Erratum to: Antimicrobials: a global alliance for optimizing their rational use in intra-abdominal infections (AGORA).

[This corrects the article DOI: 10.1186/s13017-016-0089-y.].

Regulatory Pathways for New Antimicrobial Agents: Trade-offs to Keep the Perfect From Being the Enemy of the Good.

In 2002, Shlaes and Moellering warned that pharmaceutical companies were abandoning antibiotic research and development due to changing regulatory standards regarding noninferiority (NI) clinical trials. NI trials are subject to unique biases that may yield false-positive conclusions. The US Food and Drug Administration (FDA) developed guidance to ensure that NI results truly reflect drug efficacy. These changes, intended to reduce uncertainty in trial results, have shaped trial enrollment and conduct in ways that now require reflection.

Prioritized current unmet needs for antibacterial therapies.

As a result of declining new antibacterial approvals and rising antibiotic resistance, society clearly needs new treatments for bacterial infections. Specific areas of unmet need evolve over time owing to changes in resistance patterns and treatment strategies. Our goal here is to describe and prioritize the current areas of greatest unmet need for new antibacterial development based on an understanding of the most serious treatment challenges facing patients and their providers today.

Combination therapy with iron chelation and vancomycin in treating murine staphylococcemia.

Iron acquisition is a virulence factor for Staphylococcus aureus. We assessed the efficacy of the iron chelator, deferasirox (Def), alone or in combination with vancomycin (Van) against two methicillin-resistant S. aureus (MRSA) strains in vitro and in a murine bacteremia model. In vitro time-kill assays were carried out against MRSA or vancomycin-intermediate S. aureus (VISA) strains. The impact of Def on Van binding to the surface of S. aureus was measured by flow cytometry. Furthermore, we compared the efficacy of Def, Van, or both drugs in treating S. aureus bacteremia in a murine model. Combination therapy reduced MRSA and VISA viability in vitro versus either drug alone or untreated controls (p < 0.005); this outcome was correlated with enhanced Van surface binding to S. aureus cells. In vivo, Def + Van combination therapy significantly reduced the bacterial burden in mice kidneys (p = 0.005) and spleen (p < 0.001), and reduced the severity of infection with MRSA or VISA strains compared to placebo-treated mice. Our results show that Def enhances the in vitro and in vivo capacity of Van-mediated MRSA killing via a mechanism that appears to involve increased binding of Van to the staphylococcal surface. Iron chelation is a promising, novel adjunctive therapeutic strategy for MRSA and VISA infections.

Societal costs versus savings from wild-card patent extension legislation to spur critically needed antibiotic development.

BACKGROUND: Over the last two decades, an alarming rise in infections caused by antibiotic-resistant microbes has been paralleled by an equally alarming decline in the development of new antibiotics to deal with the threat. In response to this brewing "perfect storm" of infectious diseases, the Infectious Diseases Society of America (IDSA) has released a white paper that proposes incentives to stimulate critically needed antibiotic development by pharmaceutical companies. A cornerstone of the recommendations is establishment of a "wild-card patent extension" program. This program would allow a company receiving United States (US) Food and Drug Administration (FDA) approval for a new anti-infective agent targeting a drug-resistant pathogen to extend the patent on a drug within their active portfolio. However, wild-card patent extension legislation is highly controversial due to concerns regarding its societal cost. METHODS: We performed a systematic literature review to estimate the societal cost of wild-card patent extension compared to the savings resulting from the availability of one new antibiotic to treat multi-drug-resistant Pseudomonas aeruginosa. RESULTS: We conservatively estimate that wild-card patent extension applied to one new antibiotic would cost $7.7 billion over the first 2 years, and $3.9 billion over the next 18 years. Thus, even if the new antibiotic abrogated only 50% of the annual societal cost of multidrug-resistant P. aeruginosa (estimated $2.7 billion), wild-card patent extension would be cost neutral by 10 years after approval of the new antibiotic, and would save society approximately $4.6 billion by 20 years after approval. CONCLUSIONS: Wild-card patent extension appears to be a cost-effective strategy to spur anti-infective development. Although our analysis is limited by the precision of published data, our model employed conservative assumptions.

mtDNA disease in the primary care setting.

Disorders of mitochondrial DNA (mtDNA) may commonly present to primary care physicians but go undiagnosed. A 36-year-old man with a 15-year history of psychosis, seizures, and sensorineural hearing loss and a family history of diabetes mellitus and heart disease presented to our hospital without a unifying diagnosis. Physiologic, biochemical, and genetic testing revealed deficient aerobic metabolism, a defect in mitochondrial electron transport, and the presence of an A-to-G point mutation at position 3243 of the mitochondrial leucine-transfer RNA gene, establishing the diagnosis of mitochondrial encephalopathy, lactic acidosis, and strokelike syndrome (MELAS). Diagnosing mtDNA disorders requires a careful integration of clinical signs and symptoms with pedigree analysis and multidisciplinary testing. Diagnosis is important to provide genetic counseling, avoid unnecessary evaluation, and facilitate therapy for symptomatic relief.

Type 1/Type 2 immunity in infectious diseases.

T helper type 1 (Th1) lymphocytes secrete secrete interleukin (IL)-2, interferon-gamma, and lymphotoxin-alpha and stimulate type 1 immunity, which is characterized by intense phagocytic activity. Conversely, Th2 cells secrete IL-4, IL-5, IL-9, IL-10, and IL-13 and stimulate type 2 immunity, which is characterized by high antibody titers. Type 1 and type 2 immunity are not strictly synonymous with cell-mediated and humoral immunity, because Th1 cells also stimulate moderate levels of antibody production, whereas Th2 cells actively suppress phagocytosis. For most infections, save those caused by large eukaryotic pathogens, type 1 immunity is protective, whereas type 2 responses assist with the resolution of cell-mediated inflammation. Severe systemic stress, immunosuppression, or overwhelming microbial inoculation causes the immune system to mount a type 2 response to an infection normally controlled by type 1 immunity. In such cases, administration of antimicrobial chemotherapy and exogenous cytokines restores systemic balance, which allows successful immune responses to clear the infection.

The cutaneous citadel: a holistic view of skin and immunity.

Human skin has 4 major functions: endogenous homeostasis (e.g. regulation of body temperature and fluid balance), metabolism (e.g. Vitamin D synthesis), sensory input, and to serve as a barrier to external threats (e.g. infection, mechanical injury, ultraviolet light). It is the latter function which concerns this review, for the skin's remarkable success in protecting the human body from the outside world is a major component of our immune system. The eminent pathologist, Virchow, whose work in the mid 19th century revolutionized many aspects of medical understanding, viewed the skin as an effective but inanimate barrier (1). However, recent technologies have elucidated a highly complex, dynamic interplay between the skin and other members of the immune system.

Autologous bone marrow transplantation in acute leukemia.

Autologous bone marrow transplantation can induce long-term LFS in 20% to 40% of patients with relapsed acute leukemia and should be considered as salvage therapy for patients who lack an HLA-matched donor and for patients over 45. Adult ALL patients and children with ALL in extramedullary relapse beyond second CR should receive alloBMT if at all possible. The role of ABMT in acute leukemia patients in first CR remains unclear despite randomized trials (Table 2). Because protocol deviations, early relapse, and inappropriately high treatment-related mortality unequally affected the ABMT cohort, and because recent randomized trials have used old purging methodologies, it is not possible to conclude that ABMT is not beneficial. More recent studies show that most patients are able to proceed with the intended ABMT and that modern purging may be associated with a treatment-related mortality rate of less then 5%. Immunomodulation and graft engineering uniquely suited to autologous progenitor cells indicate that ABMT should continue to be studied in the management of acute leukemia.

Novel antipsychotics and new onset diabetes.

BACKGROUND: The new antipsychotics induce minimal extrapyramidal side effects, probably due to their relatively greater affinity for certain nondopaminergic receptors than their older, conventional counterparts; however, this polyreceptor affinity may be responsible for the development of other adverse effects. One serious adverse effect that may be linked to these effects is non-insulin-dependent diabetes mellitus. METHODS: We summarize 6 new cases of clozapine- and olanzapine-associated diabetes that we have documented in our clinic. We compare our cases to previous reports and tabulate the pertinent similarities among cases. RESULTS: Two of the cases were olanzapine-associated and 4 were clozapine-associated diabetes. Five of our 6 patients had risk factors for diabetes, as have 7 of the 9 previously reported in the literature. Four of our 6 patients, and 2 of the 4 prior cases in which such data were reported, experienced substantial weight gain after starting their antipsychotics. CONCLUSIONS: Novel antipsychotics should be administered with great care to patients with risk factors for diabetes. Although the precise mechanism of the novel antipsychotic-associated diabetes is unclear, we hypothesize that histaminic and possibly serotonergic antagonism induces weight gain, which in turn leads to changes in glucose homeostasis. Additionally, serotonin1A antagonism might decrease pancreatic beta-cell responsiveness, resulting in inappropriately low insulin and hyperglycemia.

Cloning and characterization of CAD1/AAF1, a gene from Candida albicans that induces adherence to endothelial cells after expression in Saccharomyces cerevisiae.

Adherence to the endothelial cell lining of the vasculature is probably a critical step in the egress of Candida albicans from the intravascular compartment. To identify potential adhesins that mediate the attachment of this organism to endothelial cells, a genomic library from C. albicans was used to transform a nonadherent strain of Saccharomyces cerevisiae. The population of transformed yeasts was enriched for highly adherent clones by repeated passages over endothelial cells. One clone which exhibited a fivefold increase in endothelial cell adherence, compared with S. cerevisiae transformed with vector alone, was identified. This organism also flocculated. The candidal DNA fragment within this adherent/flocculent organism was found to contain a single 1.8-kb open reading frame, which was designated CAD1. It was found to be identical to AAF1. The predicted protein encoded by CAD1/AAF1 contained features suggestive of a regulatory factor. Consistent with this finding, immunoelectron microscopy revealed that CAD1/AAF1 localized to the cytoplasm and nucleus but not the cell wall or plasma membrane of the transformed yeasts. Because yeasts transformed with CAD1/AAF1 both flocculated and exhibited increased endothelial cell adherence, the relationship between adherence and flocculation was examined. S. cerevisiae expressing either of two flocculation phenotypes, Flo1 or NewFlo, adhered to endothelial cells as avidly as did yeasts expressing CAD1/AAF1. Inhibition studies revealed that the flocculation phenotype induced by CAD1/AAF1 was similar to Flo1. Thus, CAD1/AAF1 probably encodes a regulatory protein that stimulates endothelial cell adherence in S. cerevisiae by inducing a flocculation phenotype. Whether CAD1/AAF1 contributes to the adherence of C. albicans to endothelial cells remains to be determined.

Interferon-gamma differentially regulates interleukin-12 and interleukin-10 production in leprosy.

The ability of monocytes to influence the nature of the T cell response to microbial pathogens is mediated in part by the release of cytokines. Of particular importance is the release of IL-12 and IL-10 by cells of the monocyte/macrophage lineage upon encountering the infectious agent. IL-12 promotes cell mediated immunity (CMI) to intracellular pathogens by augmenting T-helper type 1 responses, whereas IL-10 downregulates these responses. The ability of IFN-gamma to modulate the balance between IL-12 and IL-10 production was examined by studying leprosy as a model. In response to Mycobacterium leprae stimulation, IFN-gamma differentially regulated IL-12 and IL-10 production resulting in upregulation of IL-12 release and downregulation of IL-10 release. Furthermore, we determined that the mechanism by which IFN-gamma downregulates IL-10 was through the induction of IL-12. The data suggest a model of lymphocyte-monocyte interaction whereby the relative presence or absence of IFN-gamma in the local microenvironment is a key determinant of the type of monocyte cytokine response, and hence the degree of CMI in the host response to infection.

Candida albicans stimulates cytokine production and leukocyte adhesion molecule expression by endothelial cells.

Endothelial cells have the potential to influence significantly the host immune response to blood-borne microbial pathogens, such as Candida albicans. We investigated the ability (of this organism to stimulate endothelial cell responses relevant to host defense in vitro. Infection with C. albicans induced endothelial cells to express mRNAs encoding E-selectin, intercellular adhesion molecule 1, vascular cell adhesion molecule 1, interleukin 6, interleukin 8, monocyte chemoattractant protein 1, and inducible cyclooxygenase (cox2). All three leukocyte adhesion molecule proteins were expressed on the surfaces of the endothelial cells after 8 h of exposure to C. albicans. An increase in secretion of all three cytokines was found after 12 h of infection. Cytochalasin D inhibited accumulation of the endothelial cell cytokine and leukocyte adhesion molecule mRNAs in response to C. albicans, suggesting that endothelial cell phagocytosis of the organism is required to induce this response. Live Candida tropicalis, Candida glabrata, a nongerminating strain of C. albicans, and killed C. albicans did not stimulate the expression of any of the cytokine or leukocyte adhesion molecule mRNAs. These findings indicate that a factor associated with live, germinating C. albicans is required for induction of endothelial cell mRNA expression. Furthermore, since endothelial cells phagocytize killed C. albicans, phagocytosis is likely necessary but not sufficient for this organism to stimulate mRNA accumulation. In conclusion, the secretion of proinflammatory cytokines and expression of leukocyte adhesion molecules by endothelial cells in response to C. albicans could enhance the host defense against this organism by contributing to the recruitment of activated leukocytes to sites of intravascular infection.

Reduced virulence of Candida albicans PHR1 mutants.

Candida albicans mutants lacking PHR1 exhibit a pH-dependent morphogenic defect which is expressed at pH 7.5, a pH comparable to that of mammalian blood (S. M. Saporito-Irwin, C. E. Birse, P. S. Sypherd, and W. A. Fonzi, Mol. Cell. Biol. 15:601-613, 1995). The in vivo relevance of this expression pattern was tested in a mouse model of systemic candidiasis. A phr1/phr1 mutant was found to be less virulent than an isogenic Phr1+ strain and exhibited altered morphological development in vivo. These results indicate that PHR1 contributes to the virulence of C. albicans.

Sterol composition of Cryptococcus neoformans in the presence and absence of fluconazole.

Analysis of the sterol compositions of 13 clinical isolates of the pathogenic yeast Cryptococcus neoformans obtained from five patients with recurring cryptococcal meningitis showed that, unlike Candida albicans, the major sterols synthesized by this yeast were obtusifoliol (range, 21.1 to 68.2%) and ergosterol (range, 0.0 to 46.5%). There was considerable variation in the sterol contents among the 13 isolates, with total sterol contents ranging from 0.31 to 5.9% of dry weight. The isolates from the five patients who had relapses had different total sterol contents and compositions in comparison with those of the pretreatment isolates, indicating either that the sterols had been changed by therapy or that the patients were infected with new isolates with different sterol compositions. Growth of the cryptococcal isolates in the presence of subinhibitory concentrations of fluconazole (0.25x the MIC) significantly altered the sterol content and pattern. The total sterol content decreased in nine isolates and increased in four isolates in response to pretreatment with fluconazole. Fluconazole had no consistent effect on ergosterol levels. In contrast, fluconazole caused a decrease in obtusifoliol levels and an increase in 4,14-dimethylzymosterol levels in all isolates. These results indicate extensive diversity in sterol content, sterol composition, and sterol synthesis in response to subinhibitory concentrations of fluconazole in C. neoformans strains. We propose that fluconazole inhibits the sterol synthesis of C. neoformans by interfering with both 14 alpha-demethylase-dependent and -independent pathways. No correlation between the sterol compositions of C. neoformans isolates and their susceptibilities to fluconazole was found.