Bacteriophage therapy and current delivery strategies for orthopedic infections: A SCOPING review.

OBJECTIVES: Interest in phages as adjunctive therapy to treat difficult infections has grown in the last decade. However, phage dosing and delivery for orthopedic infections have not been systematically summarized. METHODS: Following PRISMA-ScR guidelines, we conducted a SCOPING review through September 1st, 2023, of MEDLINE, Embase, Web of Science Core Collection, and Cochrane Central. RESULTS: In total, 77 studies were included, of which 19 (24.7%) were in vitro studies, 17 (22.1%) were animal studies, and 41 (53.2%) were studies in humans. A total of 137 contemporary patients receiving phage therapy are described. CONCLUSIONS: Direct phage delivery remains the most studied form of phage therapy, notably in prosthetic joint infections, osteomyelitis, and diabetic foot ulcers. Available evidence describing phage therapy in humans suggests favorable outcomes for orthopedic infections, though this evidence is composed largely of low-level descriptive studies. Several phage delivery devices have been described, though a lack of comparative and in-human evidence limits their therapeutic application. Limitations to the use of phage therapy for orthopedic infections that need to be overcome include a lack of understanding related to optimal dosing and phage pharmacokinetics, bacterial heterogeneity in an infection episode, and phage therapy toxicity.

Tecovirimat for the Treatment of Human Monkeypox: An Initial Series From Massachusetts, United States.

A large, ongoing multicountry outbreak of human monkeypox has the potential to cause considerable morbidity and mortality. Therapeutics for the treatment of smallpox, a related Orthopoxvirus, may be used and affect the natural history of monkeypox. We present 3 patients from our hospitals treated with tecovirimat, a pan-Orthopoxvirus inhibitor currently available under an expanded access investigational new drug protocol for monkeypox.

Low-frequency HIV-1 drug resistance mutations in antiretroviral naïve individuals in Botswana.

BACKGROUND: Individuals living with human immunodeficiency virus (HIV) who experience virological failure (VF) after combination antiretroviral therapy (cART) initiation may have had low-frequency drug resistance mutations (DRMs) at cART initiation. There are no data on low-frequency DRMs among cART-naïve HIV-positive individuals in Botswana. METHODS: We evaluated the prevalence of low-frequency DRMs among cART-naïve individuals previously sequenced using Sanger sequencing. The generated pol amplicons were sequenced by next-generation sequencing. RESULTS: We observed low-frequency DRMs (detected at <20% in 33/103 (32%) of the successfully sequenced individuals, of whom four also had mutations detected at >20%. K65R was the most common low-frequency DRM detected in 8 individuals. Eighty-two of the 103 individuals had follow-up viral load data while on cART. Twenty-seven of the 82 individuals harbored low-frequency DRMs. Only 12 of 82 individuals experienced VF. The following low-frequency DRMs were observed in four individuals experiencing VF: K65R, K103N, V108I, and Y188C. No statistically significant difference was observed in the prevalence of low-frequency DRMs between individuals experiencing VF (4/12) and those not experiencing VF (23/70) (P = .97). However, individuals with non-nucleoside reverse transcriptase inhibitors-associated low-frequency DRMs were 2.68 times more likely to experience VF (odds ratio, 2.68; 95% confidential interval, 0.4-13.9) compared with those without (P = .22). CONCLUSION: Next-generation sequencing was able to detect low-frequency DRMs in this cohort in Botswana, but these DRMs did not contribute significantly to VF.

Significant Reduction in Vaccine-Induced Antibody Levels and Neutralization Activity Among Healthcare Workers and Nursing Home Residents 6 Months Following Coronavirus Disease 2019 BNT162b2 mRNA Vaccination.

Antibody decline occurred from 2 weeks to 6 months post-BNT162b2 mRNA vaccination in nursing home (NH) residents and healthcare workers. Antispike, receptor-binding domain, and neutralization levels dropped >81% irrespective of prior infection. Notably, 69% of infection-naive NH residents had neutralizing antibodies at or below the assay's limit of detection.

Does a lack of vaccine side effects correlate with reduced BNT162b2 mRNA vaccine response among healthcare workers and nursing home residents?

BACKGROUND: The BNT162b2 SARS-CoV-2 mRNA vaccination has mitigated the burden of COVID-19 among residents of long-term care facilities considerably, despite being excluded from the vaccine trials. Data on reactogenicity (vaccine side effects) in this population are limited. AIMS: To assess reactogenicity among nursing home (NH) residents. To provide a plausible proxy for predicting vaccine response among this population. METHODS: We enrolled and sampled NH residents and community-dwelling healthcare workers who received the BNT162b2 mRNA vaccine, to assess local or systemic reactogenicity and antibody levels (immunogenicity). RESULTS: NH residents reported reactions at a much lower frequency and lesser severity than the community-dwelling healthcare workers. These reactions were mild and transient with all subjects experiencing more local than systemic reactions. Based on our reactogenicity and immunogenicity data, we developed a linear regression model predicting log-transformed anti-spike, anti-receptor-binding domain (RBD), and neutralizing titers, with a dichotomous variable indicating the presence or absence of reported reactions which revealed a statistically significant effect, with estimated shifts in log-transformed titers ranging from 0.32 to 0.37 (all p < 0.01) indicating greater immunogenicity in subjects with one or more reported reactions of varying severity. DISCUSSION: With a significantly lower incidence of post-vaccination reactions among NH residents as reported in this study, the BNT162b2 mRNA vaccine appears to be well-tolerated among this vulnerable population. If validated in larger populations, absence of reactogenicity could help guide clinicians in prioritizing vaccine boosters. CONCLUSIONS: Reactogenicity is significantly mild among nursing home residents and overall, subjects who reported post-vaccination reactions developed higher antibody titers.

Reduced BNT162b2 Messenger RNA Vaccine Response in Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2)-Naive Nursing Home Residents.

After BNT162b2 messenger RNA vaccination, antibody levels to spike, receptor-binding domain, and virus neutralization were examined in 149 nursing home residents and 110 healthcare worker controls. Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2)-naive nursing home residents' median post-second vaccine dose antibody neutralization titers are one-quarter that of SARS-CoV-2-naive healthcare workers.

Reduced BNT162b2 mRNA vaccine response in SARS-CoV-2-naive nursing home residents.

The SARS-CoV-2 pandemic impact on nursing home (NH) residents prompted their prioritization for early vaccination. To fill the data gap for vaccine immunogenicity in NH residents, we examined antibody levels after BNT162b2 mRNA vaccine to spike, receptor binding domain (RBD) and for virus neutralization in 149 NH residents and 111 health care worker controls. SARS-CoV-2-naive NH residents mount antibody responses with nearly 4-fold lower median neutralization titers and half the anti-spike level compared to SARS-CoV-2-naive healthcare workers. By contrast, SARS-CoV-2-recovered vaccinated NH residents had neutralization, anti-spike and anti-RBD titers similar to SARS-CoV-2-recovered vaccinated healthcare workers. NH residents' blunted antibody responses have important implications regarding the quality and durability of protection afforded by neoantigen vaccines. We urgently need better longitudinal evidence on vaccine effectiveness specific to NH resident populations to inform best practices for NH infection control measures, outbreak prevention and potential indication for a vaccine boost.

High Inpatient Health Care Utilization and Charges Associated With Injection Drug Use-Related Infections: A Cohort Study, 2012-2015.

Our study describes the characteristics of patients hospitalized with injection drug use-related infection over a multiyear period in a region highly impacted by the opioid epidemic. Intensive health care needs were common in this young cohort, including high rates of readmission, high hospitalization costs, and prolonged lengths of stay.

PANDAA intentionally violates conventional qPCR design to enable durable, mismatch-agnostic detection of highly polymorphic pathogens.

Sensitive and reproducible diagnostics are fundamental to containing the spread of existing and emerging pathogens. Despite the reliance of clinical virology on qPCR, technical challenges persist that compromise their reliability for sustainable epidemic containment as sequence instability in probe-binding regions produces false-negative results. We systematically violated canonical qPCR design principles to develop a Pan-Degenerate Amplification and Adaptation (PANDAA), a point mutation assay that mitigates the impact of sequence variation on probe-based qPCR performance. Using HIV-1 as a model system, we optimized and validated PANDAA to detect HIV drug resistance mutations (DRMs). Ultra-degenerate primers with 3' termini overlapping the probe-binding site adapt the target through site-directed mutagenesis during qPCR to replace DRM-proximal sequence variation. PANDAA-quantified DRMs present at frequency ≥5% (2 h from nucleic acid to result) with a sensitivity and specificity of 96.9% and 97.5%, respectively. PANDAA is an innovative advancement with applicability to any pathogen where target-proximal genetic variability hinders diagnostic development.

Surgical cure of clarithromycin resistant Mycobacterium chelonae breast implant infection: A case report and review of the literature.

Clusters of patients who obtain cosmetic surgeries abroad have developed surgical site infections due to rapid growing non-tuberculous mycobacteria (NTM). These are usually treated with a combination of surgery and months of anti-mycobacterial therapy, but poor outcomes, including permanent scarring are common. We present a case of a 36-year-old female who developed a clarithromycin-resistant M. chelonae (CRMC) infection after undergoing breast augmentation in the Dominican Republic. She underwent debridement and explant of her silicone implants, but due to a series of complications including discordant antimicrobial susceptibility testing profiles, GI side effects, and then pregnancy, she was unable to receive typical multidrug anti-mycobacterial therapy after surgery. She received close clinical follow up and demonstrated full recovery without any evidence of recurrence of infection at 9 months of follow up. We searched the literature for cases of NTM surgical site infection after breast surgery. To our knowledge, this is the first case report of confirmed NTM breast implant infection being cured with surgery alone, and only the second report of clarithromycin resistant M. chelonae in a patient without disseminated infection or pre-exposure to macrolides. The increasing prevalence of drug resistant NTM infections is an emerging concern for clinicians treating patients with complications related to medical tourism.

Use of a mutation-specific genotyping method to assess for HIV-1 drug resistance in antiretroviral-naïve HIV-1 Subtype C-infected patients in Botswana.

Background: HIV-1 drug resistance poses a major threat to the success of antiretroviral therapy. The high costs of available HIV drug resistance assays prohibit their routine usage in resource-limited settings. Pan-degenerate amplification and adaptation (PANDAA), a focused genotyping approach based on quantitative PCR (qPCR), promises a fast and cost-effective way to detect HIV drug resistance mutations (HIVDRMs).  Given the high cost of current genotyping methods, we sought to use PANDAA for screening key HIVDRMs in antiretroviral-naïve individuals at codons 103, 106 and 184 of the HIV-1 reverse transcriptase gene. Mutations selected at these positions have been shown to be the most common driver mutations in treatment failure.  Methods: A total of 103 samples from antiretroviral-naïve individuals previously genotyped by Sanger population sequencing were used to assess and verify the performance of PANDAA. PANDAA samples were run on the ABI 7500 Sequence Detection System to genotype the K103N, V106M and M184V HIVDRMs. In addition, the cost per sample and reaction times were compared. Results: Sanger population sequencing and PANDAA detected K103N mutation in three (2.9%) out of 103 participants.  There was no evidence of baseline V106M and M184V mutations observed in our study. To genotype the six HIVDRMs it costs approximately 40 USD using PANDAA, while the reagents cost per test for Sanger population sequencing is approximately 100 USD per sample. PANDAA was performed quicker compared to Sanger sequencing, 2 hours for PANDAA versus 15 hours for Sanger sequencing. Conclusion: The performance of PANDAA and Sanger population sequencing demonstrated complete concordance. PANDAA could improve patient management by providing quick and relatively cheap access to drug-resistance information.

Comparison of an in-house 'home-brew' and commercial ViroSeq integrase genotyping assays on HIV-1 subtype C samples.

BACKGROUND: Roll-out of Integrase Strand Transfer Inhibitors (INSTIs) such as dolutegravir for HIV combination antiretroviral therapy (cART) in sub-Saharan Africa necessitates the development of affordable HIV drug resistance (HIVDR) assays targeting the Integrase gene. We optimised and evaluated an in-house integrase HIV-1 drug resistance assay (IH-Int) and compared it to a commercially available assay, ViroSeq™ Integrase Genotyping kit (VS-Int) amongst HIV-1 clade C infected individuals. METHODS: We used 54 plasma samples from treatment naïve participants and one plasma sample from a patient failing INSTI based cART. Specimens were genotyped using both the VS-Int and IH-Int assays. Stanford HIV drug resistance database were used for integrase resistance interpretation. We compared the major and minor resistance mutations, pairwise nucleotide and amino-acid identity, costs and assay time. RESULTS: Among 55 specimens tested with IH-Int, 53 (96.4%) successfully amplified compared to 45/55 (81.8%) for the VS-Int assay. The mean nucleotide and amino acid similarity from 33 paired sequences was 99.8% (SD ± 0.30) and 99.8% (SD ± 0.39) for the IH-Int and VS-Int assay respectively. The reagent cost/sample were 32 USD and 147 USD for IH-Int and VS-Int assay, respectively. All sequenced samples were confirmed as HIV-1 subtype C. CONCLUSIONS: The IH-Int assay had a high amplification success rate and high concordance with the commercial assay. It is significantly cheaper compared to the commercial assay. Our assay has the needed specifications for routine monitoring of participants on Dolutegravir based regimens in Botswana.

High Morbidity and Mortality Among Patients With Sentinel Admission for Injection Drug Use-Related Infective Endocarditis.

BACKGROUND: Hospitalizations for individuals with injection drug use-related infective endocarditis (IDU-IE) represent an increasing portion of all patients with endocarditis. This study describes the evolving trends in demographics, clinical characteristics, rates of surgical intervention, and mortality among patients hospitalized with IE, comparing those with and without injection drug use. METHODS: This is a retrospective cohort study of patients admitted between January 1, 2007 to June 30, 2015 at a tertiary care center in Boston, Massachusetts. Endocarditis was defined by International Classification of Diseases, Ninth Revision code and verified by the modified Duke Criteria for IE. The clinical characteristics, microbiology, site of infection, complications of IE, and outcome were all abstracted by chart review. Rates of surgical consultation and surgical intervention within 90 days of admission were obtained, and assessment of surgical risk calculated was by EuroSCORE II (euroscore.org/calc). Subsequent hospitalizations for all causes were also reviewed. RESULTS: Injection drug use-related infective endocarditis occurred in younger patients with lower rates of diabetes, renal dysfunction, and prior cardiothoracic (CT) surgery than those without IDU. Injection drug use-related infective endocarditis was associated with higher rates of complications, CT surgery consultation, and surgery within 90 days for absolute surgical indication. Readmissions for endocarditis occurred in 20% of IDU-IE patients and 9% of those with non-IDU IE. All-cause 1-year mortality rates were similar (IDU-IE 16%, non-IDU IE 13%; P = .58). CONCLUSIONS: Despite younger age, fewer medical comorbidities, and fewer prior cardiac surgeries, all-cause 1-year mortality was similar for patients after sentinel admission for IDU-IE compared with non-IDU IE. Interventions in the acute hospital setting and after discharge are needed to support patients with IDU-IE, focusing on harm reduction and treatment of addiction to reduce the unexpectedly high mortality of this young population.

Infectious Diseases Physicians' Perspectives Regarding Injection Drug Use and Related Infections, United States, 2017.

BACKGROUND: In the context of the opioid epidemic, injection drug use (IDU)-related infections are an escalating health issue for infectious diseases (ID) physicians in the United States. METHODS: We conducted a mixed methods survey of the Infectious Diseases Society of America's Emerging Infections Network between February and April 2017 to evaluate perspectives relating to care of persons who inject drugs (PWID). Topics included the frequency of and management strategies for IDU-related infection, the availability of addiction services, and the evolving role of ID physicians in substance use disorder (SUD) management. RESULTS: More than half (53%, n = 672) of 1273 network members participated. Of these, 78% (n = 526) reported treating PWID. Infections frequently encountered included skin and soft tissue (62%, n = 324), bacteremia/fungemia (54%, n = 281), and endocarditis (50%, n = 263). In the past year, 79% (n = 416) reported that most IDU-related infections required ≥2 weeks of parenteral antibiotics; strategies frequently employed for prolonged treatment included completion of the entire course in the inpatient unit (41%, n = 218) or at another supervised facility (35%, n = 182). Only 35% (n = 184) of respondents agreed/strongly agreed that their health system offered comprehensive SUD management; 46% (n = 242) felt that ID providers should actively manage SUD. CONCLUSIONS: The majority of physicians surveyed treated PWID and reported myriad obstacles to providing care. Public health and health care systems should consider ways to support ID physicians caring for PWID, including (1) guidelines for providing complex care, including safe provision of multiweek parenteral antibiotics; (2) improved access to SUD management; and (3) strategies to assist those interested in roles in SUD management.

Four-class drug-resistant HIV-1 subtype C in a treatment experienced individual on dolutegravir-based antiretroviral therapy in Botswana.

: There are limited data on the effectiveness of dolutegravir (DTG)-based combination antiretroviral therapy (ART) in real-life settings in southern Africa where HIV-1 subtype C predominates. We report a patient infected with HIV-1 subtype C on DTG-based ART previously exposed to raltegravir who developed multidrug resistance mutations to four antiretroviral classes. There is need for drug resistance monitoring and clinical vigilance to ensure effectiveness of HIV treatment programs even in the era of DTG-based ART.

An opioid overdose curriculum for medical residents: Impact on naloxone prescribing, knowledge, and attitudes.

BACKGROUND: Despite escalating opioid overdose death rates, addiction medicine is underrepresented in residency curricula. Providing naloxone to at-risk patients, relatives, and first responders reduces overdose deaths, but rates of naloxone prescribing remain low. The goal of this study is to examine the impact of a brief curricular intervention for internal medicine residents on naloxone prescribing rates, knowledge, and attitudes. METHODS: Internal medicine residents (N = 160) at an urban, tertiary care medical center received two 1-hour didactic sessions addressing overdose prevention, including intranasal naloxone. The number of naloxone prescriptions generated by residents was compared to faculty, who received no similar intervention, in the 3-month periods before and after the curriculum. Resident knowledge and attitudes, as assessed by pre- and post-intervention surveys, were compared. RESULTS: The resident naloxone prescribing rate increased from 420 to 1270 per 100,000 inpatient discharges (P = .01) and from 0 to 370 per 100,000 ambulatory visits (P < .001) post-intervention. Similar increases were not observed among inpatient faculty, whose prescribing rate decreased from 1150 to 880 per 100,000 discharges (P = .08), or among outpatient faculty, whose rate increased from 30 to 180 per 100,000 ambulatory visits (P < .001) but was lower than the post-intervention resident rate (P = .01). Residents demonstrated high baseline knowledge about naloxone, but just 13% agreed that they were adequately trained to prescribe pre-intervention. Post-intervention, residents were more likely to agree that they were adequately trained to prescribe (Likert mean 2.5 vs. 3.9, P < .001), to agree that treating addiction is rewarding (Likert mean 2.9 vs. 3.3, P = .03), and to attain a perfect score on the knowledge composite (57% vs. 33%, P = .05). CONCLUSIONS: A brief curricular intervention improved resident knowledge and attitudes regarding intranasal naloxone for opioid overdose reversal and significantly increased prescribing rates.