Treatment options for multidrug-resistant Gram-negatives in urinary tract infections.

PURPOSE OF REVIEW: Infections due to multidrug-resistant (MDR) Gram-negative bacteria are challenging to treat because of limited treatment options and potential side effects of less frequently used anti-infectives. In the past few years, several new antimicrobial agents effective against MDR Gram-negatives have become available. This review focuses on the treatment options for complicated urinary tract infections (cUTIs) caused by MDR Gram-negatives. RECENT FINDINGS: The novel combinations, betalactam or carbapenem and betalactamase inhibitor, ceftazidime/avibactam and meropenem/vaborbactam, are effective for infections caused by KPC-carbapenemase-producing pathogens. Imipenem/relebactam, another carbapenem/betalactamase inhibitor combination, has been approved for the treatment of cUTI. However, data on the efficacy of imipenem/relebactam against carbapenem-resistant pathogens is still limited. Ceftolozane/tazobactam is mainly used for the treatment of MDR Pseudomonas aeruginosa infections. For the treatment of cUTI caused by extended-spectrum betalactamases producing Enterobacterales aminoglycosides or intravenous fosfomycin should be considered. SUMMARY: To ensure prudent use and to avoid the development of resistance to novel anti-infective substances, an interdisciplinary approach, including urologists, microbiologists, and infectious disease physicians, is strongly advised.

Clinical and microbiological profile of infections during induction phase of acute myeloid leukemia.

BACKGROUND: The primary objective of this study is to describe clinical and microbiological profile of infections during induction phase of acute myeloid leukemia (AML). PATIENTS AND METHODS: We reviewed the case records of 50 hospitalized patients with AML undergoing standard dose induction chemotherapy from January to December 2015. RESULTS: Out of 50 cases, 34 were males 16 females with median age of 30 years. Most common presenting symptoms were fever followed by bleeding diathesis. The clinical sites of infections were gastrointestinal tract including oral cavity (48%), respiratory tract (4%), skin/soft tissue (4%) and genitourinary tract (4%). Clinically (58%) or microbiologically (30%) documented infections were 88%, while 12% had fever without identifiable source. Overall, in 21 episodes microorganisms were isolated. Common sites of isolates were blood stream (11), stool (8), sputum (1) and urine (1). Gram negative infections accounted for 81% of total isolates; Escherichia coli (E. coli) being the commonest. Gram positive microorganisms were isolated in 19% of which methicillin resistant staphylococcus aureus (MRSA) was the most common. Gram negative bacterial infections were associated with higher mortality. CONCLUSION: Gastrointestinal tract is the most common clinical site of infection. Blood stream infection is the most common site for positive bacterial isolates. Gramnegative bacilli were the predominant cause of infections with E. coli being the most common pathogen isolated. Empiric antibiotic treatment for febrile neutropenia should be tailored to the locally prevalent pathogens and their susceptibility patterns.

Patterns of infectious complications in acute myeloid leukemia and myelodysplastic syndromes patients treated with 10-day decitabine regimen.

Decitabine has been explored as a reduced-intensity therapy for older or unfit patients with acute myeloid leukemia (AML). To better understand the risk of infections during decitabine treatment, we retrospectively examined the culture results from each infection-related serious adverse event that occurred among 85 AML and myelodysplastic syndromes (MDS) patients treated in a prospective clinical study using 10-day cycles of decitabine at Washington University School of Medicine. Culture results were available for 163 infection-related complications that occurred in 70 patients: 90 (55.2%) events were culture-negative, 32 (19.6%) were gram-positive bacteria, 20 (12.3%) were gram-negative bacteria, 12 (7.4%) were mixed, 6 (3.7%) were viral, 2 (1.2%) were fungal, and 1 (0.6%) was mycobacterial. Infection-related mortality occurred in 3/24 (13%) of gram-negative events, and 0/51 gram-positive events. On average, nearly one third of patients experienced an infection-related complication with each cycle, and the incidence did not decrease during later cycles. In summary, in patients receiving 10-day decitabine, infectious complications are common and may occur during any cycle of therapy. Although febrile events are commonly culture-negative, gram-positive infections are the most frequent source of culture-positive infections, but gram-negative infections represent a significant risk of mortality in AML and MDS patients treated with decitabine.

Association of Cumulative Steroid Dose with Risk of Infection after Treatment for Severe Acute Graft-versus-Host Disease.

This study aimed to characterize the incidence and risk factors of invasive fungal disease, cytomegalovirus infection, other viral diseases, and gram-negative rod infection after glucocorticoid treatment for severe acute graft-versus-host disease (GVHD) after allogeneic hematopoietic cell transplantation and to elucidate the associations of cumulative steroid dose with the risks of individual infections. The study cohort included 91 consecutive patients who developed maximum grades III and IV acute GVHD at our center. The mean cumulative prednisolone-equivalent dose was 41 mg/kg during the first 4 weeks. The cumulative incidence rates of fungal disease, cytomegalovirus disease, other viral diseases, and gram-negative rod infection at 6 months after glucocorticoid treatment were remarkably high, at 14%, 21%, 28%, and 20%, respectively. GVHD within 26 days after transplantation and low lymphocyte count at GVHD treatment were associated with increased risks of several infections. Cumulative prednisolone-equivalent steroid doses ≥ 55 mg/kg during the first 4 weeks were associated with an increased risk of fungal disease (hazard ratio, 3.65; P = .03) and cumulative doses ≥ 23 mg/kg were associated with an increased risk of non-cytomegalovirus viral diseases (hazard ratio, 4.14; P = .02). Strategies to reduce the risk of infectious complications are needed, particularly for patients who have risk factors and those who receive high cumulative steroid doses.

Prior laparotomy or corticosterone potentiates lipopolysaccharide-induced fever and sickness behaviors.

Stimulating sensitized immune cells with a subsequent immune challenge results in potentiated pro-inflammatory responses translating into exacerbated sickness responses (i.e. fever, pain and lethargy). Both corticosterone (CORT) and laparotomy cause sensitization, leading to enhanced sickness-induced neuroinflammation or pain (respectively). However, it is unknown whether this sensitization affects all sickness behaviors and immune cell responses equally. We show that prior CORT and prior laparotomy potentiated LPS-induced fever but not lethargy. Prior CORT, like prior laparotomy, was able to potentiate sickness-induced pain. Release of nitric oxide (NO) from peritoneal macrophages stimulated ex vivo demonstrates that laparotomy, but not CORT sensitizes these cells.

Is linezolid a risk factor for Gram-negative bacillus infections in intensive care unit patients? A comparative study with vancomycin.

BACKGROUND: Linezolid is frequently used in critically ill patients with ventilator-associated pneumonia. Its potent activity against Gram-positive microorganisms and its high tissue penetration may favour Gram-negative colonization and infection. The aim of our study was to evaluate the risk for Gram-negative infections in critically ill patients treated with linezolid or vancomycin. METHODS: The cases of all patients admitted over an 18-month period to a hepatic intensive care unit for ≥ 1 week, and treated with linezolid or vancomycin, were retrospectively reviewed. The main clinical characteristics and infections due to Gram-negative bacteria in the month after starting linezolid or vancomycin were obtained. RESULTS: Seventy-one patients treated with linezolid and 68 treated with vancomycin fulfilled the inclusion criteria. Co-morbidities were similar in both groups. Patients on linezolid treatment had a longer stay in the ICU (mean ± standard deviation 41 ± 38 days vs 18.4 ± 13 days), received this treatment later (14.3 ± 15.1 days vs 6.3 ± 6.5 days), had a higher mean serum creatinine concentration (1.71 ± 1.18 mg/dl vs 1.04 ± 1.04 mg/dl), more often required haemodiafiltration (29.6% vs 13.2%), and 30 day-mortality was higher (42.3% vs 20.6%) than in patients receiving vancomycin. More than 95% in both groups received a broad-spectrum beta-lactam in addition to linezolid or vancomycin. The rate of Gram-negative infection during the following month was 28.2% in the linezolid group and 26.5% in the vancomycin group (p > 0.5). CONCLUSIONS: Linezolid was more frequently used in critically ill patients with longer ICU stay and renal failure. The rate of infection due to Gram-negative microorganisms was similar in patients who received linezolid or vancomycin.

Lipopolysaccharide induces alterations in ovaries and serum level of progesterone and 17ß-estradiol in the mouse.

Our objective was to investigate the effect of gram-negative bacterial infection on the ovaries and serum level of P(4) and 17ß-E(2) during the preimplantation days of pregnancy in the mouse. We found that lipopolysaccharide alters the serum level of P(4) and E(2) during the preimplantation days of pregnancy and elevates the E(2)/P(4) ratio, which may keep the uterus nonreceptive during the preimplantation days of pregnancy and also not prepare the developing blastocysts for implantation in the mouse. A large infiltration of macrophages in the corpora lutea and appearance of graafian follicles from day 3.5 of pregnancy because of lipopolysaccharide treatment, which reflect a gram-negative bacterial infection, may be responsible for ovarian dysfunction and altered P(4) and E(2) level in serum.

Microbiological analysis of epidermal growth factor receptor inhibitor therapy-associated paronychia.

BACKGROUND: Paronychia is a well-known, but difficult to treat cutaneous toxicity associated with epidermal growth factor receptor (EGFR) inhibitor therapy. Although bacterial and fungal infections as well as mechanical trauma may play a role as co-pathogens, there is no good basis for an empirical antimicrobial chemotherapy in these patients. MATERIALS AND METHODS: We retrospectively analysed the microbiological results and resistance analysis of 42 cases of EGFR inhibitor-associated paronychia induced by cetuximab. RESULTS: We identified 20 different species, among these 72% Gram-positive bacteria, 23% Gram-negative bacteria and 5%Candida species. About half of the microbes identified may be considered as residential bacterial flora of the skin, but isolation of microbes from paronychia may indicate a pathogenic relevance for this type of reaction. Eight of our patients were treated with oral antibiotics, whereas two patients received oral antimycotic therapy. All other cases of paronychia were controlled using topical antiseptic, antibiotic and antimycotic agents. CONCLUSION: Empirical oral antibiotic treatment may be performed with oral cephalosporines, ciprofloxacin, levofloxacin or moxifloxacin, as these antimicrobials have high in vitro activity against the majority of the isolated microorganisms and reach high concentrations in the relevant tissue.

Effects of chelators (deferoxamine, deferiprone and deferasirox) on the growth of Klebsiella pneumoniae and Aeromonas hydrophila isolated from transfusion-dependent thalassemia patients.

Infections are among the leading causes of death for thalassemia major patients. The known predisposing factors of infection include prior splenectomy, iron overload and use of iron chelator such as deferoxamine (DFO). While encapsulated organisms frequently found in splenectomized patients were readily controlled by prophylactic vaccination and vigilant antibiotic treatment, ferrophilic organisms such as Yersinia and Klebsiella remain common pathogens in thalassemic patients. Yersinia infections are more prevalent in temperate regions and Klebsiella infections are commonly found in tropical and subtropical areas. While the use of DFO further aggravates the risk of Yersinia infection, oral chelators such as deferiprone (L1) do not enhance the growth of Yersinia in vitro or in vivo. We found that the growth of Klebsiella was marginally enhanced by DFO in vitro when compared to Yersinia. Such an unfavorable effect was not found in either L1 or deferasirox (DFRA) in vitro. The growth of Aeromonas was not affected by the presence of all three forms of chelators. Therefore, we suggest that factors other than DFO may account for the increased prevalence of Klebsiella and Aeromonas infection in Asian thalassemic patients.

Incidence of bacterial and fungal infections in newly diagnosed acute myeloid leukaemia patients younger than 65 yr treated with induction regimens including fludarabine: retrospective analysis of 224 cases.

OBJECTIVES: Infections are the major cause of morbidity and mortality in patients with acute myeloid leukaemia (AML). They primarily occur during the first course of induction chemotherapy and may increase the risk of leukaemia relapse, due to a significant delay in consolidation therapy. The intensification of induction chemotherapy and the use of non-conventional drugs such as fludarabine are considered responsible for the increased risk of infections. METHODS: In this study, we retrospectively analysed the infections occurred in 224 newly diagnosed AML patients

[Amiodarone-induced thyrotoxicosis: a diagnostic and therapeutic challenge]. / Amiodaron-induzierte Thyreotoxikose: Eine diagnostische und therapeu- tische Herausforderung.

Amiodaron is a widely used antiarrhytmic drug in a number of cardiac conditions. The most common side effects affect the thyroid gland (14-18% of treated patients) resulting in hypothyroidism or hyperthyroidism. We describe a complex case of amiodaron-induced thyrotoxicosis (AIT) and discuss the pathogenesis of the different subtypes (AIT I, II and mixed forms) and the diagnostic and therapeutic challenges in such patients.

Unexpected hospital-acquired bacteraemia in patients at low risk of bloodstream infection: the role of a heparin drip.

Following a cluster of cases of unexpected hospital-acquired bacteraemia suspected to be related to an intravenous (iv) heparin drip, all cases of hospital-acquired primary bloodstream infection (BSI) in patients at low risk of bacteraemia were analysed over a four-year period. Ninety-six bacteraemic patients (6%) from 1618 episodes of hospital-acquired bacteraemia had a peripheral iv line as the only risk factor. These patients were divided into two groups: 60 patients with phlebitis and 36 without local signs of inflammation. Baseline features of the two groups were comparable, but in univariate and multivariate analysis, a significant association was found between iv heparin use, predominance of Gram-negative organisms (especially Klebsiella, Serratia and Enterobacter species), and absence of phlebitis. In spite of clear statistical association, however, the means by which the heparin solution became contaminated with Gram-negative organisms remained unknown. Following implementation of infection control methods concerning heparin handling, no more cases occurred. Unexpected hospital-acquired Gram-negative bacteraemia in patients with peripheral iv lines should prompt investigation of potential infusate-related infection, especially in patients without phlebitis and those receiving iv heparin.

Clinical implications of antibiotic-induced endotoxin release in septic shock.

Antibiotic-induced release of bacterial cell wall components can have immediate adverse effects for the patient. This article reviews the data on endotoxin release after initiation of antibiotic therapy and its role in the pathogenesis of sepsis and septic shock. Antibiotics differ in their potential to liberate endotoxins from bacterial cell walls. When used for treatment of systemic Gram-negative infection, some classes of beta-lactam antibiotics lead to markedly increased levels of free endotoxins while treatment with carbapenems and aminoglycosides produces relatively low amounts of endotoxins. Antibiotics that induce the formation of long, aberrant bacterial cells before effectively killing the microorganisms show the highest degree of endotoxin liberation. There is increasing evidence from animal models and clinical studies of sepsis that the antibiotic-mediated release of biologically active cell wall components derived from Gram-positive, Gram-negative or fungal organisms is associated with a rapid clinical deterioration.

Waterhouse-Friderichsen syndrome secondary to Capnocytophaga canimorsus septicemia and demonstration of bacteremia by peripheral blood smear.

Waterhouse-Friderichsen syndrome caused by Capnocytophaga canimorsus septicemia was fatal in a previously healthy 47-year-old woman. The patient died suddenly in less than 12 hours after presentation, in spite of supportive measures, including ventilation, antibiotic coverage, pressor therapy, and multiple transfusions of blood products. The diagnosis of infection due to an unusual organism was suspected earlier in the course of management after review of the peripheral blood smear. The importance of the findings in the blood smear and their correlation with infection due to this organism are discussed.

Substituting dexamethasone for prednisone complicates remission induction in children with acute lymphoblastic leukemia.

BACKGROUND: The authors report the occurrence of fatal or near-fatal sepsis in 16 of 38 children with newly diagnosed acute lymphoblastic leukemia (ALL) treated with a new induction regimen that differed from its predecessor by the substitution of dexamethasone for prednisone. METHODS: The frequency of septic deaths among 38 children who received multiagent remission induction therapy, including dexamethasone (6 mg/m(2)) daily for 28 days (pilot protocol 91-01P), was compared with the frequency of septic deaths among children previously treated (protocol 87-01) and subsequently treated (protocol 91-01) in consecutive Dana-Farber Cancer Institute (DFCI) ALL trials with induction therapy that included 21 and 28 days of prednisone (40 mg/m(2)), respectively. Except for dexamethasone in protocol 91-01P, the remission induction agents used were identical in substance to those used in protocol 87-01. Protocol 91-01, the successor 91-01P, was also similar, with the exception of the deletion of a single dose of L-asparaginase. RESULTS: Sixteen of the 38 children (42%) treated on the DFCI 91-01P had documented gram positive or gram negative sepsis (17 episodes) during remission induction, including 4 toxic deaths (11%). In contrast, there were 4 induction deaths among 369 children (1%) treated on protocol 87-01 (P = 0.0035) and 1 induction death among 377 children (<1%) treated on protocol 91-01 (P = 0.0003). CONCLUSIONS: Substitution of dexamethasone for prednisone or methylprednisolone in an otherwise intensive conventional induction regimen for previously untreated children with ALL resulted in an alarmingly high incidence of septic episodes and toxic deaths. Awareness of this complication, considering that the substitution has no apparent benefit in the efficacy of remission induction, argues against its routine use in intensive induction regimens for children with ALL.