Experience With Four-Month Rifapentine and Moxifloxacin-Based Tuberculosis Treatment in San Francisco.

Background: A multicountry randomized controlled trial has demonstrated that pan-susceptible pulmonary tuberculosis (TB) can be successfully treated with a 4-month regimen of daily isoniazid, rifapentine, moxifloxacin, and pyrazinamide (HPMZ). We piloted HPMZ in San Francisco (SF) using a modified version of the US Centers for Disease Control and Prevention HPMZ treatment guidelines. Methods: In this retrospective cohort, patients consecutively referred to SF TB clinic were evaluated for HPMZ eligibility based on preestablished inclusion/exclusion criteria. All underwent evaluation and management according to national recommendations. We reviewed the medical records of those initiated on HPMZ. Results: From August 2021 to December 2023, 30 (18.8%) of 160 patients diagnosed with active TB met HPMZ inclusion criteria; of these, 22 (13.8%) started HPMZ. The median age (range) was 32.5 (14-86) years, 17 (77.3%) were otherwise healthy, and 19 (86.4%) had pulmonary TB, including 7 (36.8%) with cavitary disease. Eighteen (81.8%) patients had an adverse event, with 11 (50%) prematurely discontinuing HPMZ; the most common adverse events were vomiting, elevated transaminases, and rash. To date, 9 (40.9%) have completed treatment, with most achieving criteria for cure. One patient was diagnosed with possible TB recurrence and restarted standard TB treatment. Conclusions: Our experience, with half of patients to date prematurely discontinuing HPMZ, illustrates the challenge of extrapolating findings from TB clinical trials commonly conducted in high-incidence, non-US settings to US clinical practice. Further experience may help identify best practices for implementing HPMZ, including identifying predictors of which patients may be most likely to benefit from and tolerate this regimen.

Identifying Implementation Determinants and Strategies for Long-Acting Injectable Cabotegravir-Rilpivirine in People With HIV Who Are Virally Unsuppressed.

BACKGROUND: Early evidence suggests long-acting injectable cabotegravir and rilpivirine (LA-CAB/RPV) may be beneficial for people with HIV (PWH) who are unable to attain viral suppression (VS) on oral therapy. Limited guidance exists on implementation strategies for this population. SETTING: Ward 86, a clinic serving publicly insured PWH in San Francisco. METHODS: We describe multilevel determinants of and strategies for LA-CAB/RPV implementation for PWH without VS, using the Consolidated Framework for Implementation Research. To assess patient and provider-level determinants, we drew on pre-implementation qualitative data. To assess inner and outer context determinants, we undertook a structured mapping process. RESULTS: Key patient-level determinants included perceived ability to adhere to injections despite oral adherence difficulties and care engagement challenges posed by unmet subsistence needs; strategies to address these determinants included a direct-to-inject approach, small financial incentives, and designated drop-in days. Provider-level determinants included lack of time to obtain LA-CAB/RPV, assess injection response, and follow-up late injections; strategies included centralizing eligibility review with the clinic pharmacist, a pharmacy technician to handle procurement and monitoring, regular multidisciplinary review of patients, and development of a clinic protocol. Ward 86 did not experience many outer context barriers because of rapid and unconstrained inclusion of LA-CAB/RPV on local formularies and ability of its affiliated hospital pharmacy to stock the medication. CONCLUSIONS: Multilevel strategies to support LA-CAB/RPV implementation for PWH without VS are required, which may necessitate additional resources in some settings to implement safely and effectively. Advocacy to eliminate outer-context barriers, including prior authorizations and specialty pharmacy restrictions, is needed.

A Dose-Finding Study to Guide Use of Verapamil as an Adjunctive Therapy in Tuberculosis.

Induction of mycobacterial efflux pumps is a cause of Mycobacterium tuberculosis (Mtb) drug tolerance, a barrier to shortening antitubercular treatment. Verapamil inhibits Mtb efflux pumps that mediate tolerance to rifampin, a cornerstone of tuberculosis (TB) treatment. Verapamil's mycobacterial efflux pump inhibition also limits Mtb growth in macrophages in the absence of antibiotic treatment. These findings suggest that verapamil could be used as an adjunctive therapy for TB treatment shortening. However, verapamil is rapidly and substantially metabolized when co-administered with rifampin. We determined in a dose-escalation clinical trial of persons with pulmonary TB that rifampin-induced clearance of verapamil can be countered without toxicity by the administration of larger than usual doses of verapamil. An oral dosage of 360 mg sustained-release (SR) verapamil given every 12 hours concomitantly with rifampin achieved median verapamil exposures of 903.1 ng.h/mL (area under the curve (AUC)0-12 h ) in the 18 participants receiving this highest studied verapamil dose; these AUC findings are similar to those in persons receiving daily doses of 240 mg verapamil SR but not rifampin. Moreover, norverapamil:verapamil, R:S verapamil, and R:S norverapamil AUC ratios were all significantly greater than those of historical controls receiving SR verapamil in the absence of rifampin. Thus, rifampin administration favors the less-cardioactive verapamil metabolites and enantiomers that retain similar Mtb efflux inhibitory activity to verapamil, increasing overall benefit. Finally, rifampin exposures were 50% greater after verapamil administration, which may also be advantageous. Our findings suggest that a higher dosage of verapamil can be safely used as adjunctive treatment in rifampin-containing treatment regimens.

A dose-finding study to guide use of verapamil as an adjunctive therapy in tuberculosis.

Induction of mycobacterial efflux pumps is a cause of Mycobacterium tuberculosis (Mtb) drug tolerance, a barrier to shortening antitubercular treatment. Verapamil inhibits Mtb efflux pumps that mediate tolerance to rifampin, a cornerstone of tuberculosis treatment. Verapamil's mycobacterial efflux pump inhibition also limits Mtb growth in macrophages in the absence of antibiotic treatment. These findings suggest that verapamil could be used as an adjunctive therapy for TB treatment shortening. However, verapamil is rapidly and substantially metabolized when co-administered with rifampin. We determined in a dose-escalation clinical trial that rifampin-induced clearance of verapamil can be countered without toxicity by the administration of larger than usual doses of verapamil. An oral dosage of 360 mg sustained-release (SR) verapamil given every 12 hours concomitantly with rifampin achieved median verapamil exposures of 903.1 ng.h/ml (AUC 0-12h), similar to those in persons receiving daily doses of 240 mg verapamil SR but not rifampin. Norverapamil:verapamil, R:S verapamil and R:S norverapamil AUC ratios were all significantly greater than those of historical controls receiving SR verapamil in the absence of rifampin, suggesting that rifampin administration favors the less-cardioactive verapamil metabolites and enantiomers. Finally, rifampin exposures were significantly greater after verapamil administration. Our findings suggest that a higher dosage of verapamil can be safely used as adjunctive treatment in rifampin-containing treatment regimens.

Demonstration Project of Long-Acting Antiretroviral Therapy in a Diverse Population of People With HIV.

BACKGROUND: Intramuscular cabotegravir (CAB) and rilpivirine (RPV) is the only long-acting antiretroviral therapy (LA-ART) regimen approved for people with HIV (PWH). Long-acting ART holds promise for improving outcomes among populations with barriers to adherence but is only approved for PWH who have virologic suppression with use of oral ART before initiating injectables. OBJECTIVE: To examine LA-ART in a population of PWH that includes those with viremia. DESIGN: Observational cohort study. SETTING: Urban academic safety-net HIV clinic. PATIENTS: Publicly insured adults living with HIV with and without viral suppression, high rates of unstable housing, mental illness, and substance use. INTERVENTION: Demonstration project of long-acting injectable CAB-RPV. MEASUREMENTS: Descriptive statistics summarizing cohort outcomes to date, based on pharmacy team logs and electronic medical record data. RESULTS: Between June 2021 and November 2022, 133 PWH at the Ward 86 HIV Clinic were started on LA-ART, 76 of whom had virologic suppression while using oral ART and 57 of whom had viremia. The median age was 46 years (IQR, 25 to 68 years); 117 (88%) were cisgender men, 83 (62%) had non-White race, 56 (42%) were experiencing unstable housing or homelessness, and 45 (34%) had substance use. Among those with virologic suppression, 100% (95% CI, 94% to 100%) maintained suppression. Among PWH with viremia, at a median of 33 days, 54 of 57 had viral suppression, 1 showed the expected 2-log10 reduction in HIV RNA level, and 2 experienced early virologic failure. Overall, 97.5% (CI, 89.1% to 99.8%) were projected to achieve virologic suppression by a median of 33 weeks. The current virologic failure rate of 1.5% in the cohort is similar to that across registrational clinical trials at 48 weeks. LIMITATION: Single-site study. CONCLUSION: This project demonstrates the ability of LA-ART to achieve virologic suppression among PWH, including those with viremia and challenges to adherence. Further data on the ability of LA-ART to achieve viral suppression in people with barriers to adherence are needed. PRIMARY FUNDING SOURCE: National Institutes of Health, City and County of San Francisco, and Health Resources and Services Administration.

First Demonstration Project of Long-Acting Injectable Antiretroviral Therapy for Persons With and Without Detectable Human Immunodeficiency Virus (HIV) Viremia in an Urban HIV Clinic.

BACKGROUND: Long-acting injectable antiretroviral therapy (LAI-ART) is approved for treatment-naive or experienced people with human immunodeficiency virus (HIV; PWH) based on trials that only included participants with viral suppression. We performed the first LAI-ART demonstration project to include PWH unable to achieve or maintain viral suppression due to challenges adhering to oral ART. METHODS: Ward 86 is a large HIV clinic in San Francisco that serves publicly insured and underinsured patients. We started patients on LAI-ART via a structured process of provider referral, multidisciplinary review (MD, RN, pharmacist), and monitoring for on-time injections. Inclusion criteria were willingness to receive monthly injections and a reliable contact method. RESULTS: Between June 2021 and April 2022, 51 patients initiated LAI-ART, with 39 receiving at least 2 follow-up injections by database closure (median age, 46 years; 90% cisgender men, 61% non-White, 41% marginally housed, 54% currently using stimulants). Of 24 patients who initiated injections with viral suppression (median CD4 cell count, 706 cells/mm3), 100% (95% confidence interval [CI], 86%-100%) maintained viral suppression. Of 15 patients who initiated injections with detectable viremia (median CD4 cell count, 99 cells/mm3; mean log10 viral load, 4.67; standard deviation, 1.16), 12 (80%; 95% CI, 55%-93%) achieved viral suppression, and the other 3 had a 2-log viral load decline by a median of 22 days. CONCLUSIONS: This small demonstration project of LAI-ART in a diverse group of patients with high levels of substance use and marginal housing demonstrated promising early treatment outcomes, including in those with detectable viremia due to adherence challenges. More data on LAI-ART in hard-to-reach populations are needed.

Lymphogranuloma venereum as a cause of persistent perianal ulcers.

Lymphogranuloma venereum (LGV) has been increasingly reported, and many clinicians are familiar with it as a cause of proctocolitis or inguinal adenopathy. On the other hand, LGV is less commonly considered as a cause of isolated genital ulcerative disease in comparison to other etiologies such as syphilis or herpes simplex. We report a case of persistent perianal ulcerations due to LGV in an HIV-positive patient, confirmed by nucleic acid amplification testing.

Disseminated Mycobacterium bovis Infection Complicated by Meningitis and Stroke: A Case Report.

We describe a case of a 19-year-old female presenting with Mycobacterium bovis meningitis, a rarely encountered infection. We discuss the use of pyrosequencing to aid in prompt diagnosis of M. bovis infection, as well as treatment strategies and challenges given the organism's intrinsic resistance to pyrazinamide.

Profile of delamanid for the treatment of multidrug-resistant tuberculosis.

New approaches to the treatment of multidrug-resistant and extensively drug-resistant tuberculosis (TB) are badly needed. Not only is the success rate of current treatment regimens suboptimal but existing regimens require multiple drugs and lengthy courses and may lead to significant toxicities. The treatment landscape is beginning to shift, however, with the recent approvals of the new TB drugs bedaquiline and delamanid. Delamanid, a dihydro-imidazooxazole, has been shown to have excellent activity against Mycobacterium tuberculosis in both in vitro and in murine TB models. It has also recently been reported to improve rates of sputum culture conversion in patients with multidrug-resistant TB when added to an optimized background regimen. Although generally well tolerated, delamanid has been associated with QT prolongation, which may be of particular clinical concern when paired with other TB drugs that may also have this effect, most notably the fluoroquinolones. Ongoing studies will help to clarify delamanid's role in the treatment of drug-resistant TB.

Verapamil, and its metabolite norverapamil, inhibit macrophage-induced, bacterial efflux pump-mediated tolerance to multiple anti-tubercular drugs.

Drug tolerance likely represents an important barrier to tuberculosis treatment shortening. We previously implicated the Mycobacterium tuberculosis efflux pump Rv1258c as mediating macrophage-induced tolerance to rifampicin and intracellular growth. In this study, we infected the human macrophage-like cell line THP-1 with drug-sensitive and drug-resistant M. tuberculosis strains and found that tolerance developed to most antituberculosis drugs, including the newer agents moxifloxacin, PA-824, linezolid, and bedaquiline. Multiple efflux pump inhibitors in clinical use for other indications reversed tolerance to isoniazid and rifampicin and slowed intracellular growth. Moreover, verapamil reduced tolerance to bedaquiline and moxifloxacin. Verapamil's R isomer and its metabolite norverapamil have substantially less calcium channel blocking activity yet were similarly active as verapamil at inhibiting macrophage-induced drug tolerance. Our finding that verapamil inhibits intracellular M. tuberculosis growth and tolerance suggests its potential for treatment shortening. Norverapamil, R-verapamil, and potentially other derivatives present attractive alternatives that may have improved tolerability.

Antimicrobial efflux pumps and Mycobacterium tuberculosis drug tolerance: evolutionary considerations.

The need for lengthy treatment to cure tuberculosis stems from phenotypic drug resistance, also known as drug tolerance, which has been previously attributed to slowed bacterial growth in vivo. We discuss recent findings that challenge this model and instead implicate macrophage-induced mycobacterial efflux pumps in antimicrobial tolerance. Although mycobacterial efflux pumps may have originally served to protect against environmental toxins, in the pathogenic mycobacteria, they appear to have been repurposed for intracellular growth. In this light, we discuss the potential of efflux pump inhibitors such as verapamil to shorten tuberculosis treatment by their dual inhibition of tolerance and growth.

Methicillin-resistant Staphylococcus aureus colonization, behavioral risk factors, and skin and soft-tissue infection at an ambulatory clinic serving a large population of HIV-infected men who have sex with men.

We conducted a prospective cohort study of 795 outpatients, many of whom were human immunodeficiency virus-infected men who have sex with men, to characterize risk of skin and soft-tissue infection (SSTI) associated with methicillin-resistant Staphylococcus aureus (MRSA) nares and perianal colonization. Multivariate analysis revealed that perianal colonization, drug use, and prior SSTIs were strongly associated with development of an SSTI. Of the patients who were colonized with MRSA at study entry, 36.7% developed an SSTI during the ensuing 12 months, compared with 8.1% of persons who were not colonized with MRSA.

Emergence of multidrug-resistant, community-associated, methicillin-resistant Staphylococcus aureus clone USA300 in men who have sex with men.

BACKGROUND: Infection with multidrug-resistant, community-associated, methicillin-resistant Staphylococcus aureus (MRSA) has been reported but seems to be isolated. OBJECTIVE: To determine the incidence of a multidrug-resistant MRSA clone (USA300) in San Francisco, and to determine risk factors for the infection. DESIGN: Population-based survey and cross-sectional study using chart review. SETTING: 9 hospitals in San Francisco (population-based survey) and 2 outpatient clinics in San Francisco and Boston (cross-sectional study). PATIENTS: Persons with culture-proven MRSA infections in 2004 to 2006. MEASUREMENTS: Annual incidence, spatial clustering, and risk factors for multidrug-resistant USA300 infection. Pulsed-field gel electrophoresis, polymerase chain reaction assays, and DNA sequencing were used to characterize MRSA isolates. RESULTS: The overall incidence of multidrug-resistant USA300 infection in San Francisco was 26 cases per 100,000 persons (95% CI, 16 to 36 cases per 100,000 persons); the incidence was higher in 8 contiguous ZIP codes with a higher proportion of male same-sex couples. Male-male sex was a risk factor for multidrug-resistant USA300 infection (relative risk, 13.2 [CI, 1.7 to 101.6]; P < 0.001) independent of past MRSA infection (relative risk, 2.1 [CI, 1.2 to 3.7]; P = 0.007) or clindamycin use (relative risk, 2.1 [1.2 to 3.6]; P = 0.007). The risk seemed to be independent of HIV infection. In San Francisco, multidrug-resistant USA300 manifested most often as infection of the buttocks, genitals, or perineum. In Boston, the infection was recovered exclusively from men who had sex with men. LIMITATIONS: The study was retrospective, and sexual risk behavior was not assessed. CONCLUSION: Infection with multidrug-resistant USA300 MRSA is common among men who have sex with men, and multidrug-resistant MRSA infection might be sexually transmitted in this population. Further research is needed to determine whether existing efforts to control epidemics of other sexually transmitted infections can control spread of community-associated, multidrug-resistant MRSA.

Treatment and outcomes of infections by methicillin-resistant Staphylococcus aureus at an ambulatory clinic.

Community-acquired methicillin-resistant Staphylococcus aureus (MRSA) skin and soft tissue infections (SSTI) have become increasingly common. This study's objectives were to describe the clinical spectrum of MRSA in a community health center and to determine whether the use of specific antimicrobials correlated with increased probability of clinical resolution of SSTI. A retrospective chart review of 399 sequential cases of culture-confirmed S. aureus SSTI, including 227 cases of MRSA SSTI, among outpatients at Fenway Community Health (Boston, MA) from 1998 to 2005 was done. The proportion of S. aureus SSTI due to MRSA increased significantly from 1998 to 2005 (P<0.0001). Resistance to clindamycin was common (48.2% of isolates). At the beginning of the study period, most patients with MRSA SSTI empirically treated with antibiotics received a beta-lactam, whereas by 2005, 76% received trimethoprim-sulfamethoxazole (TMP-SMX) (P<0.0001). Initially, few MRSA isolates were sensitive to the empirical antibiotic, but 77% were susceptible by 2005 (P<0.0001). A significantly higher percentage of patients with MRSA isolates had clinical resolution on the empirical antibiotic by 2005 (P=0.037). Use of an empirical antibiotic to which the clinical isolate was sensitive was associated with increased odds of clinical resolution on empirical therapy (odds ratio=5.91), controlling for incision and drainage and HIV status. MRSA now accounts for the majority of SSTI due to S. aureus at Fenway, and improved rates of clinical resolution on empirical antibiotic therapy have paralleled increasing use of empirical TMP-SMX for these infections. TMP-SMX appears to be an appropriate empirical antibiotic for suspected MRSA SSTI, especially where clindamycin resistance is common.