Preclinical mouse models suggest that the gut microbiome modulates tumor response to checkpoint blockade immunotherapy; however, this has not been well-characterized in human cancer patients. Here we examined the oral and gut microbiome of melanoma patients undergoing anti–programmed cell death 1 protein (PD-1) immunotherapy (n = 112). Significant differences were observed in the diversity and composition of the patient gut microbiome of responders versus nonresponders. Analysis of patient fecal microbiome samples (n = 43, 30 responders, 13 nonresponders) showed significantly higher alpha diversity (P < 0.01) and relative abundance of bacteria of the Ruminococcaceae family (P < 0.01) in responding patients. Metagenomic studies revealed functional differences in gut bacteria in responders, including enrichment of anabolic pathways. Immune profiling suggested enhanced systemic and antitumor immunity in responding patients with a favorable gut microbiome as well as in germ-free mice receiving fecal transplants from responding patients. Together, these data have important implications for the treatment of melanoma patients with immune checkpoint inhibitors.

IRIS is common among HIV-infected persons coinfected with M. tuberculosis, M. avium complex, or C. neoformans. Antiretroviral drug-naive patients who start HAART in close proximity to the diagnosis of an opportunistic infection and have a rapid decline in HIV-1 RNA level should be monitored for development of this disorder.

The authors note that due to a printer's error, on page 4460, Fig. 2 appears incorrectly in part. The middle and bottom panels were transposed. The corrected figure and its legend appear below. MGAS5005∆ccpA comp∆ccpA

This study of human immunodeficiency virus (HIV)-infected patients coinfected with Cryptococcus neoformans found that 30% of patients who initiated highly active antiretroviral therapy developed immune reconstitution inflammatory syndrome (IRIS). Patients with C. neoformans-related IRIS had higher cerebrospinal fluid opening pressures, glucose levels, and white blood cell counts, compared with patients with typical HIV-associated C. neoformans meningitis.

To colonize and cause disease at distinct anatomical sites, bacterial pathogens must tailor gene expression in a microenvironment-specific manner. The molecular mechanisms that control the ability of the human bacterial pathogen group A Streptococcus (GAS) to transition between infection sites have yet to be fully elucidated. A key regulator of GAS virulence gene expression is the CovR-CovS two-component regulatory system (also known as CsrR-CsrS). covR and covS mutant strains arise spontaneously during invasive infections and, in in vivo models of infection, rapidly become dominant. Here, we compared wild-type GAS with covR, covS, and covRS isogenic mutant strains to investigate the heterogeneity in the types of natural mutations that occur in covR and covS and the phenotypic consequences of covR or covS mutation. We found that the response regulator CovR retains some regulatory function in the absence of CovS and that CovS modulates CovR to significantly enhance repression of one group of genes (e.g., the speA, hasA, and ska genes) while it reduces repression of a second group of genes (e.g., the speB, grab, and spd3 genes). We also found that different in vivo-induced covR mutations can lead to strikingly different transcriptomes. While covS mutant strains show increased virulence in several invasive models of infection, we determined that these mutants are significantly outcompeted by wild-type GAS during growth in human saliva, an ex vivo model of upper respiratory tract infection. We propose that CovS-mediated regulation of CovR activity plays an important role in the ability of GAS to cycle between pharyngeal and invasive infections.

The institution of highly active antiretroviral therapy (HAART) in HIV-infected patients restores protective immune responses against a wide variety of pathogens and dramatically decreases mortality. In a subset of patients receiving HAART, immune reconstitution is associated with a pathological inflammatory response leading to substantial short-term morbidity and even mortality. The past several years have seen marked advances in our clinical understanding of the immune reconstitution inflammatory syndrome (IRIS), but many questions remain. This article summarizes recent data on clinical risk factors for the development of IRIS. A consistent finding from multiple groups is that IRIS develops in a substantial percentage of HIV-infected patients who have an underlying opportunistic infection and receive HAART. As the use of HAART stands to markedly increase over the next several years, optimal care of patients receiving HAART will need to incorporate monitoring for and treating complications of IRIS.

Background Despite increasing data on the impact of the microbiome on cancer, the dynamics and role of the microbiome in infection during acute myelogenous leukemia (AML) therapy are unknown. Thus, we sought to determine relationships between microbiome composition and infectious outcomes in AML patients receiving induction chemotherapy (IC). Methods Buccal and fecal specimens (478 samples) were collected twice weekly from 34 AML patients undergoing IC. Oral and stool microbiomes were characterized by 16S rRNA V4 sequencing using Illumina MiSeq. Microbial diversity and genera composition were associated with clinical outcomes. Results Baseline stool α-diversity was significantly lower in patients that developed infections during IC compared to those that did not (P = 0.047). Significant decreases in both oral and stool microbial α-diversity were observed over the course of IC, with a linear correlation between α-diversity change at the two sites (P = 0.02). Loss of both oral and stool α-diversity was significantly associated with carbapenem receipt (P < 0.01). Domination events by the majority of genera were transient (median duration = 1 sample), while the number of domination events by pathogenic genera significantly increased over the course of IC (P=0.002). Moreover, patients who lost microbial diversity over the course of induction chemotherapy were significantly more likely to contract a microbiologically documented infection within the 90 days post-IC neutrophil recovery (P=0.04). Conclusion These data present the largest longitudinal analyses of oral and stool microbiomes in AML patients and suggest that microbiome measurements could assist with mitigation of infectious complications of AML therapy.

A multicenter, retrospective study of patients infected with carbapenem-resistant Pseudomonas aeruginosa who were treated with ceftolozane/tazobactam was performed. Among 35 patients, pneumonia was the most common indication and treatment was successful in 26 (74%). Treatment failure was observed in all cases where isolates demonstrated ceftolozane-tazobactam minimum inhibitory concentrations ≥8 μg/mL.