Overcoming an Extremely Drug Resistant (XDR) Pathogen: Avibactam Restores Susceptibility to Ceftazidime for Burkholderia cepacia Complex Isolates from Cystic Fibrosis Patients.

Burkholderia multivorans is a significant health threat to persons with cystic fibrosis (CF). Infections are difficult to treat as this pathogen is inherently resistant to multiple antibiotics. Susceptibility testing of isolates obtained from CF respiratory cultures revealed that single agents selected from different antibiotic classes were unable to inhibit growth. However, all isolates were found to be susceptible to ceftazidime when combined with the novel non-ß-lactam ß-lactamase inhibitor, avibactam (all minimum inhibitor concentrations (MICs) were ≤8 mg/L of ceftazidime and 4 mg/L of avibactam). Furthermore, a major ß-lactam resistance determinant expressed in B. multivorans, the class A carbapenemase, PenA was readily inhibited by avibactam with a high k2/K of (2 ± 1) × 106 µM-1 s-1 and a slow koff of (2 ± 1) × 10-3 s-1. Mass spectrometry revealed that avibactam formed a stable complex with PenA for up to 24 h and that avibactam recyclized off of PenA, re-forming the active compound. Crystallographic analysis of PenA-avibactam revealed several interactions that stabilized the acyl-enzyme complex. The deacylation water molecule possessed decreased nucleophilicity, preventing decarbamylation. In addition, the hydrogen-bonding interactions with Lys-73 were suggestive of a protonated state. Thus, Lys-73 was unlikely to abstract a proton from Ser-130 to initiate recyclization. Using Galleria mellonella larvae as a model for infection, ceftazidime-avibactam was shown to significantly (p < 0.001) improve survival of larvae infected with B. multivorans. To further support the translational impact, the ceftazidime-avibactam combination was evaluated using susceptibility testing against other strains of Burkholderia spp. that commonly infect individuals with CF, and 90% of the isolates were susceptible to the combination. In summary, ceftazidime-avibactam may serve as a preferred therapy for people that have CF and develop Burkholderia spp. infections and should be considered for clinical trials.

Novel hybrid laparoscopic sacrocolpopexy for pelvic organ prolapse with a severe paravaginal defect.

Abdominal sacrocolpopexy is the gold standard for treating pelvic organ prolapse (POP) because of safety and durable good results. More recently laparoscopic sacrocolpopexy (LSC), a less invasive approach, has become popular. Although these surgeries are versatile and can treat almost all patients with POP, these techniques have shortcomings. Specifically, reinforcement of lateral vaginal defects are not very strong, thus patients with POP and a severe paravaginal defect are not good candidates for abdominal or laparoscopic sacrocolpopexy. To overcome this problem, we developed a novel type of LSC, which can reinforce severe paravaginal defects by using a reversed T-shaped anterior mesh combining the advantage of transvaginal mesh surgery. We refer to this novel surgery as 'hybrid LSC'. Thus far, eight patients have successfully undergone this surgery. Hybrid LSC is a simple and secure method, and is an alternative treatment for POP with a severe paravaginal defect.

Novel hybrid mesh surgery combines sacrocolpopexy with transvaginal mesh placement for pelvic organ prolapse.

Mesh surgeries, such as sacrocolpopexy and transvaginal mesh surgery, are commonly used to treat pelvic organ prolapse. Although mesh surgeries have a high success rate, they are unsuitable for some patients. For a patient with pelvic organ prolapse and highly calcified multiple fibroids, we performed hybrid sacrocolpopexy combined with transvaginal mesh surgery with a method modified for the patient's condition. Three months after surgery, the results were highly satisfactory. This approach is simple, secure, and versatile for patients who are not good candidates for conventional mesh surgeries. This novel hybrid mesh surgery is an option for treating various types of pelvic organ prolapse.

Evaluation of laparoendoscopic single-site gynecologic surgery with a multitrocar access system.

OBJECTS: Laparoendoscopic single-site surgery (LESS) is an ideal approach for gynecologic surgery and yields better cosmetic results. However, a standard umbilical approach with LESS is not appropriate for gynecologic surgery requiring intra-abdominal suturing and dissection requiring traction. Therefore, we have developed a new multitrocar access system for gynecologic LESS. The purpose of this study was to evaluate the efficacy of gynecologic LESS using this access system. METHODS: This access system consists of one 12-mm trocar, two 5-mm trocars, and a 5-mm flexible laparoscope. Two 5-mm trocars with small port heads were inserted cross-wise on opposite sides of the sleeve of the centrally positioned 12-mm trocar to maintain triangulation. Thirty-eight patients with various gynecologic conditions underwent LESS with this access system. The results of these surgeries were retrospectively compared to those of conventional laparoscopic procedures. RESULTS: Of the 38 LESS procedures performed with this access system, none was up-converted, converted to an open laparotomy, or required blood transfusion. The Salpingo-oophorectomy with LESS had several benefits, such as no extension of the skin incision of the trocar site and no leakage of the contents of the ovarian cyst into the peritoneal cavity, over that with conventional laparoscopy. A comparison of LESS (11 patients) and conventional laparoscopy (16 patients) for total hysterectomy showed no significant difference in total blood loss (234.0 mL vs. 221.6 mL) or the weight of the resected uterus (276.0 g vs. 285.0 g), although the mean total operative time was greater with LESS (199.0 min vs. 168.5 min). CONCLUSION: Our multitrocar access system is safe and secure, and can be adapted for various gynecologic surgeries involving complicated procedures. LESS with this access system achieves results comparable to those of conventional laparoscopy with 4 ports, although the operative time is longer.

Proliferative response to phenytoin and nifedipine in gingival fibroblasts cultured from humans with gingival fibromatosis.

The response of gingival fibroblasts cultured from humans with gingival fibromatosis to phenytoin (PHT) and nifedipine (NIF) was investigated. PHT and NIF induced proliferation, and increased the expression of immunoreactive endothelin-1 (ET-1). ET-1 (0.1 nm-1 microm) itself also induced proliferation in a concentration-dependent manner. The proliferation was inhibited by BQ-123 (ETA receptor antagonist; 1 microm) and TAK044 (ETA/ETB receptor antagonist; 1 microm), but not by BQ-788 (ETB receptor antagonist; 1 microm). The proliferation induced by PHT (0.25 microm) and NIF (0.25 microm) was inhibited by BQ-123 (1 microm). In addition, the results of Western blot analysis indicated the presence of ETA and ETB receptors in/on the fibroblasts. These findings suggest that PHT- and NIF-induced gingival proliferation may be mediated by endogenously generated ET-1, possibly via ETA receptors.