat-, anticipation-, and error-related cardiac deceleration to show that deceleration is an adaptive mechanism dynamically attenuating the baroreceptor signal associated with each heartbeat to minimise its impact on exteroceptive processing. This mechanism allows to enhance attention afforded to external signal and prepare an appropriate course of action. Conversely, acceleration is associated with a reduced need to attend externally, enhanced action tendencies and behavioural readjustment. This novel account demonstrates that dynamic adjustments in heart rate serve the purpose of regulating the level of precision afforded to internal versus external evidence in order to optimise perception and action. This highlights that the importance of cardiac signal in adaptive behaviour lies in its dynamic regulation.

Clinical effects and pharmacokinetics of racemic methadone and its optical isomers.

The respiratory and pupillary effects of oral l-, d-, and d,l-methadone were studied in healthy male volunteers 21 to 35 yr of age. The mean half-life of drug in blood was 22 hr for racemic methadone, 24 hr for l-methadone, and 25 hr for d-methadone. The effects of d-methadone were not significantly different from the placebo response at a 7.5 mg dose, whereas a 50 and 100 mg dose slightly depressed respiration in one subject each. Both 7.5 mg of l-methadone and 15 mg of d,l-methadone induced intense and sustained respiratory depression and miosis. The changes induced by l-methadone were of longer duration than those of d,l-methadone, lasting more than 72 hr in some subjects. Whole blood drug concentration correlated well with respiratory depression and miosis for l- and d,,l-methadone. The potency ratio of l-methadone to d,l-methdone, calculated from blood drug concentration data, was found to be 3.0 for respiratory depression and 2.7 for miosis. The antiduretic effect of 15 mg of d,l-methadone was investigated in three subjects and was found to persist for as long as measurements were taken, namely 11 and 12 hr in two subjects. d,l-Methadone administered frequently for pain may have cumulative effects on respiratory control and ability to excrete a water load.

Mitral repair in complete atrioventricular canal. Ease of correction in early infancy.

During the past 5 years all patients with complete atrioventricular (AV) were subjected to surgical correction regardless of age. Thus we were able to assess the ease and reliability of mitral repair in early infancy. Key features of operation include division of bridging leaflets when indicated, selection of a patch sufficiently small to prevent postoperative annular dilation, attachment of the leaflets to the patch with continuous nonpledget-supported sutures at a level determined by the chordal structure, and, based on the size of the mural leaflet, construction of a bicuspid or tricuspid mitral valve. Operative mortality and postoperative morbidity were no greater in patients under 6 months of age than in older patients. Reoperation for mitral regurgitation was required in three patients. In all of them, the primary reason for the failure of repair was that the mitral valve had been left tricuspid; in two of them, the mitral anulus was dilated, as well. Repair was uniformly accomplished by bicuspidization, combined in two instances with a Wooler-type annuloplasty and shortening of the free margin of the aortic leaflet. The absence of secondary scarring of the leaflets in the patients under 6 months of age facilitated repair in this age group. Early repair is possible, and preferable, provided that meticulous attention is paid to the technical features of the repair and a proper decision is made with regard to treatment of the mitral "cleft."

Disruption of the ascending aorta: surgical management.

A disruptive injury to the ascending aorta during a cardiac operation is a serious and often fatal event. Such an injury is described in which the aorta disrupted at the site of the proximal aortocoronary anastomoses. It was possible to repair the aorta using an intraluminal sutureless graft after other techniques of repair failed.

Effect of femoral head size on wear of the polyethylene acetabular component.

A technique was developed to determine the wear of the acetabular component of a total hip replacement by examination of standardized initial and follow-up radiographs. Three hundred and eighty-five hips were followed for at least 9.5 years after replacement. The least amount and rate of linear wear were associated with use of a femoral head that had a diameter of twenty-eight millimeters (p less than 0.001). The greatest amount and mean rate of linear wear occurred with twenty-two-millimeter components, but these differences were not statistically significant. The greatest volumetric wear and mean rate rate of volumetric wear were seen with thirty-two-millimeter components (p less than 0.001). A wider radiolucent line in acetabular Zone 1 was associated with use of the thirty-two-millimeter head. The amounts of resorption of the proximal part of the femoral neck and of lysis of the proximal part of the femur both correlated positively with the extent of linear and volumetric wear; this suggests an association between the amount of debris from wear and these changes in the femoral neck and proximal part of the femur.

beta-Galactosidase gene mutations in patients with slowly progressive GM1 gangliosidosis.

Three unrelated North American cases with slowly progressive forms of GM1 gangliosidosis were found to have two unique point mutations and a 9 bp insertion in the coding region of the gene encoding beta-galactosidase. Case 1 was noted to have a 9 bp insertion ¿CAGAATTTT¿ on one allele between nucleotides 730 and 731 with no other mutations identified in the other allele. In case 2, two point mutations were found: a unique G-->A transition at nucleotide 602 causing an Arg-->His substitution in codon 201 (mutation R201H); and a previously identified G-->T transition at nucleotide 1527 causing a Trp-->Cys substitution in codon 509 (mutation W509C), which has been noted in adult and chronic forms of GM1 gangliosidosis. Case 3 had a unique point mutation (A-->G transition at nucleotide 797) resulting in a Asn-->Ser amino acid substitution in codon 266 (mutation N266S), with no other mutations found in the same or the other allele. Single-strand conformation polymorphism performed on over 100 controls did not demonstrate the presence of the point mutations R201H or N266S. Also, the mutant proteins coded by the two point mutations did not show enzymatic activity in the Cos-1 cell expression system confirming that these mutations are associated with low enzyme activity.

Mucoepidermoid tracheal adenoma during pregnancy.

A 30-year-old, 36-week pregnant, female was admitted to the hospital with progressive "asthma" and wheezing. She was markedly dyspneic and unable to lie down or to sleep for periods over an hour. Bronchoscopy demonstrated an endobronchial tumor just above the carina. Following ventilating tracheal bronchoscopy with dilatation of the trachea and establishment of an airway through the tumor, a cesarean section was performed with resultant delivery of a healthy, female, infant. A partial abruptio placentae was noted. Under the same anesthetic, a right posterior lateral thoracotomy with resection of the tracheal tumor was performed. Preoperative and operative considerations are described.

Knee extensor mechanics after subtotal excision of the patella.

Two sets of six fresh frozen autopsy specimens were used to test the quadriceps force requirements for knee extension after sequential distal-to-proximal and proximal-to-distal excisions of the patella. The quadriceps force as a function of knee flexion angle was recorded for varying amounts of excision and compared with the results for total patellectomy. Excision of the proximal one half or less resulted in lower force requirements when compared with total patellectomy. The effects of removal of the proximal three-fourths length of patella were inconsistent and actually increased the force requirements in three knees. The effects of distal to proximal excisions indicate a biomechanical advantage to maintaining a fragment equal to at least three fourths the length of the proximal patella. Retaining a fragment of adequate size preserves at least some of the mechanical advantage provided by the intact patella.

Effects of acetabular abduction on cup wear rates in total hip arthroplasty.

This study was designed to determine the effect of acetabular abduction on the polyethylene wear rates of the acetabular component. The hypothesis of this study is that acetabular placement, in particular abduction, effects contact forces and therefore polyethylene wear. A total of 364 total hip arthroplasties that were performed between 1974 and 1976 were included in this study. The cemented all-polyethylene acetabular components were the same for each case and came from a single supplier. The polyethylene wear rates were calculated by measuring the shortest radius from the center of the prosthetic femoral head to a point on the outer surface of the acetabular cup. An immediate postoperative radiograph was compared with a follow-up radiograph at least 9.5 years later. A standardized radiograph was used to prevent differences due to magnification. The abduction or inclination of the acetabular cups was measured in all of the patients. The amount of acetabular cup abduction was measured relative to the ischial tuberosity line. The mean abduction was 44.1 degrees with a standard deviation of 9.2 degrees and a median of 44 degrees. The range of abduction was from 0 degrees to 85 degrees. This analysis failed to show a correlation between the amount of acetabular abduction and polyethylene wear rates (Pearson's correlation coefficient = 0.0679; P = .20). With a sample size of 364, there is over a 95% change (statistical power) of detecting an underlying true correlation between wear and abduction that is greater than or equal to 0.20. We were unable to demonstrate a difference in wear that would correlate with the differing degrees of abduction of the acetabular socket. We felt that the radiographic measurements of wear were quite accurate. This method of determining acetabular abduction has also been documented and supported in previous literature and has allowed us to accurately determine acetabular abduction. The results of our study demonstrate that within the normal ranges described by our study, polyethylene wear did not significantly increase with increased abduction of the acetabular component.