Capsid Inhibition with Lenacapavir in Multidrug-Resistant HIV-1 Infection.

BACKGROUND: Patients with multidrug-resistant human immunodeficiency virus type 1 (HIV-1) infection have limited treatment options. Lenacapavir is a first-in-class capsid inhibitor that showed substantial antiviral activity in a phase 1b study. METHODS: In this phase 3 trial, we enrolled patients with multidrug-resistant HIV-1 infection in two cohorts, according to the change in the plasma HIV-1 RNA level between the screening and cohort-selection visits. In cohort 1, patients were first randomly assigned in a 2:1 ratio to receive oral lenacapavir or placebo in addition to their failing therapy for 14 days; during the maintenance period, starting on day 15, patients in the lenacapavir group received subcutaneous lenacapavir once every 6 months, and those in the placebo group received oral lenacapavir, followed by subcutaneous lenacapavir; both groups also received optimized background therapy. In cohort 2, all the patients received open-label oral lenacapavir with optimized background therapy on days 1 through 14; subcutaneous lenacapavir was then administered once every 6 months starting on day 15. The primary end point was the percentage of patients in cohort 1 who had a decrease of at least 0.5 log10 copies per milliliter in the viral load by day 15; a key secondary end point was a viral load of less than 50 copies per milliliter at week 26. RESULTS: A total of 72 patients were enrolled, with 36 in each cohort. In cohort 1, a decrease of at least 0.5 log10 copies per milliliter in the viral load by day 15 was observed in 21 of 24 patients (88%) in the lenacapavir group and in 2 of 12 patients (17%) in the placebo group (absolute difference, 71 percentage points; 95% confidence interval, 35 to 90). At week 26, a viral load of less than 50 copies per milliliter was reported in 81% of the patients in cohort 1 and in 83% in cohort 2, with a least-squares mean increase in the CD4+ count of 75 and 104 cells per cubic millimeter, respectively. No serious adverse events related to lenacapavir were identified. In both cohorts, lenacapavir-related capsid substitutions that were associated with decreased susceptibility developed in 8 patients during the maintenance period (6 with M66I substitutions). CONCLUSIONS: In patients with multidrug-resistant HIV-1 infection, those who received lenacapavir had a greater reduction from baseline in viral load than those who received placebo. (Funded by Gilead Sciences; CAPELLA ClinicalTrials.gov number, NCT04150068.).

Early Introduction and Community Transmission of SARS-CoV-2 Omicron Variant, New York, New York, USA.

The Omicron variant of SARS-CoV-2 has become dominant in most countries and has raised significant global health concerns. As a global commerce center, New York, New York, USA, constantly faces the risk for multiple variant introductions of SARS-CoV-2. To elucidate the introduction and transmission of the Omicron variant in the city of New York, we created a comprehensive genomic and epidemiologic analysis of 392 Omicron virus specimens collected during November 25-December 11, 2021. We found evidence of 4 independent introductions of Omicron subclades, including the Omicron subclade BA.1.1 with defining substitution of R346K in the spike protein. The continuous genetic divergence within each Omicron subclade revealed their local community transmission and co-circulation in New York, including both household and workplace transmissions supported by epidemiologic evidence. Our study highlights the urgent need for enhanced genomic surveillance and effective response planning for better prevention and management of emerging SARS-CoV-2 variants.

SARS-CoV-2 Continuous Genetic Divergence and Changes in Multiplex RT-PCR Detection Pattern on Positive Retesting Median 150 Days after Initial Infection.

Being in the epicenter of the COVID-19 pandemic, our lab tested 193,054 specimens for SARS-CoV-2 RNA by diagnostic multiplex reverse transcription polymerase chain reaction (mRT-PCR) starting in March 2020, of which 17,196 specimens resulted positive. To investigate the dynamics of virus molecular evolution and epidemiology, whole genome amplification (WGA) and Next Generation Sequencing (NGS) were performed on 9516 isolates. 7586 isolates with a high quality were further analyzed for the mutation frequency and spectrum. Lastly, we evaluated the utility of the mRT-PCR detection pattern among 26 reinfected patients with repeat positive testing three months after testing negative from the initial infection. Our results show a continuation of the genetic divergence in viral genomes. Furthermore, our results indicate that independent mutations in the primer and probe regions of the nucleocapsid gene amplicon and envelope gene amplicon accumulate over time. Some of these mutations correlate with the changes of detection pattern of viral targets of mRT-PCR. Our data highlight the significance of a continuous genetic divergence on a gene amplification-based assay, the value of the mRT-PCR detection pattern for complementing the clinical diagnosis of reinfection, and the potential for WGA and NGS to identify mutation hotspots throughout the entire viral genome to optimize the design of the PCR-based gene amplification assay.

Co-Infection with 4 Species of Mycobacteria Identified by Using Next-Generation Sequencing.

We identified co-infection with 4 species of mycobacteria in a woman in New York, New York, USA, by using next-generation sequencing. This procedure is useful for identifying co-infections with multiple mycobacteria, tracing the geographic origin of strains, investigating transmission dynamics in susceptible populations, and gaining insight into prevention and control.

Evaluation of Remel Spectra CRE Agar for Detection of Carbapenem-Resistant Bacteria from Rectal Swabs Obtained from Residents of a Long-Term-Care Facility.

We compared the Remel Spectra CRE agar plate to CDC standard methodology for the isolation of carbapenem-resistant Enterobacteriaceae (CRE) from 300 rectal swab specimens obtained from patients residing in a long-term-care facility (LTCF). Multiplex PCR experiments were performed on isolates to identify specific Klebsiella pneumoniae carbapenemases (KPC) and additional ß-lactamases. Of the 300 patients, 72 (24%) harbored CRE and were PCR positive for KPC enzymes. The Remel Spectra CRE plates detected KPC-type CRE in isolates from 70 of 72 patients (97.2%), while the CDC method detected CRE in 56 of 72 (77.8%). CRE identification results were available in 18 h compared to 36 h for the CDC method. Remel Spectra CRE agar plates can provide useful means for a fast and reliable method for detecting KPC-type CRE and for accelerated institution of appropriate infection control precautions.

Identification of extended-spectrum-ß-lactamase-positive Klebsiella pneumoniae urinary tract isolates harboring KPC and CTX-M ß-lactamases in nonhospitalized patients.

Forty-seven extended-spectrum-ß-lactamase-positive Klebsiella pneumoniae urinary tract isolates from nonhospitalized patients were identified, and 79% harbored KPC and/or CTX-M ß-lactamases. Approximately 90% of the isolates were resistant to trimethoprim-sulfamethoxazole and levofloxacin, and 40% were resistant to a carbapenem, while 92% were susceptible to polymyxin B, 87% were susceptible to tigecycline, and 79% were susceptible to fosfomycin. Increased use of broader-spectrum antibiotics may help to prevent their dissemination and reduce the risk of progression to invasive disease.

Omadacycline for the treatment of Mycobacterium abscessus infections: Case series and review of the literature.

Treatment of Mycobacterium abscessus infections are problematic due to inherent multidrug resistance and lack of response to antibacterials commonly used as therapy for other mycobacterial infections. We report the clinical success of five patients who received definitive-treatment with an omadacycline-containing combination regimen for M. abscessus infection.

Efficacy and safety of the novel capsid inhibitor lenacapavir to treat multidrug-resistant HIV: week 52 results of a phase 2/3 trial.

BACKGROUND: Lenacapavir, a first-in-class HIV-1 capsid inhibitor, is in development as a long-acting agent for treating and preventing HIV-1. We aimed to evaluate the efficacy and safety of lenacapavir with an optimised background regimen in adults living with multidrug-resistant HIV-1 up to 52 weeks. METHODS: This ongoing, international, phase 2/3 trial at 42 sites included adults living with multidrug-resistant HIV-1. In cohort 1, 36 participants were randomly assigned (2:1) to add oral lenacapavir (600 mg, days 1 and 2; 300 mg, day 8) or placebo to an existing failing regimen. At day 15, those on oral lenacapavir received subcutaneous lenacapavir 927 mg every 26 weeks; those on placebo started lenacapavir (2-week oral lead-in then subcutaneous). Cohort 1 started an optimised background regimen on day 15. In cohort 2 (non-randomised), 36 participants started an optimised background regimen concurrent with lenacapavir (oral to subcutaneous). Here we report the secondary endpoints of plasma HIV-1 RNA of less than 50 copies per mL or less than 200 copies per mL at week 52 (US Food and Drug Administration snapshot algorithm) in cohort 1 along with results for cohorts 1 and 2 combined. This trial is registered with ClinicalTrials.gov, NCT04150068, and clinicaltrialregister.eu, EudraCT 2019-003814-16 and is ongoing. FINDINGS: Of 72 participants, 46 (64%) had CD4 counts of less than 200 cells per µL and 38 (53%) had no more than one fully active antiretroviral drug at baseline. In cohort 1, 30 of 36 participants (83%, 95% CI 67-94) had less than 50 HIV-1 RNA copies per mL and 31 of 36 participants (86%, 71-95) had less than 200 HIV RNA copies per mL, at week 52. In all, nine participants (four in cohort 1, five in cohort 2) had emergent lenacapavir resistance; four resuppressed (HIV-1 RNA <50 copies per mL) while maintaining lenacapavir use. One participant discontinued study drug owing to injection site reaction. INTERPRETATION: In participants with multidrug-resistant HIV-1, subcutaneous lenacapavir in combination with an optimised background regimen resulted in a high rate of virological suppression up to 52 weeks. FUNDING: Gilead Sciences.

A case of Lactobacillus jensenii associated native valve endocarditis.

Lactobacillus jensenii is rarely reported as a cause of endocarditis in immunocompetent patients. We describe a case of Lactobacillus jensenii associated native valve endocarditis that was identified using matrix-assisted laser desorption/ionization-time of flight (MALDI-TOF) technology. While most Lactobacillus species are generally resistant to vancomycin, Lactobacillus jensenii is frequently susceptible, but treatment requires accurate susceptibility results followed by timely medical and surgical intervention. Probiotic use in patients can be a risk factor for infection with Lactobacillus species.

Fatal case of disseminated cryptococcal infection and meningoencephalitis in the setting of prolonged glucocorticoid use in a Covid-19 positive patient.

Based on the RECOVERY trial, glucocorticoids have become the mainstay of treatment for COVID-19, thus increasing the risk of opportunistic infections. We report a case of disseminated Cryptococcus neoformans with documented meningoencephalitis in a patient with severe COVID-19 in the setting of prolonged glucocorticoid administration with poor outcome likely due to adrenal involvement.

Combination antibiotic therapy for treatment of a patient with infected prosthesis and peri-prosthetic abscess due to Klebsiella pneumoniae harboring New Delhi Metallo (NDM) beta-lactamase.

Treatment options for patients infected with multi-drug resistant gram-negative bacteria harboring metallo-beta-lactamases (MBLs) requires precision therapy. We present the case of a 20 year-old male with a right distal femoral peri-prosthetic abscess with presumed infected hardware and osteomyelitis in whom four multi-drug resistant gram negative bacteria were isolated. The rapid identification of an MBL producing organism, novel combination of therapy, and prompt infection prevention enforcement and education led to appropriate treatment of our patient as well as prevention of spread of organisms during and after hospitalization. This case illustrated successful management of multiple challenges faced by patients infected and/or harboring extensively resistant bacteria.

Implementation of a Collaborated Antimicrobial Stewardship Program and Outpatient Parenteral Antimicrobial Therapy (OPAT) Unit-driven Monoclonal Antibody Therapy Program for COVID-19 at an NYC Hospital.

OBJECTIVES: This study aimed to assess the processes and clinical outcomes of a joint collaboration between Antimicrobial Stewardship Program (ASP) and the outpatient parenteral antimicrobial therapy (OPAT) unit for delivery of monoclonal antibody therapy for mild-to-moderate COVID-19. METHODS: We carried out a retrospective, interim analysis of our COVID-19 monoclonal antibody therapy program. Outcomes included clinical response, incidence of hospitalization, and adverse events. RESULTS: A total of 175 patients (casirivimab-imdevimab, n = 130; bamlanivimab, n = 45) were treated between December 2020 and March 1, 2021. The median time from symptom onset was 6 (IQR 4, 8) days at time of treatment. Of 135 patients available for follow-up, 71.9% and 85.9% of patients reported symptom improvement within 3 and 7 days of treatment, respectively. A total of 9 (6.7%) patients required COVID-19-related hospitalization for progression of symptoms, all within 14 days of treatment. A total of 7 (4%) patients experienced an infusion-related reaction. CONCLUSIONS: ASP-OPAT collaboration is a novel approach to implement an efficient and safe monoclonal antibody therapy program for the treatment of mild-to-moderate COVID-19.

Streptococcus pseudoporcinus: Case Reports and Review of the Literature.

Streptococcus pseudoporcinus is a beta-hemolytic Gram-positive, catalase-negative, nonmotile coccus arranged in short chains, usually found in the female genitourinary tract and differentiated from Streptococcus porcinus in 2006. Only two human infections associated with this organism have been reported to date: one in a patient with a first digit wound infection and another with lower extremity cellulitis. We describe two novel cases of Streptococcus pseudoporcinus causing endocarditis in one and pneumonia with empyema in another, illustrating the potential of these bacteria to cause severe invasive and life-threatening disease.

A report of two cases of tuberculous arthritis of the ankle.

UNLABELLED: Tuberculosis (TB) is a major global health problem, and musculoskeletal TB occurs in approximately 10% of extrapulmonary cases. In this article we describe 2 cases of ankle joint tuberculous arthritis. Both of the patients were immunocompromised and presented with chronic pain and swelling. Both patients described a history of antecedent ankle trauma. The clinical presentations were consistent with chronic septic arthritis and were nonspecific as to a particular etiology. The pathology and microbiology results revealed infection with Mycobacterium tuberculosis. Tuberculous infection of bone and joint must be considered when predisposing epidemiological factors are present to avoid delay in therapy. Further exploration into the relationship of trauma to tuberculosis recrudescence is warranted. LEVEL OF CLINICAL EVIDENCE: 4.

Carbapenem-resistant Escherichia coli harboring Klebsiella pneumoniae carbapenemase beta-lactamases associated with long-term care facilities.

Nine carbapenem-resistant Escherichia coli isolates harboring Klebsiella pneumoniae carbapenemase (KPC)-2 or KPC-3 enzymes were identified in patients residing in 7 distinct long-term care facilities. Cefotaxime-hydrolyzing (CTX-M)-type beta-lactamases were also documented in 3 isolates. The identification of these enzymes in patients staying in long-term care facilities should be of great concern to all components of health care systems.

Endocarditis due to Corynebacterium amycolatum.

Corynebacterium amycolatum, a normal inhabitant of human skin, is a Gram-positive, non-spore-forming, mycolic acid-free, aerobic or facultative anaerobic bacillus. Since its description in 1988, it has only rarely been associated with infective endocarditis. This paper describes a case of infective endocarditis successfully treated by combination therapy with daptomycin and rifampicin. To the best of our knowledge, this is the first case report of C. amycolatum endocarditis from the USA successfully treated with these agents.

Sudden onset of verrucous plaques to the face and trunk: a case of reactivation cutaneous histoplasmosis in the setting of HIV.

A 66-year-old Columbian man presented with a 15-day history of generalized weakness, cough, fever, and verrucous, ulcerating plaques of the face, upper chest, upper back, and arms. The patient proved to be HIV positive. Histopathologic examination showed a diffuse lymphocytic infiltrate coupled with a striking number of yeast forms within macrophages. The clinical presentation and histopathologic alterations are consistent with the diagnosis disseminated Histoplasma capsulatum. This case emphasizes the importance of increasing awareness of histoplasmosis in nonendemic areas as a result of the large subgroup of immunocompromised patients at risk. Disseminated histoplasmosis can be a treatable HIV complication if recognized early, although is unfortunately a harbinger for an overall poor prognosis.

Sudden onset of verrucous plaques to the face and trunk: a case of cutaneous histoplasmosis in the setting of HIV.

A 66-year-old Columbian man presented with a 15-day history of generalized weakness, cough, fever, and verrucous, ulcerating plaques of the face, upper chest and back, and arms. The patient proved to be HIV positive. Histopathologic examination showed a diffuse lymphocytic infiltrate coupled with a striking number of yeast forms within macrophages. The clinical presentation and histopathologic alterations are consistent with the diagnosis disseminated Histoplasma capsulatum. This case emphasizes the importance of increasing awareness of histoplasmosis in nonendemic areas as a result of the large subgroup of immunocompromised patients at risk. Disseminated histoplasmosis can be a treatable HIV complication if recognized early, though is unfortunately a harbinger for an overall poor prognosis.

Superior Efficacy and Improved Renal and Bone Safety After Switching from a Tenofovir Disoproxil Fumarate- to a Tenofovir Alafenamide-Based Regimen Through 96 Weeks of Treatment.

We previously demonstrated superior efficacy and safety advantages in HIV-infected, virologically suppressed adults switched to a regimen containing tenofovir alafenamide (TAF) as compared with those remaining on a tenofovir disoproxil fumarate (TDF) regimen through week 48. We now report long-term data through week 96. In this randomized, active-controlled, multicenter, open-label, noninferiority trial (ClinicalTrials.gov No. NCT01815736), we randomized virologically suppressed (HIV-1 RNA <50 copies/ml) adults (2:1) to receive a once-daily, single-tablet regimen containing elvitegravir (EVG), cobicistat (COBI), emtricitabine (FTC), and TAF group or to continue one of four TDF-containing regimens (TDF group) for 96 weeks. We evaluated efficacy (HIV-1 RNA <50 copies/ml using the FDA snapshot algorithm) and prespecified bone and renal endpoints at week 96. We randomized and treated 1,436 participants in this study (TAF n = 959, TDF n = 477). At week 96, TAF was superior to TDF in virologic efficacy, with 93% on TAF and 89% on TDF having HIV-1 RNA <50 copies/ml (difference 3.7%, 95% confidence interval: 0.4%-7.0%). Improvements in hip and spine bone mineral density for those assigned to TAF versus TDF continued through week 96 (p < .001). Significant improvements in urine protein or albumin to creatinine ratios were also seen among those in the TAF group versus TDF through week 96 (p < .001). There were no cases of investigator-reported proximal renal tubulopathy in the TAF group as compared with one case in the TDF group. Switching to EVG/COBI/FTC/TAF (E/C/F/TAF) was associated with statistically significant efficacy and safety advantages over remaining on a standard-of-care TDF-based regimen.