Real-World Clinical Use and Outcomes of Telavancin for the Treatment of Bone and Joint Infections: Results from the Telavancin Observational Use Registry (TOUR™).

BACKGROUND: Additional antibiotic options are needed to treat bone and joint infections caused by penicillin-resistant Gram-positive pathogens. OBJECTIVE: This subanalysis of the Telavancin Observational Use Registry (TOUR™) aimed to record real-world telavancin usage patterns in patients with bone and joint infections treated with telavancin. METHODS: TOUR was a multicenter observational-use registry study conducted at 45 US sites between January 2015 and March 2017. Patient characteristics, infection type, infecting pathogen(s), previous treatment, telavancin dosing and duration, clinical response, and adverse event data were collected by retrospective medical chart reviews. As such, inclusion/exclusion criteria were limited, and any patient receiving at least one dose of telavancin at the discretion of the treating physician was eligible. Patients were assessed as either positive clinical response, failed treatment, or indeterminate outcome. RESULTS: Of the 1063 patients enrolled in TOUR, 27.4% (291/1063) were patients with bone and joint infections including osteomyelitis (with or without prosthetic material), acute septic arthritis, and prosthetic joint infections. Most of these patients had osteomyelitis without prosthetic material (191/291; 66.0%). Among patients assessed at the end of treatment, 211/268 (78.7%) achieved a positive clinical response, 26/268 (9.7%) failed treatment, and 31/268 (11.6%) had an indeterminate outcome. The most frequent pathogen was methicillin-resistant Staphylococcus aureus (110/291; 37.8%). The median (interquartile range [IQR as Q1, Q3]) telavancin dose was 750.0 mg (IQR, 750, 750 mg) or 8.2 mg/kg (IQR, 6.8, 9.7 mg/kg) administered for a median of 26 days (IQR, 12, 42 days). These assessments were recorded in the registry ≥ 30 days after the last dose of telavancin was administered. CONCLUSIONS: Real-world data from the TOUR study show that clinicians are using once-daily telavancin with positive clinical outcomes for the treatment of bone and joint infections caused by Gram-positive pathogens. CLINICAL TRIAL REGISTRATION: This trial was registered with ClinicalTrials.gov (NCT02288234) on 11 November, 2014.

Hypodermic needle fixation without fluoroscopy versus k-wire fixation with fluoroscopy for distal phalangeal fractures: a comparative study.

BACKGROUND: Distal phalanx fractures are frequently encountered in our daily practice. They are often caused by crush injuries and are the most frequent work-related hand fractures. Different types of fixation have been proposed for displaced fractures. METHODS: A retrospective study was performed on two fixation types. Twenty-four distal phalanx fractures were treated with k-wire fixation with fluoroscopic control in a main operating room setting. Twenty-five distal phalanx fractures were treated with hypodermic needle fixation without fluoroscopic control in an emergency treatment room setting. Clinical and radiological data were collected on fracture type, fracture healing and complications. The cost of both types of surgery was assessed. RESULTS: No significant difference in healing time, union, delayed union and non-union was found between the two groups. Loosening was significantly more frequent in the hypodermic needle group, without affecting clinical or radiographic outcome. No infections were encountered in both groups. Surgery performed in the emergency treatment room reduced the cost with 9000 dollars when compared to surgery performed the main operating room. CONCLUSION: Treatment of displaced distal phalanx fractures with hypodermic needle fixation yields good results. Performing this procedure in a treatment room is safe and might reduce operative time, institutional costs and radiation exposure for both surgeon and patients.

Review of Doravirine Resistance Patterns Identified in Participants During Clinical Development.

BACKGROUND: Doravirine (DOR) is a novel non-nucleoside reverse transcriptase inhibitor (NNRTI) approved for the treatment of HIV-1 infection in patients with no known DOR resistance-associated mutations. DOR was rationally designed to address limitations associated with other approved NNRTIs, particularly resistance from common NNRTI resistance-associated mutants containing K103N, Y181C, or G190A reverse transcriptase substitutions. SETTING: Data to date from both in vitro studies and clinical trials have been compiled to summarize the resistance profile of DOR. METHODS: We analyzed data from in vitro studies and phase 2 and 3 trials to assess the emergence of resistance-associated mutations and their impact on efficacy among participants treated with DOR. RESULTS: DOR exhibited a distinct resistance profile compared with efavirenz and rilpivirine in vitro and in vivo; mutant viruses that were resistant to DOR showed limited cross-resistance to efavirenz and rilpivirine. In clinical trials, the development of DOR resistance-associated substitutions in reverse transcriptase was uncommon. CONCLUSION: Overall, minimal cross-resistance across NNRTIs was observed for DOR and limited development of DOR-related resistance. These data should assist clinicians in further understanding the resistance profile of DOR, so appropriate treatment decisions can be made for their patients.

Antimicrobial Agent Shortages: The New Norm for Infectious Diseases Physicians.

BACKGROUND: In 2012, the US Food and Drug Administration (FDA) required drug manufacturers to give advance notice of impending drug shortages. A survey of infectious diseases (ID) physicians was undertaken to determine the impact of this requirement and to follow-up on prior perceptions of ID physicians on shortages of antimicrobial agents. METHODS: We used a web-based survey of ID physician members of the Emerging Infections Network in 2016. RESULTS: Of the 701 of 1597 members (44%) who responded, 70% reported the need to modify their antimicrobial choice because of a shortage in the prior 2 years. A majority (73%) reported the shortages affected patient care or outcomes by the use of broader-spectrum (75%), more costly (58%), less effective second-line (45%), or more toxic agents (37%). The most commonly reported antimicrobials in short supply were piperacillin-tazobactam, ampicillin-sulbactam, meropenem, cefotaxime, and cefepime. Respondents learned of shortages from hospital notification, from a colleague, contact from pharmacy after ordering the agent in short supply, or FDA or other website. The antimicrobial stewardship programs (ASPs) of a majority (83%) of respondents' institutions had developed approaches to deal with shortages. Although 71% indicated that communications were sufficient, most (87%) did not perceive any improvement in communications about shortages since the 2012 FDA requirement. CONCLUSIONS: The persistence of antimicrobial agent shortages reported by ID physicians is disturbing as is the resulting need to use broader-spectrum or more toxic agents. The prominent role of ASPs in helping to deal with shortages, effective communication channels, and the lack of perceived improvement in FDA's communication strategy merit further consideration.

HDAC inhibition induces HIV-1 protein and enables immune-based clearance following latency reversal.

Promising therapeutic approaches for eradicating HIV include transcriptional activation of provirus from latently infected cells using latency-reversing agents (LRAs) and immune-mediated clearance to purge reservoirs. Accurate detection of cells capable of producing viral antigens and virions, and the measurement of clearance of infected cells, is essential to assessing therapeutic efficacy. Here, we apply enhanced methodology extending the sensitivity limits for the rapid detection of subfemtomolar HIV gag p24 capsid protein in CD4+ T cells from ART-suppressed HIV+ individuals, and we show viral protein induction following treatment with LRAs. Importantly, we demonstrate that clinical administration of histone deacetylase inhibitors (HDACis; vorinostat and panobinostat) induced HIV gag p24, and ex vivo stimulation produced sufficient viral antigen to elicit immune-mediated cell killing using anti-gp120/CD3 bispecific antibody. These findings extend beyond classical nucleic acid endpoints, which are confounded by the predominance of mutated, defective proviruses and, of paramount importance, enable assessment of cells making HIV protein that can now be targeted by immunological approaches.

Telavancin in the Treatment of Concurrent Staphylococcus aureus Bacteremia: A Retrospective Analysis of ATLAS and ATTAIN Studies.

INTRODUCTION: Concurrent Staphylococcus aureus bacteremia (SAB) worsens outcomes and increases mortality in patients with complicated skin and skin structure infections (cSSSI), hospital-acquired bacterial pneumonia, and ventilator-associated bacterial pneumonia (HABP/VABP). These challenges highlight the need for alternative treatments. Telavancin (TLV), a bactericidal lipoglycopeptide with high in vitro potency, effectively treats patients with cSSSI and HABP/VABP caused by Gram-positive pathogens, particularly S. aureus. METHODS: This retrospective analysis evaluated patients from the Assessment of Telavancin in Complicated Skin and Skin Structure Infections and Assessment of Telavancin for Treatment of Hospital-Acquired Pneumonia studies with baseline, concurrent SAB. Differences in the clinical cure rates at test-of-cure and safety outcomes were compared for TLV vs vancomycin (VAN) treatment groups. RESULTS: A total of 105 patients, 32 cSSSI and 73 HABP/VABP, had baseline, concurrent SAB. The clinical cure rates for all-treated SAB patients in the cSSSI (TLV 57.1% and VAN 54.5%) and HABP/VABP (TLV 54.3% and VAN 47.2%) groups were comparable. For both types of infections, the safety profile of TLV and VAN showed similar incidences of adverse events (AEs), serious AEs, or AEs leading to discontinuation. One VAN-treated patient died in the cSSSI group, and there were 13 deaths in each treatment arm of the HABP/VABP group. CONCLUSION: This retrospective analysis demonstrated that TLV is clinically comparable in both efficacy and safety to VAN, and, therefore, may be an appropriate therapeutic option for the treatment of patients with HABP/VABP or cSSSI and concurrent SAB. Given the limited sample size in this subgroup, the interpretation of these results is limited. FUNDING: Theravance Biopharma Antibiotics, Inc.

P2-quinazolinones and bis-macrocycles as new templates for next-generation hepatitis C virus NS3/4a protease inhibitors: discovery of MK-2748 and MK-6325.

With the goal of identifying inhibitors of hepatitis C virus (HCV) NS3/4a protease that are potent against a wide range of genotypes and clinically relevant mutant viruses, several subseries of macrocycles were investigated based on observations made during the discovery of MK-5172. Quinazolinone-containing macrocycles were identified as promising leads, and optimization for superior cross-genotype and mutant enzyme potency as well as rat liver and plasma concentrations following oral dosing, led to the development of MK-2748. Additional investigation of a series of bis-macrocycles containing a fused 18- and 15-membered ring system were also optimized for the same properties, leading to the discovery of MK-6325. Both compounds display the broad genotype and mutant potency necessary for clinical development as next-generation HCV NS3/4a protease inhibitors.

Monitoring of Outpatient Parenteral Antimicrobial Therapy and Implementation of Clinical Pharmacy Services at a Community Hospital Infusion Unit.

BACKGROUND: In 2004, the Infectious Diseases Society of America (IDSA) published monitoring guidelines for outpatient parenteral antimicrobial therapy (OPAT), but no assessment of their utilization has been reported. We evaluated adherence to these recommendations by physicians at infusion centers and then piloted a program of supervision of monitoring by pharmacists. METHODS: Phase I: We performed a retrospective case-control study of patients who received OPAT over 1 year at 2 hospital infusion centers. Controls were patients treated by an infectious diseases (ID) physician, and cases were those without an ID physician. Patients were excluded if they received fewer than 3 days of OPAT. Clinical pharmacy monitoring services were then implemented for patients on OPAT prescribed by non-ID physicians at 1 hospital's infusion unit. Two outcomes were measured: adherence to guidelines on monitoring and attainment of goal vancomycin and aminoglycoside serum concentrations when appropriate. The results for non-ID physicians were compared to both ID physicians and subsequently a pharmacist. RESULTS: Ninety-nine patients were included in the retrospective study. Compared with patients who had ID physician supervision, the non-ID physicians who prescribed OPAT for 39 patients had lower adherence to monitoring recommendations (35.9% vs 68.3%, P = .003). No difference could be detected in achievement of goal vancomycin and aminoglycoside serum concentrations for the 14 cases and 19 controls requiring therapeutic drug monitoring (57.1% vs 68.4%, respectively, P = .765). Seven patients were enrolled in the study after pharmacy monitoring was implemented. Adherence to monitoring recommendations for these patients was significantly improved compared to the prior patients who lacked ID physician supervision (35.9% vs 100%, P = .0065). CONCLUSION: Non-ID physicians are less likely to monitor OPAT according to the IDSA guidelines than ID physicians; however, pharmacist oversight improves adherence to recommendations. Further studies of monitoring of OPAT by pharmacists should investigate the impact of pharmacist involvement on prevention of adverse events and hospital readmissions.

Discovery of MK-8742: an HCV NS5A inhibitor with broad genotype activity.

The NS5A protein plays a critical role in the replication of HCV and has been the focus of numerous research efforts over the past few years. NS5A inhibitors have shown impressive in vitro potency profiles in HCV replicon assays, making them attractive components for inclusion in all oral combination regimens. Early work in the NS5A arena led to the discovery of our first clinical candidate, MK-4882 [2-((S)-pyrrolidin-2-yl)-5-(2-(4-(5-((S)-pyrrolidin-2-yl)-1H-imidazol-2-yl)phenyl)benzofuran-5-yl)-1H-imidazole]. While preclinical proof-of-concept studies in HCV-infected chimpanzees harboring chronic genotype 1 infections resulted in significant decreases in viral load after both single- and multiple-dose treatments, viral breakthrough proved to be a concern, thus necessitating the development of compounds with increased potency against a number of genotypes and NS5A resistance mutations. Modification of the MK-4882 core scaffold by introduction of a cyclic constraint afforded a series of tetracyclic inhibitors, which showed improved virologic profiles. Herein we describe the research efforts that led to the discovery of MK-8742, a tetracyclic indole-based NS5A inhibitor, which is currently in phase 2b clinical trials as part of an all-oral, interferon-free regimen for the treatment of HCV infection.

Emergence of resistance-associated variants after failed triple therapy with vaniprevir in treatment-experienced non-cirrhotic patients with hepatitis C-genotype 1 infection: a population and clonal analysis.

BACKGROUND: Vaniprevir with P/R improved SVR rates over P/R alone in treatment-experienced patients with chronic HCV-genotype 1 infection, but treatment failure presents therapeutic challenges. We identified RAVs from non-cirrhotic patients failing to achieve SVR on vaniprevir-containing regimens from a dose/duration-ranging trial of triple-combination therapy. METHODS: Using population analysis, resistance sequencing was performed on all baseline samples and on samples at virologic failure in the vaniprevir arms. Longitudinal clonal analyses were performed on viral isolates from six vaniprevir recipients experiencing breakthrough viremia. RESULTS: Baseline RAVs were detected in two patients subsequently experiencing virologic failure. At virologic failure, the majority of RAVs had substitutions at R155, A156, or D168. Clonal analyses identified novel double/triple variants emerging with continuing vaniprevir dosing. CONCLUSIONS: RAVs were predominantly observed at R155, A156, and/or D168 during virologic failure on vaniprevir/P/R. Double/triple RAVs were identified in patients remaining viremic on triple therapy, suggesting evolution of resistance under selective pressure.

Antiviral activity of boceprevir monotherapy in treatment-naive subjects with chronic hepatitis C genotype 2/3.

BACKGROUND & AIMS: To examine the antiviral activity of boceprevir, a hepatitis C virus (HCV) protease inhibitor, in HCV genotype (G) 2/3-infected patients. METHODS: We assessed boceprevir and telaprevir activity against an HCV G2 and G3 isolates enzyme panel, in replicon, and in phenotypic cell-based assays. Additionally, a phase I study evaluated the antiviral activity of boceprevir monotherapy (200mg BID, 400mg BID, or 400mg TID) vs. placebo for 14 days in HCV G2/3 treatment-naive patients. RESULTS: Boceprevir and telaprevir similarly inhibited G1 and G2 NS3/4A enzymes and replication in G1 and G2 replicon and cell-based assays. However, telaprevir demonstrated lower potency than boceprevir against HCV G3a enzyme (Ki=75 nM vs. 17 nM), in the G3a replicon assay (EC50=953 nM vs. 159 nM), and against HCV G3a NS3 isolates (IC50=3312 nM vs. 803 nM) in the cell-based assay. In HCV G2/3-infected patients, boceprevir (400 mg TID) resulted in a maximum mean decrease in HCV RNA of -1.60 log vs. -0.21 log with placebo. CONCLUSIONS: In vitro, boceprevir is more active than telaprevir against the HCV G3 NS3/4A enzyme in cell-based and biochemical assays and against G3 isolates in replicon assays. In HCV G2/3-infected treatment-naive patients, decreases in HCV RNA levels with boceprevir (400 mg TID) were comparable to those observed with the same dose in HCV treatment-experienced G1-infected patients.

Perspectives and concerns regarding antimicrobial agent shortages among infectious disease specialists.

Antimicrobial shortages have made treating certain infections more difficult. A web-based survey asking about experience with antimicrobial drug shortages was distributed in 2011 to 1328 infectious diseases physician members of the Emerging Infectious Diseases Network of the Infectious Diseases Society of America. A majority (78%) of 627 respondents reported needing to modify antimicrobial choices because of drug shortages within the past 2 years. Antimicrobials most often reported as not available or available but in short supply were trimethoprim-sulfamethoxazole injection (by 65% of respondents), amikacin (by 58%), aztreonam (by 31%), and foscarnet (by 22%). Most respondents (55%) reporting a shortage indicated that the shortage adversely affected patient outcomes and that they were forced to use alternative and second line agents which were either less effective, more toxic, or more costly. Most (70%) indicated that they learned about the shortage from contact with the pharmacy after trying to prescribe a drug in short supply. More effective means of informing physicians about drug shortages is critical to lessen the impact on patient care.

Development of macrocyclic inhibitors of HCV NS3/4A protease with cyclic constrained P2-P4 linkers.

A series of macrocyclic compounds containing a cyclic constraint in the P2-P4 linker region have been discovered and shown to exhibit excellent HCV NS3/4a genotype 3a and genotype 1b R155K, A156T, A156V, and D168V mutant activity while maintaining high rat liver exposure. The effect of the constraint is most dramatic against gt 1b A156 mutants where ~20-fold improvements in potency are achieved by introduction of a variety of ring systems into the P2-P4 linker.

Development of potent macrocyclic inhibitors of genotype 3a HCV NS3/4A protease.

A series of macrocyclic compounds containing 2-substituted-quinoline moieties have been discovered and shown to exhibit excellent HCV NS3/4a genotype 3a and genotype 1b R155K mutant activity while maintaining the high rat liver exposure. Cyclization of the 2-substituted quinoline substituent led to a series of tricyclic P2 compounds which also display superb gt3a potency.

MK-5172, a selective inhibitor of hepatitis C virus NS3/4a protease with broad activity across genotypes and resistant variants.

HCV NS3/4a protease inhibitors are proven therapeutic agents against chronic hepatitis C virus infection, with boceprevir and telaprevir having recently received regulatory approval as add-on therapy to pegylated interferon/ribavirin for patients harboring genotype 1 infections. Overcoming antiviral resistance, broad genotype coverage, and a convenient dosing regimen are important attributes for future agents to be used in combinations without interferon. In this communication, we report the preclinical profile of MK-5172, a novel P2-P4 quinoxaline macrocyclic NS3/4a protease inhibitor currently in clinical development. The compound demonstrates subnanomolar activity against a broad enzyme panel encompassing major hepatitis C virus (HCV) genotypes as well as variants resistant to earlier protease inhibitors. In replicon selections, MK-5172 exerted high selective pressure, which yielded few resistant colonies. In both rat and dog, MK-5172 demonstrates good plasma and liver exposures, with 24-h liver levels suggestive of once-daily dosing. When administered to HCV-infected chimpanzees harboring chronic gt1a or gt1b infections, MK-5172 suppressed viral load between 4 to 5 logs at a dose of 1 mg/kg of body weight twice daily (b.i.d.) for 7 days. Based on its preclinical profile, MK-5172 is anticipated to be broadly active against multiple HCV genotypes and clinically important resistance variants and highly suited for incorporation into newer all-oral regimens.

Discovery of MK-5172, a Macrocyclic Hepatitis C Virus NS3/4a Protease Inhibitor.

A new class of HCV NS3/4a protease inhibitors containing a P2 to P4 macrocyclic constraint was designed using a molecular modeling-derived strategy. Building on the profile of previous clinical compounds and exploring the P2 and linker regions of the series allowed for optimization of broad genotype and mutant enzyme potency, cellular activity, and rat liver exposure following oral dosing. These studies led to the identification of clinical candidate 15 (MK-5172), which is active against genotype 1-3 NS3/4a and clinically relevant mutant enzymes and has good plasma exposure and excellent liver exposure in multiple species.

Sustained viral response in a hepatitis C virus-infected chimpanzee via a combination of direct-acting antiviral agents.

Efforts to develop novel, interferon-sparing therapies for treatment of chronic hepatitis C (HCV) infection are contingent on the ability of combination therapies consisting of direct antiviral inhibitors to achieve a sustained virologic response. This work demonstrates a proof of concept that coadministration of the nucleoside analogue MK-0608 with the protease inhibitor MK-7009, both of which produced robust viral load declines as monotherapy, to an HCV-infected chimpanzee can achieve a cure of infection.

Discovery of MK-1220: A Macrocyclic Inhibitor of Hepatitis C Virus NS3/4A Protease with Improved Preclinical Plasma Exposure.

The discovery of MK-1220 is reported along with the development of a series of HCV NS3/4A protease inhibitors containing a P2 to P4 macrocyclic constraint with improved preclinical pharmacokinetics. Optimization of the P2 heterocycle substitution pattern as well as the P3 amino acid led to compounds with greatly improved plasma exposure following oral dosing in both rats and dogs while maintaining excellent enzyme potency and cellular activity. These studies led to the identification of MK-1220.

A rare case of synchronous invasive ductal carcinoma of the breast and follicular lymphoma.

Synchronous presentation of breast cancer and lymphoma is extremely rare. Few cases are reported in the literature. We describe a case of invasive ductal carcinoma of the breast with micrometastasis to a non-sentinel lymph node and subsequent incidental finding of a low-grade follicular lymphoma in an axillary node of a 52-year-old woman. The characteristic immunohistochemical profile of the lymphoma is described.

Discovery of vaniprevir (MK-7009), a macrocyclic hepatitis C virus NS3/4a protease inhibitor.

A new class of HCV NS3/4a protease inhibitors which contain a P2 to P4 macrocyclic constraint was designed using a molecular-modeling derived strategy. Exploration of the P2 heterocyclic region, the P2 to P4 linker, and the P1 side chain of this class of compounds via a modular synthetic strategy allowed for the optimization of enzyme potency, cellular activity, and rat liver exposure following oral dosing. These studies led to the identification of clinical candidate 35b (vaniprevir, MK-7009), which is active against both the genotype 1 and genotype 2 NS3/4a protease enzymes and has good plasma exposure and excellent liver exposure in multiple species.