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.

Pharmacokinetic and Pharmacodynamic Profiling of Minocycline for Injection following a Single Infusion in Critically Ill Adults in a Phase IV Open-Label Multicenter Study (ACUMIN).

Intravenous (i.v.) minocycline is increasingly used to treat infections caused by multidrug-resistant (MDR) Acinetobacter baumannii Despite its being approved nearly 50 years ago, published information on its pharmacokinetic (PK) profile is limited. This multicenter study examined the PK and probability of pharmacokinetic-pharmacodynamic (PK-PD) target attainment profile of i.v. minocycline in critically ill patients, with suspected or documented infection with Gram-negative bacteria. The PK study population included 55 patients who received a single 200-mg i.v. dose of minocycline. Plasma PK samples were collected predose and 1, 4, 12, 24, 36, and 48 h after initiation of minocycline. Total and unbound minocycline concentrations were determined at each time point. Probabilities of achieving the PK-PD targets associated with stasis and 1-log killing (free area under the curve above the MIC [fAUC:MIC] of 12 and 18, respectively) in an immunocompetent animal pneumonia infection model of A. baumannii were evaluated. A two-compartment population PK model with zero-order i.v. input and first-order elimination, which estimated a constant fraction unbound (fub) for minocycline, best characterized the total and unbound plasma minocycline concentration-time data. The only two covariates retained in the final PK model were body surface area (associated with central volume of distribution) and albumin (associated with fub). In the PK-PD probability of target attainment analyses, minocycline 200 mg i.v. every 12 h (Q12H) was predicted to result in a suboptimal PK-PD profile for patients with A. baumannii infections with MIC values of >1 mg/liter. Like all PK-PD profiling studies of this nature, these findings need clinical confirmation.

Hospital-acquired Pneumonia and Ventilator-associated Pneumonia in Children: A Prospective Natural History and Case-Control Study.

BACKGROUND: Clinical trials for antibiotics designed to treat hospital-acquired and ventilator-associated bacterial pneumonias (HABP/VABP) are hampered by making these diagnoses in a way that is acceptable to the United States Food and Drug Administration and consistent with standards of care. We examined laboratory and clinical features that might improve pediatric HABP/VABP trial efficiency by identifying risk factors predisposing children to HABP/VABP and describing the epidemiology of pediatric HABP/VABP. METHODS: We prospectively reviewed the electronic medical records of patients <18 years of age admitted to intensive and intermediate care units (ICUs) if they received qualifying respiratory support or were started on antibiotics for a lower respiratory tract infection or undifferentiated sepsis. Subjects were followed until HABP/VABP was diagnosed or they were discharged from the ICU. Clinical, laboratory and imaging data were abstracted using structured chart review. We calculated HABP/VABP incidence and used a stepwise backward selection multivariable model to identify risk factors associated with development of HABP/VABP. RESULTS: A total of 862 neonates, infants and children were evaluated for development of HABP/VABP; 10% (82/800) of those receiving respiratory support and 12% (103/862) overall developed HABP/VABP. Increasing age, shorter height/length, longer ICU length of stay, aspiration risk, blood product transfusion in the prior 7 days and frequent suctioning were associated with increased odds of HABP/VABP. The use of noninvasive ventilation and gastric acid suppression were both associated with decreased odds of HABP/VABP. CONCLUSIONS: Food and Drug Administration-defined HABP/VABP occurred in 10%-12% of pediatric patients admitted to ICUs. Risk factors vary by age group.

Clinical Experience with Telavancin: Real-World Results from the Telavancin Observational Use Registry (TOUR™).

BACKGROUND: Telavancin-a lipoglycopeptide antibacterial agent active against Gram-positive pathogens including methicillin-sensitive and -resistant Staphylococcus aureus (MRSA)-is approved in the USA for once-daily intravenous use. This registry study captured patient characteristics, prescribing patterns, and treatment outcomes associated with telavancin use in real-world clinical practice. OBJECTIVE: This prospective, multicenter, observational study will characterize current real-world practice patterns for the use of telavancin in the USA by describing demographic and clinical conditions, examining the process of care and rationale for use, and describing the clinical effectiveness and selected safety outcomes among patients treated with telavancin. METHODS: The Telavancin Observational Use Registry (TOUR™) is an observational multicenter registry study. Clinical data-including patient demographics, pathogens, telavancin dosing and treatment duration, and adverse events-along with investigators' assessments of outcome, were collected through retrospective medical chart review. RESULTS: Data from 1063 patients were collected from 45 US sites. Of these patients, 29.4% were ≥ 65 years of age [mean age ± standard deviation, 55.2 ± 15.4 years; median age (interquartile range), 57.0 (46.0-66.0)], 53.4% were male, and 83.4% were White. The primary infections in these patients included complicated skin and skin-structure infection (48.7%), bone and joint infections (27.4%), bacteremia and endocarditis (14.2%), and lower respiratory tract infections (8.5%). The predominant pathogen identified was MRSA (37.7%). The mean telavancin dose and duration of treatment were 741.7 ± 194.3 mg and 17 ± 17 days, respectively. Of the 964 (90.7%) patients for whom an end-of-treatment assessment was available, 77.7% had a positive clinical response, 10.1% failed treatment, and 12.2% had indeterminate outcomes. CONCLUSIONS: Real-world data collected from the TOUR study show once-daily telavancin is being used for the treatment of a variety of Gram-positive infections with generally positive clinical outcomes.

Fulminant Septicemia from Aeromonas hydrophilia in a Nonmobile Diabetic Patient.

We report an unusual case of Aeromonas hydrophilia septicemia in a nonmobile diabetic patient secondary to contaminated well water used for bathing with a portal of entry through chronic forefoot and heel ulcers. To date, there are no documented cases similar to this patient's presentation. Aeromonas hydrophilia is commonly distributed among aquatic environments and tends to be found during warmer months. It is a rare cause of disease but can be life threatening and deadly, as in our case, in immunocompromised individuals. As podiatric physicians, we must remain diligent and have a high index of suspicion to identify patients at risk for this rare but serious infection and administer treatment aggressively to limit morbidity and mortality.

Antimicrobial salvage therapy for persistent staphylococcal bacteremia using daptomycin plus ceftaroline.

PURPOSE: Guidelines recommend daptomycin combination therapy as an option for methicillin-resistant Staphylococcus aureus (MRSA) bacteremia after vancomycin failure. Recent data suggest that combining daptomycin with a ß-lactam may have unique benefits; however, there are very limited clinical data regarding the use of ceftaroline with daptomycin. METHODS: All 26 cases from the 10 medical centers in which ceftaroline plus daptomycin was used for treatment of documented refractory staphylococcal bacteremia from March 2011 to November 2012 were included. In vitro (synergy studies, binding assays, cathelicidin LL-37 killing assays), and in vivo (virulence assays using a murine subcutaneous infection model) studies examining the effects of ceftaroline with daptomycin were also performed. FINDINGS: Daptomycin plus ceftaroline was used in 26 cases of staphylococcal bacteremia (20 MRSA, 2 vancomycin-intermediate S aureus, 2 methicillin-susceptible S aureus [MSSA], 2 methicillin-resistant S epidermidis). Bacteremia persisted for a median of 10 days (range, 3-23 days) on previous antimicrobial therapy. After daptomycin plus ceftaroline was started, the median time to bacteremia clearance was 2 days (range, 1-6 days). In vitro studies showed ceftaroline synergy against MRSA and enhanced MRSA killing by cathelicidin LL-37 and neutrophils. Ceftaroline also induced daptomycin binding in MSSA and MRSA to a comparable degree as nafcillin. MRSA grown in subinhibitory concentrations of ceftaroline showed attenuated virulence in a murine subcutaneous infection model. IMPLICATIONS: Ceftaroline plus daptomycin may be an option to hasten clearance of refractory staphylococcal bacteremia. Ceftaroline offers dual benefit via synergy with both daptomycin and sensitization to innate host defense peptide cathelicidin LL37, which could attenuate virulence of the pathogen.

Nitazoxanide versus vancomycin in Clostridium difficile infection: a randomized, double-blind study.

BACKGROUND: Vancomycin is the only US Food and Drug Administration-approved drug for treatment of Clostridium difficile infection (CDI). Metronidazole has been widely used for this purpose but may be inferior to vancomycin, especially for hospitalized patients with severe disease. We report a prospective, double-blind, randomized controlled trial comparing nitazoxanide with vancomycin for treatment of CDI. METHODS: Fifty patients with CDI were randomized to receive vancomycin or nitazoxanide for 10 days. An initial response was considered to be the absence of all CDI symptoms between days 11 and 13, and a final response was considered to be lack of symptom recurrence by day 31. RESULTS: One patient fulfilled an exclusion criterion and was removed from the study. Twenty-seven patients received vancomycin, and 23 received nitazoxanide; 23 and 18 patients, respectively, completed the full course of treatment. Initial responses occurred in 20 (74%) of 27 patients treated with vancomycin and in 17 (77%) of 22 patients treated with nitazoxanide (95% confidence interval, -24% to +28%). In those who completed therapy, response rates were 87% (20 of 23 patients) in the vancomycin group and 94% (17 of 18 patients) in the nitazoxanide group (95% confidence interval, -18% to +30%). Times to complete resolution of symptoms were similar in the 2 groups (P = .55). Two patients in the vancomycin group and 1 patient in the nitazoxanide group experienced relapse within 31 days after beginning treatment. Sustained response rates were 78% (18 of 23 patients) for the vancomycin group, and 89% (16 of 18 patients) for the nitazoxanide group (95% confidence interval, -18% to +35%). CONCLUSIONS: The small sample precludes conclusions about noninferiority of nitazoxanide to vancomycin. Nevertheless, this is the first recent randomized controlled trial to compare any antimicrobial agent other than metronidazole with vancomycin. Results suggest that nitazoxanide may be as effective as vancomycin in treating CDI. TRIAL REGISTRATION: ClinicalTrials.gov identifier: NCT00384527.

Risk factors for Burkholderia cepacia complex bacteremia among intensive care unit patients without cystic fibrosis: a case-control study.

BACKGROUND: The Burkholderia cepacia complex is associated with colonization or disease in patients with cystic fibrosis (CF). For patients without CF, this complex is poorly understood apart from its presence in occasional point source outbreaks. OBJECTIVE: To investigate risk factors for B. cepacia bacteremia in hospitalized, intensive care unit patients without CF. METHODS: We identified patients with 1 or more blood cultures positive for B. cepacia between May 1, 1996, and March 31, 2002, excluding those with CF. Control patients were matched to case patients by ward, duration of hospitalization, and onset date of bacteremia. Matched analyses were used to identify risk factors for B. cepacia bacteremia. RESULTS: We enrolled 40 patients with B. cepacia bacteremia into the study. No environmental or other point source for B. cepacia complex was identified, although horizontal spread was suspected. Implementation of contact precautions was effective in decreasing the incidence of B. cepacia bacteremia. We selected 119 matched controls. Age, sex, and race were similar between cases and controls. In multivariable analysis, renal failure that required dialysis, recent abdominal surgery, 2 or more bronchoscopic procedures before detection of B. cepacia bacteremia, tracheostomy, and presence of a central line before detection of B. cepacia bacteremia were independently associated with development of B. cepacia bacteremia, whereas presence of a percutaneous feeding tube was associated with a lower risk of disease. CONCLUSIONS: B. cepacia complex is an important emerging group of nosocomial pathogens in patients with and patients without CF. Nosocomial spread is likely facilitated by cross-transmission, frequent pulmonary procedures, and central venous access. Infection control measures appear useful for limiting the spread of virulent, transmissible clones of B. cepacia complex.

Correlation of penicillin Binding protein 2a detection with oxacillin resistance in Staphylococcus aureus and discovery of a novel penicillin binding protein 2a mutation.

We compared a rapid slide latex agglutination test (LAT; Oxoid, Basingstoke, United Kingdom) that detects penicillin binding protein 2a (PBP2a) with MicroScan conventional panels (Dade Behring, West Sacramento, CA) for detection of oxacillin resistance in Staphylococcus aureus. The PBP2a LAT demonstrated 99% agreement with MicroScan oxacillin MIC results for 388 isolates of S. aureus. All 249 oxacillin-resistant isolates gave strong positive reactions in the LAT (100% sensitivity). Three of the 139 oxacillin-susceptible isolates were also strongly positive and one was weakly positive in the LAT (97.1% specificity). The three oxacillin-susceptible isolates with strongly positive reactions were further characterized. The mecA gene was detected in all three by PCR; one isolate was determined to be resistant to oxacillin by reference broth microdilution testing (MIC, 8 microg/ml), one isolate was inducibly resistant to oxacillin (MIC of 16 microg/ml after overnight induction), and one isolate remained susceptible regardless of the method used for testing. Sequence analysis of a 2.1-kb gene fragment of the mecA gene from the susceptible isolate revealed a one-base substitution at nucleotide position 1449 which results in a Met-to-Ile change for amino acid residue 483. This amino acid substitution has not been previously reported and may be associated with a change in the function of PBP2a resulting in oxacillin susceptibility. An additional 487 isolates were tested in parallel with the both the LAT and MicroScan panels using criteria in which only strong (3 to 4+) or repeatedly weak (1 to 2+) LAT reactions were considered positive, and the results showed 99.4% agreement. The PBP2a LAT provided rapid and reliable detection of oxacillin resistance and proved a useful adjunct to the phenotypic method. Both methods provided reliable detection of oxacillin-resistant S. aureus and facilitated the discovery of a novel, functionally impaired form of PBP2a.

Peripheral neuropathy associated with prolonged use of linezolid.

We present a case of a woman who developed severe, painful peripheral neuropathy while receiving linezolid therapy for 6 months. Nerve conduction studies indicated a sensory-motor axonal neuropathy. Extensive assessment did not show alternative explanations for her neuropathy. At the time of death 1 month after discontinuing linezolid, the neuropathy had not resolved. A review of published material shows a growing body of evidence that long-term use of linezolid may be associated with severe peripheral and optic neuropathy. 21 cases have been reported. In most cases, optic neuropathies resolved after stopping linezolid but peripheral neuropathies did not. The duration of therapy rather than indication for treatment seems to be the most important factor. The mechanism of toxicity is unknown but certain pharmacological properties of linezolid that may play a part are proposed. This report highlights the importance of post-approval surveillance and reporting of serious adverse drug effects, and potential consequences of off-label use of pharmaceuticals. It further demonstrates the critical role clinicians have in communicating awareness of emerging drug toxicities.

Virulence associated with outbreak-related strains of Burkholderia cepacia complex among a cohort of patients with bacteremia.

The Burkholderia cepacia complex includes 9 genomovars. The relative virulence of each is unknown. Host and pathogen features associated with mortality were evaluated among patients with B. cepacia complex bacteremia. Cases were ascertained through review of blood culture results for the period of May 1996 through May 2002. Isolates were identified to species level with 16S rDNA and recA-based species-specific polymerase chain reaction analyses and recA restriction fragment-length polymorphism. Strain typing was performed with pulsed-field gel electrophoresis. Fifty-three patients with B. cepacia complex bacteremia were identified; only 9 (17%) had cystic fibrosis. Twenty-five patients (47%) died within 14 days of bacteremia. After controlling for comorbid conditions and therapeutic interventions, 2 outbreak-related strains of Burkholderia cenocepacia (genomovar III) were associated with 14-day mortality (odds ratio, 5.5; 95% confidence interval, 1.20-25.02). B. cenocepacia is an emerging nosocomial pathogen. Certain strains are associated with an enhanced capacity for interpatient spread and poor outcome.

Preclinical evaluation of two real-time, reverse transcription-PCR assays for detection of the severe acute respiratory syndrome coronavirus.

We verified the analytical performance characteristics of a previously described real-time reverse transcription-PCR (RT-PCR) assay targeting the open reading frame (ORF) 1b region of the severe acute respiratory syndrome coronavirus (SARS-CoV) with RNA transcripts. We then compared it to a novel nucleocapsid gene real-time RT-PCR assay with genomic RNA. The assays differed only in the primer and probe sequences and final concentrations. A commercially available armored RNA (Ambion, Austin, Tex.) was evaluated as positive control for the ORF 1b assay. The analytical sensitivity, reproducibility, amplification efficiency, and dynamic range of the assays were similar. Both were specific for SARS-CoV as determined by testing against human CoV 229E and OC43, specimens from patients without SARS, and by BLAST searches of GenBank for primer and probe sequence homology. The armored RNA was found to be a suitable positive control for the ORF 1b assay that could be reliably recovered and amplified from a variety of clinical specimens.