Antibiotic resistance in the patient with cancer: Escalating challenges and paths forward

Infection is the second leading cause of death in patients with cancer. Loss of efficacy in antibiotics due to antibiotic resistance in bacteria is an urgent threat against the continuing success of cancer therapy. In this review, the authors focus on recent updates on the impact of antibiotic resistance in the cancer setting, particularly on the ESKAPE pathogens (Enterococcus faecium, Staphylococcus aureus, Klebsiella pneumoniae, Acinetobacter baumannii, Pseudomonas aeruginosa, and Enterobacter spp.). This review highlights the health and financial impact of antibiotic resistance in patients with cancer. Furthermore, the authors recommend measures to control the emergence of antibiotic resistance, highlighting the risk factors associated with cancer care. A lack of data in the etiology of infections, specifically in oncology patients in United States, is identified as a concern, and the authors advocate for a centralized and specialized surveillance system for patients with cancer to predict and prevent the emergence of antibiotic resistance. Finding better ways to predict, prevent, and treat antibiotic-resistant infections will have a major positive impact on the care of those with cancer

Acute SIV Infection in Sooty Mangabey Monkeys Is Characterized by Rapid Virus Clearance from Lymph Nodes and Absence of Productive Infection in Germinal Centers

Lymphoid tissue immunopathology is a characteristic feature of chronic HIV/SIV infection in AIDS-susceptible species, but is absent in SIV-infected natural hosts. To investigate factors contributing to this difference, we compared germinal center development and SIV RNA distribution in peripheral lymph nodes during primary SIV infection of the natural host sooty mangabey and the non-natural host pig-tailed macaque. Although SIV-infected cells were detected in the lymph node of both species at two weeks post infection, they were confined to the lymph node paracortex in immune-competent mangabeys but were seen in both the paracortex and the germinal center of SIV-infected macaques. By six weeks post infection, SIV-infected cells were no longer detected in the lymph node of sooty mangabeys. The difference in localization and rate of disappearance of SIV-infected cells between the two species was associated with trapping of cell-free virus on follicular dendritic cells and higher numbers of germinal center CD4+ T lymphocytes in macaques post SIV infection. Our data suggests that fundamental differences in the germinal center microenvironment prevent productive SIV infection within the lymph node germinal centers of natural hosts contributing to sustained immune competency

Mycobacterium tuberculosis releases an antacid that remodels phagosomes

International audienc

Mycobacterial Metabolic Syndrome: Triglyceride Accumulation Decreases Growth Rate and Virulence of Mycobacterium Tuberculosis

Mycobacterium tuberculosis (Mtb) mutants lacking the operon Rv1411c-1410c encoding a lipoprotein, Rv1411c (LprG) and a putative transporter, Rv1410c (Rv1410) are dramatically attenuated for growth in mice. Previous work in our lab, using the model organism Mycobacterium smegmatis, suggested that this operon regulated the lipid content of the cell wall. Work in other laboratories characterizing LprG as a lipid-binding lipoprotein lead us to hypothesize that these bacteria grew poorly due to loss of a key lipid important in the host-pathogen interaction. Based on structural and biochemical studies we hypothesized that this attenuation was due to a lipid transport defect. Using whole cell lipidomic analysis, we found changes in LprG-1410 mutants including accumulation of triacylglyceride (TAG) species in the absence of the transport system. We have identified TAG in outer membrane fractions and supernatants of Mtb, have demonstrated the ability of LprG to transport TAG in an in vitro vesicle transfer assay, and have co-crystallized LprG with TAG. Moreover, accumulation of intracellular TAG substantially decreases growth under carbon stress in vitro and in vivo in the mouse model. Our results suggest a far different model – that TAG is ordinarily transported out of the cell and, in the absence of a transporter, limits cell proliferation independent of the host immune response. This suggests that TAG is a key metabolic regulator of cellular growth within the host

Antibiotic resistance in the patient with cancer: Escalating challenges and paths forward

Infection is the second leading cause of death in patients with cancer. Loss of efficacy in antibiotics due to antibiotic resistance in bacteria is an urgent threat against the continuing success of cancer therapy. In this review, the authors focus on recent updates on the impact of antibiotic resistance in the cancer setting, particularly on the ESKAPE pathogens (Enterococcus faecium, Staphylococcus aureus, Klebsiella pneumoniae, Acinetobacter baumannii, Pseudomonas aeruginosa, and Enterobacter spp.). This review highlights the health and financial impact of antibiotic resistance in patients with cancer. Furthermore, the authors recommend measures to control the emergence of antibiotic resistance, highlighting the risk factors associated with cancer care. A lack of data in the etiology of infections, specifically in oncology patients in United States, is identified as a concern, and the authors advocate for a centralized and specialized surveillance system for patients with cancer to predict and prevent the emergence of antibiotic resistance. Finding better ways to predict, prevent, and treat antibiotic-resistant infections will have a major positive impact on the care of those with cancer

Antibiotic Development Incentives That Reflect Societal Value of Antibiotics

TO THE EDITOR—Rome and Kesselheim [1] claimed that rewarding developers of novel antibiotics with transferable exclusivity vouchers is an expensive approach to promoting antibiotic development. This analysis is incomplete as it focuses only on the cost of bringing new antibiotics to market without acknowledging their societal value. The authors also did not suggest an alternative approach. With patients running out of treatment options for resistant infections, failing to strengthen the antibiotic pipeline is not a reasonable option

Antibiotic Development Incentives That Reflect Societal Value of Antibiotics

TO THE EDITOR—Rome and Kesselheim [1] claimed that rewarding developers of novel antibiotics with transferable exclusivity vouchers is an expensive approach to promoting antibiotic development. This analysis is incomplete as it focuses only on the cost of bringing new antibiotics to market without acknowledging their societal value. The authors also did not suggest an alternative approach. With patients running out of treatment options for resistant infections, failing to strengthen the antibiotic pipeline is not a reasonable option

White Paper: Developing Antimicrobial Drugs for Resistant Pathogens, Narrow-Spectrum Indications, and Unmet Needs.

Despite progress in antimicrobial drug development, a critical need persists for new, feasible pathways to develop antibacterial agents to treat people infected with drug-resistant bacteria. Infections due to resistant gram-negative bacilli continue to cause unacceptable morbidity and mortality rates. Antibacterial agents have been historically studied in noninferiority clinical trials that focus on a single site of infection (eg, complicated urinary tract infections, intra-abdominal infections), yet these designs may not be optimal, and often are not feasible, for study of infections caused by drug-resistant bacteria. Over the past several years, multiple stakeholders have worked to develop consensus regarding paths forward with a goal of facilitating timely conduct of antimicrobial development. Here we advocate for a novel and pragmatic approach and, toward this end, present feasible trial designs for antibacterial agents that could enable conduct of narrow-spectrum, organism-specific clinical trials and ultimately approval of critically needed new antibacterial agents

Lipidomic Analysis Links Mycobactin Synthase K to Iron Uptake and Virulence in M. tuberculosis

The prolonged survival of Mycobacterium tuberculosis (M. tb) in the host fundamentally depends on scavenging essential nutrients from host sources. M. tb scavenges non-heme iron using mycobactin and carboxymycobactin siderophores, synthesized by mycobactin synthases (Mbt). Although a general mechanism for mycobactin biosynthesis has been proposed, the biological functions of individual mbt genes remain largely untested. Through targeted gene deletion and global lipidomic profiling of intact bacteria, we identify the essential biochemical functions of two mycobactin synthases, MbtK and MbtN, in siderophore biosynthesis and their effects on bacterial growth in vitro and in vivo. The deletion mutant, ΔmbtN, produces only saturated mycobactin and carboxymycobactin, demonstrating an essential function of MbtN as the mycobactin dehydrogenase, which affects antigenicity but not iron uptake or M. tb growth. In contrast, deletion of mbtK ablated all known forms of mycobactin and its deoxy precursors, defining MbtK as the essential acyl transferase. The mbtK mutant showed markedly reduced iron scavenging and growth in vitro. Further, ΔmbtK was attenuated for growth in mice, demonstrating a non-redundant role of hydroxamate siderophores in virulence, even when other M. tb iron scavenging mechanisms are operative. The unbiased lipidomic approach also revealed unexpected consequences of perturbing mycobactin biosynthesis, including extreme depletion of mycobacterial phospholipids. Thus, lipidomic profiling highlights connections among iron acquisition, phospholipid homeostasis, and virulence, and identifies MbtK as a lynchpin at the crossroads of these phenotypes