Increase In Serious Infections Research Articles

Isolation and Molecular Characterization of a Novel Lytic Bacteriophage That Inactivates MDR Klebsiella pneumoniae Strains.

The worldwide increase in serious infections caused by multidrug-resistant (MDR) K. pneumoniae emphasizes the urgent need of new therapeutic strategies for the control of this pathogen. There is growing interest in the use of bacteriophages (or phages) to treat K. pneumoniae infections, and newly isolated phages are needed. Here, we report the isolation and physical/biological/molecular characterization of a novel lytic phage and its efficacy in the control of MDR K. pneumoniae. The phage vB_KpnS_Uniso31, referred to hereafter as phage Kpn31, was isolated from hospital wastewater using K. pneumoniae CCCD-K001 as the host. Phage Kpn31 presents a siphovirus-like morphotype and was classified as Demerecviridae; Sugarlandvirus based on its complete genome sequence. The 113,444 bp Kpn31 genome does not encode known toxins or antimicrobial resistance genes, nor does it encode depolymerases related sequences. Phage Kpn31 showed an eclipse time of 15 min and a burst size of 9.12 PFU/host cell, allowing us to conclude it replicates well in K. pneumoniae CCCD-K001 with a latency period of 30 min. Phage Kpn31 was shown to be effective against at least six MDR K. pneumoniae clinical isolates in in vitro antibacterial activity assays. Based on its features, phage Kpn31 has potential for controlling infections caused by MDR K. pneumoniae.

Rituximab-induced hypogammaglobulinemia and infection risk in pediatric patients

Rituximab is a B-cell depleting agent used in B-cell malignancies and autoimmune diseases. A subset of adult patients may develop prolonged and symptomatic hypogammaglobulinemia following rituximab treatment. However, this phenomenon has not been well delineated in the pediatric population. This study sought to determine the prevalence, risk factors, and clinical significance of hypogammaglobulinemia following rituximab therapy in children. This was a multicenter, retrospective cohort study that extracted clinical and immunological data from pediatric patients who received rituximab. The cohort comprised 207 patients (median age, 12.0 years). Compared to baseline values, there was a significant increase in hypogammaglobulinemia post-rituximab therapy, with an increase in prevalence of hypo-IgG (28.7%-42.6%; P= .009), hypo-IgA (11.1%-20.4%; P= .02), and hypo-IgM (20.0%-62.0%; P< .0001). Additionally, low IgG levels at any time post-rituximab therapy were associated with a higher risk of serious infections (34.4% vs 18.9%; odds ratio, 2.3; 95% CI, 1.1-4.8; P= .03). Persistent IgG hypogammaglobulinemia was observed in 27 of 101 evaluable patients (26.7%). Significant risk factors for persistent IgG hypogammaglobulinemia included low IgG and IgA levels pre-rituximab therapy. Nine patients (4.3%) within the study were subsequently diagnosed with a primary immunodeficiency, 7 of which received rituximab for autoimmune cytopenias. Hypogammaglobulinemia post-rituximab treatment is frequently diagnosed within the pediatric population. Low IgG levels are associated with a significant increase in serious infections, and underlying primary immunodeficiencies are relatively common in children receiving rituximab, thus highlighting the importance of immunologic monitoring both before and after rituximab therapy.

Interventions for idiopathic steroid-resistant nephrotic syndrome in children.

Interventions for idiopathic steroid-resistant nephrotic syndrome in children.

Risk of serious infection in biological treatment of patients with rheumatoid arthritis: a systematic review and meta-analysis

Serious infections are a major concern for patients considering treatments for rheumatoid arthritis. Evidence is inconsistent as to whether biological drugs are associated with an increased risk of serious infection compared with traditional disease-modifying antirheumatic drugs (DMARDs). We did a systematic review and meta-analysis of serious infections in patients treated with biological drugs compared with those treated with traditional DMARDs. We did a systematic literature search with Medline, Embase, Cochrane Central Register of Controlled Trials, and ClinicalTrials.gov from their inception to Feb 11, 2014. Search terms included "biologics", "rheumatoid arthritis" and their synonyms. Trials were eligible for inclusion if they included any of the approved biological drugs and reported serious infections. We assessed the risk of bias with the Cochrane Risk of Bias Tool. We did a Bayesian network meta-analysis of published trials using a binomial likelihood model to assess the risk of serious infections in patients with rheumatoid arthritis who were treated with biological drugs, compared with those treated with traditional DMARDs. The odds ratio (OR) of serious infection was the primary measure of treatment effect and calculated 95% credible intervals using Markov Chain Monte Carlo methods. The systematic review identified 106 trials that reported serious infections and included patients with rheumatoid arthritis who received biological drugs. Compared with traditional DMARDs, standard-dose biological drugs (OR 1.31, 95% credible interval [CrI] 1.09-1.58) and high-dose biological drugs (1.90, 1.50-2.39) were associated with an increased risk of serious infections, although low-dose biological drugs (0.93, 0.65-1.33) were not. The risk was lower in patients who were methotrexate naive compared with traditional DMARD-experienced or anti-tumour necrosis factor biological drug-experienced patients. The absolute increase in the number of serious infections per 1000 patients treated each year ranged from six for standard-dose biological drugs to 55 for combination biological therapy, compared with traditional DMARDs. Standard-dose and high-dose biological drugs (with or without traditional DMARDs) are associated with an increase in serious infections in rheumatoid arthritis compared with traditional DMARDs, although low-dose biological drugs are not. Clinicians should discuss the balance between benefit and harm with the individual patient before starting biological treatment for rheumatoid arthritis. Rheumatology Division at the University of Alabama at Birmingham.

AB0332 Rituximab & immunoglobulin level monitoring in rheumatoid arthritis – a clinical audit

BackgroundBiological therapies such as rituximab are increasingly employed for the treatment of rheumatoid arthritis (RA). By binding to the CD20 cell surface antigen, rituximab induces apoptosis and complement-mediated lysis of...

Biologic Gout Drug Fails an FDA Panel Safety Sniff Test

Silver Spring, Md. – Safety concerns about a possible increased cancer risk have scuttled, for now, the approval of the interleukin-1 inhibitor rilonacept. A Food and Drug Administration advisory panel unanimously voting in May against recommending its approval. The FDA's Arthritis Advisory Committee voted 11 to 0 that the safety and efficacy data on rilonacept did not support approval for the prevention of gout flares during the initiation of uric acid-lowering therapy in adults with gout. Rilonacept, marketed as Arcalyst, was approved by the FDA in 2008 for the chronic treatment of familial cold autoinflammatory syndrome and Muckle-Wells syndrome (or cryopyrinassociated periodic syndromes), rare genetic disorders. Preclinical and clinical data indicate that interleukin-1 (IL-1) plays a role in triggering gout flares during the initiation of uric acid–lowering therapy, according to Regeneron Pharmaceuticals, which makes the drug. The dose for which Regeneron was seeking approval was a loading dose of 160 mg followed by a weekly dose of 80 mg for 16 weeks. Over a period of 16 weeks, treatment with the 80-mg dose was associated with a statistically significant reduction in the mean number of gout flares – the primary end point – compared with placebo. Those on the 80-mg dose had a mean of 0.29–0.35 gout flares per patient, compared with a mean of about one gout flare per patient on placebo, with no significant differences between the two rilonacept doses. In the two studies, 19% and almost 26% of those on the 80-mg dose had at least one gout flare, compared with almost half of those on placebo. Several panelists raised the issue of whether it was worth exposing patients to a biologic therapy when they had a 50% chance of not having a flare. In a pooled database of the two pivotal studies and two other gout studies comparing the effectiveness of the 160-mg dose of rilonacept in about 1,000 patients to placebo in almost 400 patients, no significant increase in serious infections was observed in patients treated for 16 weeks. However, six malignancies were diagnosed during treatment with rilonacept, compared with none among those on placebo. FDA reviewers noted that while this number was low and the types of malignancies were not unusual for the typical gout patient, the lack of any malignancies among those on placebo and the biologic plausibility for an increased malignancy risk with a biologic immunosuppressant was a concern and suggested it would be useful to have data on a period longer than 16 weeks. Although most panelists agreed there was evidence that the treatment was effective in reducing gout flares, they said the effect was modest, and that they would be reluctant to use it as a first-line treatment. They said that it would be useful for patients who are intolerant or refractory to NSAIDs and/or colchicine, but added that these types of patients comprised only a small group of patients in the pivotal trial, and that 16 weeks was not long enough to evaluate safety because it was likely that the treatment would be used for longer periods of time. Several panel members questioned why the company did not compare rilonacept to an active control, such as colchicine, which is one of the main drugs used to prevent gout flares during the initiation of uric acid–lowering therapy. The FDA usually follows the recommendations of its advisory panels. The panelists have been cleared of potential conflicts of interest related to the topic of the meeting. Occasionally, a panelist may be given a waiver but not at this meeting.

Initiation of Tumor Necrosis Factor-α Antagonists and the Risk of Hospitalization for Infection in Patients With Autoimmune Diseases

Although tumor necrosis factor (TNF)-α antagonists are increasingly used in place of nonbiologic comparator medications, their safety profile remains incomplete. To determine whether initiation of TNF-α antagonists compared with nonbiologic comparators is associated with an increased risk of serious infections requiring hospitalization. Within a US multi-institutional collaboration, we assembled retrospective cohorts (1998-2007) of patients with rheumatoid arthritis (RA), inflammatory bowel disease (IBD), and psoriasis, psoriatic arthritis, or ankylosing spondylitis (psoriasis and spondyloarthropathies) combining data from Kaiser Permanente Northern California, New Jersey and Pennsylvania Pharmaceutical Assistance programs, Tennessee Medicaid, and national Medicaid/Medicare. TNF-α antagonists and nonbiologic regimens were compared in disease-specific propensity score (PS)-matched cohorts using Cox regression models with nonbiologics as the reference. Baseline glucocorticoid use was evaluated as a separate covariate. Infections requiring hospitalization (serious infections) during the first 12 months after initiation of TNF-α antagonists or nonbiologic regimens. Study cohorts included 10,484 RA, 2323 IBD, and 3215 psoriasis and spondyloarthropathies matched pairs using TNF-α antagonists and comparator medications. Overall, we identified 1172 serious infections, most of which (53%) were pneumonia and skin and soft tissue infections. Among patients with RA, serious infection hospitalization rates were 8.16 (TNF-α antagonists) and 7.78 (comparator regimens) per 100 person-years (adjusted hazard ratio [aHR], 1.05 [95% CI, 0.91-1.21]). Among patients with IBD, rates were 10.91 (TNF-α antagonists) and 9.60 (comparator) per 100 person-years (aHR, 1.10 [95% CI, 0.83-1.46]). Among patients with psoriasis and spondyloarthropathies, rates were 5.41 (TNF-α antagonists) and 5.37 (comparator) per 100 person-years (aHR, 1.05 [95% CI, 0.76-1.45]). Among patients with RA, infliximab was associated with a significant increase in serious infections compared with etanercept (aHR, 1.26 [95% CI, 1.07-1.47]) and adalimumab (aHR, 1.23 [95% CI, 1.02-1.48]). Baseline glucocorticoid use was associated with a dose-dependent increase in infections. Among patients with autoimmune diseases, compared with treatment with nonbiologic regimens, initiation of TNF-α antagonists was not associated with an increased risk of hospitalizations for serious infections.

Initiation of rheumatoid arthritis treatments and the risk of serious infections

In clinical trials of RA patients on traditional DMARDs, the addition of TNF-alpha antagonists increased infections compared with addition of placebo. Our objective was to compare serious infections following initiation of different RA regimens. Prior comparative studies of DMARD initiation have yielded conflicting results. We estimated hospitalization rates for infections following initiation of TNF-alpha antagonists, other DMARDs and oral glucocorticoids in Tennessee Medicaid-enrolled RA patients (1995-2005). Exposure time was measured using pharmacy information and infections were identified using validated definitions. Initiation of RA regimens was compared using Cox regression models with MTX as the reference. Sensitivity analyses excluded glucocorticoid users, applied a first exposure carried forward approach, restricted observations to 2002-05 and first episodes of use and explored effects of unmeasured confounders. We identified 28 906 new episodes of medication use, including TNF-alpha antagonists (8%), MTX alone (15%) and glucocorticoids alone (57%). Compared with MTX initiation, TNF-alpha antagonist initiation did not significantly increase the risk of hospitalizations for pneumonia [adjusted hazard ratio (aHR) 1.61; 95% CI 0.85, 3.03] or any infection (aHR 1.31; 95% CI 0.78, 2.19). Initiation of LEF, SSZ or HCQ did not increase serious infections, compared with MTX. Both initiation and concurrent glucocorticoid use were associated with a dose-dependent increase in serious infections. Sensitivity analyses showed consistent results. Compared with initiation of MTX alone, initiation of TNF-alpha antagonists was not associated with a large increase in the risk of serious infections. Glucocorticoid use was associated with a dose-dependent increase in the risk of these infections.

Serious infections in patients with ankylosing spondylitis with and without TNF blockers: a systematic review and meta-analysis of randomised placebo-controlled trials

BackgroundTumour necrosis factor (TNF) blockers are known to increase the risk of serious infections in rheumatoid arthritis. Despite wide use of TNF blockers in ankylosing spondylitis (AS), the infection risk...

Bcl-2 Antisense (oblimersen sodium) Plus Dacarbazine in Patients With Advanced Melanoma: The Oblimersen Melanoma Study Group

Chemotherapy resistance in melanoma has been linked to antiapoptotic effects mediated by Bcl-2 protein. We evaluated whether targeting Bcl-2 using an antisense oligonucleotide (oblimersen sodium) could improve the efficacy of systemic chemotherapy in patients with advanced melanoma. We randomly assigned chemotherapy-naïve patients with advanced melanoma to treatment with dacarbazine (1,000 mg/m2) alone or preceded by a 5-day continuous intravenous infusion of oblimersen sodium (7 mg/kg/d) every 3 weeks for up to eight cycles. Patients were stratified by Eastern Cooperative Oncology Group performance status, liver metastases, disease site, and serum lactate dehydrogenase (LDH). The primary efficacy end point was overall survival. Among 771 patients randomly assigned, the addition of oblimersen to dacarbazine yielded a trend toward improved survival at 24-month minimum follow-up (median, 9.0 v 7.8 months; P = .077) and significant increases in progression-free survival (median, 2.6 v 1.6 months; P < .001), overall response (13.5% v 7.5%; P = .007), complete response (2.8% v 0.8%), and durable response (7.3% v 3.6%; P = .03). A significant interaction between baseline serum LDH and treatment was observed; oblimersen significantly increased survival in patients whose baseline serum LDH was not elevated (median overall survival, 11.4 v 9.7 months; P = .02). Neutropenia and thrombocytopenia were increased in the oblimersen-dacarbazine group; however, there was no increase in serious infections or bleeding events. The addition of oblimersen to dacarbazine significantly improved multiple clinical outcomes in patients with advanced melanoma and increased overall survival in patients without an elevated baseline serum LDH.

Economic analysis of unrelated allogeneic bone marrow transplantation: results from the randomized clinical trial of T-cell depletion vs unmanipulated grafts for the prevention of graft-versus-host disease

Unrelated-donor marrow transplantation is a potential option for transplant candidates lacking a compatible related donor. The T-cell Depletion Study compared the 3-year disease-free survival for patients receiving T-cell-depleted (TCD) donor marrow (n = 203) vs unmanipulated donor marrow with methotrexate and cyclosporine (M/C) (n = 207). Hospital costs during index admission were documented with billing data, while hospital costs during subsequent 6-month follow-up were estimated from case report forms. Patients with index admission billing were included in the analysis (TCD = 119, M/C = 127). Total hospital length of stay (LOS) was similar across groups, with medians 47.0 days for TCD and 52.0 days for M/C (P = 0.72). Total hospital costs were comparable, 145,115 dollars vs 141,981 dollars (P = 0.63) for TCD and M/C, respectively. However, controlling for site and patient characteristics, TCD was associated with a 12.1% reduction in LOS for the index admission (95% CI -19.4%, -4.3%). Independent of treatment, HLA matching (6/6) was associated with an 8.6% (95% CI -17.4%, +1.2%) reduction in the index admission LOS, while cost was lower by 15.8% (95% CI -26.7%, -3.3%). Treatment costs were similar for TCD and M/C study groups. Savings on reduced cost for treating acute graft-versus-host disease were likely offset by increase in serious infections in the TCD arm.

Health effects of kava use in an eastern Arnhem Land Aboriginal community.

Heavy kava use in Aboriginal communities has been linked to various health effects, including anecdotes of sudden cardiac deaths. To examine associations between kava use and potential health effects. A cross-sectional study was carried out within a kava-using east Arnhem Land Aboriginal community in tropical northern Australia. One-hundred-and-one adults who were current, recent or non-users of kava were enrolled in March 2000. Main outcome measures were physical, anthropometric, biochemical, haematological, immunological and neurocognitive assessments. Kava users more frequently showed a characteristic dermopathy (P<0.001). They had increased levels of gamma-glutamyl transferase and alkaline phosphatase (P<0.001). Lymphocyte counts were significantly lower in kava users (P<0.001). Fibrinogen, plasminogen activator inhibitor-1 and neurocognitive tests were not different between kava use categories. IgE and IgG antibodies were elevated across the whole group, as were C-reactive protein and homocysteine. Kava use was associated with dermopathy, liver function abnormalities and decreased lymphocytes. If kava continues to be used by Aboriginal populations, monitoring should focus on the health consequences of these findings, including a possible increase in serious infections. The interaction between kava, alcohol and other substances requires further study. Although markers of cardiovascular risk are increased across the population, these were not higher in kava users, and this increase may be linked to the large infectious pathogen burden reflective of the socioeconomic disadvantage seen in many remote Aboriginal communities.

New treatment possibilities in rheumatoid arthritis: REVIEW

It is very difficult to predict future treatment modalities especially in diseases like rheumatoid arthritis (RA) with unknown etiology and pathogenesis. In the near future, traditional disease-modifying antirheumatic drugs (DMARD) alone, in combination with each other, or together with cyclosporine, FK506, Rapamycin, or Leflunomide, will probably be the main treatment for RA. Currently biological anti-TNFalpha agents like humanized MAb and recombinant TNF-receptor constructs are now launched in the market. This therapy alone, or in combination with methotrexate is very effective in RA patients. There are, however, concerns over increase in serious infections. Autologous stem cell transplantation will probably be used in certain patient with serious autoimmune diseases.

Upper respiratory tract infections in family practice.

The causative pathogens in the majority of mild to moderate upper respiratory tract infections are Streptococcus pneumoniae, Haemophilus influenzae and Moraxella catarrhalis. Bacterial infections of the respiratory tract are often treated empirically; however, the recent increase in serious infections caused by S. pneumoniae and rising antimicrobial resistance rates have prompted experts to reevaluate the therapeutic approaches to treatment of these infections. Although amoxicillin continues to be considered a first line therapy, some situations warrant alternative therapies. Antimicrobial therapy must provide effective coverage of the potential pathogens, yet issues of compliance must also be addressed to ensure clinical success. Ease of administration, taste and the potential for adverse events are important considerations for the pediatric population. Clinical trials support the use of alternative therapies in the treatment of patients with upper respiratory tract infections.

Patterns of H. influenzae Infection in the Post-Vaccine Era.

The Haemophilus influenzae type b (HIB) vaccine efficiently protects young children against serious type b infections, but some experts have worried that its success may be diluted by an increase in serious infections caused by other serotypes of the organism. This survey …

Severe Invasive Group A Streptococcal Infections In Ontario, Canada: 1987-1991

During the past few years, there has been an apparent increase in serious infections due to group A streptococci (GAS) worldwide. We describe our experience with severe invasive GAS infections in Ontario, Canada, during the past 5 years (February 1987 through December 1991). A case was defined as the isolation of GAS from blood or normally sterile tissue in association with hypotension (systolic blood pressure, < 90 mm Hg). Fifty cases were identified in patients ranging in age from 4 to 100 years (median age, 47 years); 29 (58%) of the patients died. A primary focus of infection was identified in 38 cases (76%), with soft tissue being the site involved most frequently (68%). No focus of infection was found in 12 patients, and 36 patients (72%) were bacteremic. Complications included acute respiratory distress syndrome (21 of 50), acute renal failure (20 of 50), hypocalcemia (19 of 24), elevated creatinine kinase values (21 of 27), coagulation abnormalities (15 of 21), and hepatitis (15 of 24). Eleven cases (22%) were nosocomial; one of these was secondary to another nosocomial case. Thirty-three isolates were available for M and T typing and for determination of the presence of the genes for streptococcal pyrogenic exotoxin (SPE). The most frequent types were M1T1 (10) and M12/T12 (8). Twelve isolates possessed the speA gene, and 16 isolates had the speC gene. Only three isolates possessed both speA and speC. All isolates possessed the speB gene.

Sulphasalazine in rheumatoid arthritis: desensitising the patient with a skin rash.

Sulphasalazine has been shown to be useful in the management of rheumatoid arthritis. However, its use may be complicated by a skin rash. Eight patients with a rash have undergone desensitisation, the aim of which was to achieve a daily dose of 2 g sulphasalazine. This was successful in five patients, partially successful in two, and failed in one patient. Desensitisation to sulphasalazine is a simple outpatient procedure, which subsequently allows the majority of patients developing a skin rash to continue treatment.

1 Polypeptide Antibiotics of Medicinal Interest

Publisher Summary This chapter discusses that since the discovery of tyrothricin—the first peptide antibiotic isolated—more than a hundred antibiotic substances containing one or more amino acids or moieties derived from amino acids have been described. However, despite considerable efforts, the structures of relatively few peptide antibiotics have been determined and ultimately proved by synthesis. There are several reasons for this. First, many of these antibiotics, after their discovery, characterization, and evaluation, were not of sufficient practical importance and work on them was discontinued. Second, they have relatively complicated structures. Unlike the peptide hormones, which are composed of a limited number of natural amino acids found in proteins, many peptide antibiotics contain a large variety of components other than amino acids. Besides the frequently occurring amino acids not isolated from proteins many other components, such as hydroxy acids, amino sugars, fatty acids, and pyrimidine derivatives are also present. They also often contain unusual peptide linkages, unknown in proteins. Furthermore, most of the peptide antibiotics are of cyclic nature and for this reason are resistant to enzymatic attack, which makes their structural elucidation in many instances more complicated. A third reason for this lack of knowledge may be the present limited therapeutic importance of the peptide antibiotics, mainly as a result of their narrow antimicrobial spectrum and their relatively high toxicity. However, the recent increase in serious infections caused by gram-negative bacteria and their growing resistance to the broad spectrum antibiotics has shifted focus to some of the peptide antibiotics, which are the most active inhibitors of these organisms.