Transient neonatal antibiotic exposure increases susceptibility to late-onset sepsis driven by microbiota-dependent suppression of type 3 innate lymphoid cells.

Extended early antibiotic exposure in the neonatal intensive care unit is associated with an increased risk for the development of late-onset sepsis (LOS). However, few studies have examined the mechanisms involved. We sought to determine how the neonatal microbiome and intestinal immune response is altered by transient early empiric antibiotic exposure at birth. Neonatal mice were transiently exposed to broad-spectrum antibiotics from birth for either 3- (SE) or 7-days (LE) and were examined at 14-days-old. We found that mice exposed to either SE or LE showed persistent expansion of Proteobacteria (2 log difference, P < 0.01). Further, LE mice demonstrated baseline translocation of E. coli into the liver and spleen and were more susceptible K. pneumoniae-induced sepsis. LE mice had a significant and persistent decrease in type 3 innate lymphoid cells (ILC3) in the lamina propria. Reconstitution of the microbiome with mature microbiota by gavage in LE mice following antibiotic exposure resulted in an increase in ILC3 and partial rescue from LOS. We conclude that prolonged exposure to broad spectrum antibiotics in the neonatal period is associated with persistent alteration of the microbiome and innate immune response resulting in increased susceptibility to infection that may be partially rescued by microbiome reconstitution.

Oestrogen promotes healing in a bacterial LPS model of delayed cutaneous wound repair.

Wound infection is a major clinical problem, yet understanding of bacterial host interactions in the skin remains limited. Microbe-derived molecules, known as pathogen-associated molecular patterns, are recognised in barrier tissues by pattern-recognition receptors. In particular, the pathogen-associated molecular pattern, lipopolysaccharide (LPS), a component of microbial cell walls and a specific ligand for Toll-like receptor 4, has been widely used to mimic systemic and local infection across a range of tissues. Here we administered LPS derived from Klebsiella pneumoniae, a species of bacteria that is emerging as a wound-associated pathogen, to full-thickness cutaneous wounds in C57/BL6 mice. Early in healing, LPS-treated wounds displayed increased local apoptosis and reduced proliferation. Subsequent healing progression was delayed with reduced re-epithelialisation, increased proliferation, a heightened inflammatory response and perturbed wound matrix deposition. Our group and others have previously demonstrated the beneficial effects of 17ß-estradiol treatment across a range of preclinical wound models. Here we asked whether oestrogen would effectively promote healing in our LPS bacterial infection model. Intriguingly, co-treatment with 17ß-estradiol was able to promote re-epithelialisation, dampen inflammation and induce collagen deposition in our LPS-delayed healing model. Collectively, these studies validate K. pneumoniae-derived LPS treatment as a simple yet effective model of bacterial wound infection, while providing the first indication that oestrogen could promote cutaneous healing in the presence of infection, further strengthening the case for its therapeutic use.

Ampicillin and amoxicillin use and the risk of Klebsiella pneumoniae liver abscess in Taiwan.

BACKGROUND: Klebsiella pneumoniae liver abscess (KPLA) is prevalent in East Asia. Use of amoxicillin/ampicillin may lead to overgrowth of K. pneumoniae in the intestine and predispose to KPLA. We used an animal study and nationwide population-based database to investigate the association between ampicillin/amoxicillin use and KPLA in Taiwan. METHODS: In an animal study, ampicillin or sterile water was administered orogastrically in serotype K1 K. pneumoniae-colonized mice and the outcome was compared. We identified 855 cases with liver abscess and selected 3420 age- and sex-matched control subjects from the National Health Insurance Research Database. Conditional logistic regression was used to estimate the adjusted odds ratios (ORs) for the association between recent use of ampicillin/amoxicillin and KPLA. RESULTS: Ampicillin administration predisposed K. pneumoniae-colonized mice to increased bacterial burden, liver abscess and necrosis, and lethality. The population-based study showed that the adjusted OR associating the use of ampicillin/amoxicillin within the past 30 days with KPLA was 3.5 (95% confidence interval, 2.5-5.1). No association was found with use in the past 31-90 days. CONCLUSIONS: Ampicillin/amoxicillin therapy started within the past 30 days was associated with increased risk for KPLA. We should avoid the overuse of these antibiotics to prevent undesired disease in the endemic area.

Effects of copper nanoparticle exposure on host defense in a murine pulmonary infection model.

BACKGROUND: Human exposure to nanoparticles (NPs) and environmental bacteria can occur simultaneously. NPs induce inflammatory responses and oxidative stress but may also have immune-suppressive effects, impairing macrophage function and altering epithelial barrier functions. The purpose of this study was to assess the potential pulmonary effects of inhalation and instillation exposure to copper (Cu) NPs using a model of lung inflammation and host defense. METHODS: We used Klebsiella pneumoniae (K.p.) in a murine lung infection model to determine if pulmonary bacterial clearance is enhanced or impaired by Cu NP exposure. Two different exposure modes were tested: sub-acute inhalation (4 hr/day, 5 d/week for 2 weeks, 3.5 mg/m(3)) and intratracheal instillation (24 hr post-exposure, 3, 35, and 100 µg/mouse). Pulmonary responses were evaluated by lung histopathology plus measurement of differential cell counts, total protein, lactate dehydrogenase (LDH) activity, and inflammatory cytokines in bronchoalveolar lavage (BAL) fluid. RESULTS: Cu NP exposure induced inflammatory responses with increased recruitment of total cells and neutrophils to the lungs as well as increased total protein and LDH activity in BAL fluid. Both inhalation and instillation exposure to Cu NPs significantly decreased the pulmonary clearance of K.p.-exposed mice measured 24 hr after bacterial infection following Cu NP exposure versus sham-exposed mice also challenged with K.p (1.4 × 10(5) bacteria/mouse). CONCLUSIONS: Cu NP exposure impaired host defense against bacterial lung infections and induced a dose-dependent decrease in bacterial clearance in which even our lowest dose demonstrated significantly lower clearance than observed in sham-exposed mice. Thus, exposure to Cu NPs may increase the risk of pulmonary infection.

Septic shock due to Klebsiella pneumoniae after medical abortion with misoprostol-only regimen.

OBJECTIVE: To report a case of a healthy woman who was admitted to the hospital with septic shock caused by a common uropathogen after self-administration of misoprostol for pregnancy termination. DESIGN: Case report. SETTING: Tertiary hospital. PATIENT(S): A 38-year-old woman, gravida 5, para 3, who developed septic shock after medical termination of pregnancy. INTERVENTION(S): Suction curettage, antibiotic treatment, plasma and platelet transfusions. MAIN OUTCOME MEASURE(S): Klebsiella pneumoniae was isolated from blood samples. RESULT: Ten days after her admission she was discharged home in good condition on oral antibiotics. CONCLUSION(S): Severe infections leading to septic shock from common pathogen bacteria can occur after medical termination of pregnancy, independently of the regimen used.

Antibiotic-associated hemorrhagic colitis caused by cytotoxin-producing Klebsiella oxytoca.

Klebsiella oxytoca was recently described as the causative organism for antibiotic-associated hemorrhagic colitis (AAHC). It is currently not known if this novel gastrointestinal infection exists in children. AAHC is usually preceded by antibiotic treatment with penicillins, which are frequently prescribed for pediatric patients. In contrast to colitis caused by Clostridium difficile, colitis caused by K oxytoca is usually segmental and located predominantly in the right colon. Patients with AAHC typically present with abdominal pain and almost always bloody diarrhea. We present here the case of an adolescent patient who developed acute abdominal pain and bloody diarrhea after antibiotic treatment for acute urinary infection with amoxicillin-clavulanate. Right-sided colitis was verified by abdominal sonography. Stool culture tested negative for common gastrointestinal pathogens but yielded K oxytoca. Toxin production of the isolated strain was verified in a cell-culture assay. Cessation of the causative antibiotic treatment led to rapid improvement and cessation of bloody diarrhea within 3 days. We report here the first (to our knowledge) pediatric case of K oxytoca infection causing AAHC. Establishing the diagnosis of AAHC by culturing K oxytoca and demonstrating right-sided colitis with noninvasive imaging studies might prevent unnecessary invasive procedures in children with bloody diarrhea.

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.

Ablation of SP-A has a negative impact on the susceptibility of mice to Klebsiella pneumoniae infection after ozone exposure: sex differences.

BACKGROUND: Surfactant protein A (SP-A) enhances phagocytosis of bacteria, including Klebsiella pneumoniae, by alveolar macrophages. Ozone, a major air pollutant, can cause oxidation of surfactant and may influence lung immune function. Immune function may also be affected by sex-specific mechanisms. We hypothesized that ablation of SP-A has a negative impact on the susceptibility of mice to Klebsiella pneumoniae infection after ozone exposure, and that sex differences in the effect of ozone do exist. METHODS: Male and female SP-A (-/-) mice on the C57BL/6J background were exposed to ozone or to filtered air (FA) used as a control and then infected intratracheally with K. pneumoniae bacteria. Survival rate was monitored during a 14-day period. In addition, protein oxidation levels and in vivo phagocytosis were checked 1 h after inoculation of PBS used as a sham control and after inoculation of K. pneumoniae bacteria in PBS, respectively. RESULTS: We found: 1) ozone exposure followed by K. pneumoniae infection decreases survival and alveolar macrophage phagocytic function of SP-A (-/-) mice compared to filtered air exposure (p < 0.05), and females are more affected than males; 2) SP-A (-/-) mice (exposed either to ozone or FA) are more susceptible to infection with K. pneumoniae than wild type (WT) mice regarding their survival rate and macrophage phagocytic function; the phagocytic function of FA SP-A(-/-) is similar to that of ozone exposed WT. 3) ozone exposure appears to increase infiltration of PMNs, total protein, and SP-A oxidation in WT mice; infiltration of PMNs and total protein oxidation appears to be more pronounced in female mice in response to ozone; 4) ozone exposure increases SP-A oxidation in WT females significantly more than in males. CONCLUSION: Absence (i.e. ablation of SP-A in SP-A (-/-) mice) or reduction of functional activity of SP-A (i.e. oxidation of SP-A in WT mice) increases the susceptibility of mice to experimental pneumonia after ozone exposure, and in both cases females are more affected by ozone exposure than males.

Sex differences in the impact of ozone on survival and alveolar macrophage function of mice after Klebsiella pneumoniae infection.

BACKGROUND: Sex differences have been described in a number of pulmonary diseases. However, the impact of ozone exposure followed by pneumonia infection on sex-related survival and macrophage function have not been reported. The purpose of this study was to determine whether ozone exposure differentially affects: 1) survival of male and female mice infected with Klebsiella pneumoniae, and 2) the phagocytic ability of macrophages from these mice. METHODS: Male and female C57BL/6 mice were exposed to O3 or to filtered air (FA) (control) and then infected intratracheally with K. pneumoniae bacteria. Survival was monitored over a 14-day period, and the ability of alveolar macrophages to phagocytize the pathogen in vivo was investigated after 1 h. RESULTS: 1) Both male and female mice exposed to O3 are significantly more susceptible to K. pneumoniae infection than mice treated with FA; 2) although females appeared to be more resistant to K. pneumoniae than males, O3 exposure significantly increased the susceptibility of females to K. pneumoniae infection to a greater degree than males; 3) alveolar macrophages from O3-exposed male and female mice have impaired phagocytic ability compared to macrophages from FA-exposed mice; and 4) the O3-dependent reduction in phagocytic ability is greater in female mice. CONCLUSION: O3 exposure reduces the ability of mice to survive K. pneumoniae infection and the reduced phagocytic ability of alveolar macrophages may be one of the contributing factors. Both events are significantly more pronounced in female mice following exposure to the environmental pollutant, ozone.

Multiple opportunistic infections after high-dose steroid therapy for giant cell arteritis in a patient previously treated with a purine analog.

We present the case of a 74-y-old HIV-negative female who suffered simultaneously from multiple opportunistic infections and a Klebsiella pneumoniae sepsis during high-dose steroids for giant cell arteritis. The patient was treated with a purine analog due to hairy cell leukaemia 10 y previously. Purine analog therapy can lead to long lasting defects in cell-mediated immunity. In these patients, treatment with steroids should be closely monitored with CD4 counts.

[Anticancer chemotherapy, risk factor for infection at the operated site in cervicofacial surgery]. / Chimiothérapie anti-cancéreuse, facteur de risque d'infections du site opératoire en chirurgie propre cervico-faciale.

BACKGROUND: In order to evaluate occurrence and risk factors for wound infection (WI) in head and neck uncontaminated surgery, we carried out a prospective study. METHODS: From january 1997 through january 1999, we prospectively evaluated 212 wounds of all patients having uncontaminated head and neck surgery at the Oscar Lambret Cancer Center (neck dissections, parotidectomies, thyroidectomies, explorative cervicotomies, cutaneous resections). No antibiotic prophylaxis was given. WI was defined as a wound with pus. Statistical evaluation was performed using the chi 2 test. In univariate analysis, differences were considered significant p < 0.05. RESULTS: The overall WI rate was 6.6% (14/212). In univariate analysis, previous chemotherapy is the only risk factor for WI were: (p < 0.00001). Multivariate analysis was not performed. CONCLUSION: Like other cancer locations, chemotherapy was a major risk factor for WI. In these cases, a phase ill trial could confirm efficacy of standard antibiotic.

A phase I trial of a 3-day topotecan Q 21 days for recurrent epithelial cancers of the ovary, fallopian tube, and peritoneum.

OBJECTIVE: This trial was undertaken to determine the dose limiting toxicity (DLT) and maximum tolerated dose (MTD) of topotecan that can be administered for 3 days q 21 days. A 3-day schedule is more convenient and less expensive than standard 5-day dosing. METHODS: Patients with recurrent epithelial ovary, tubal, or peritoneal carcinoma were treated with escalating doses of topotecan beginning at 2.50 mg/m(2) as an outpatient days 1-3 q 21 days. Colony stimulating factors were not employed prophylactically, but could be added for grade 4 marrow toxicity. RESULTS: Twenty patients with a median age of 61 (range 46-80) and performance status of 0 or 1 were entered. All patients had received at least one prior paclitaxel/platinum regimen; 6 had received two. Ninety-one cycles were delivered (median = 6) and 98.9% were on schedule. Grade 4 neutropenia was seen in 17 of 20 patients (85%) in cycle 1 and in 38 of 91 (41.8%) total cycles. Sixteen of 20 patients (80%) started G-CSF on cycle 2. Two of 91 (2.2%) cycles had grade 4 thrombocytopenia. Four cycles (4.4%) were associated with febrile neutropenia. Two patients experienced grade 4 neurotoxicity (DLT) at 4.25 mg/m(2). Other nonhematologic toxicity was mild. CONCLUSIONS: Topotecan can be safely administered on schedule as an outpatient days 1-3 q 21 days. Neurotoxicity was the DLT when G-CSF was added; the MTD was 3.75 mg/m(2). There was minimal other nonhematologic toxicity. Neutropenia was predictable and easily managed with G-CSF. Febrile neutropenia was uncommon and thrombocytopenia was rare at the doses evaluated.

Cancrum oris (noma) in a patient with acute lymphoblastic leukaemia. A complication of chemotherapy induced neutropenia.

Cancrum oris (noma) has been most commonly described in malnourished debilitated children with poor oral hygiene following systemic childhood infections such as measles, pertussis or scarlet fever. We describe a patient who developed this condition during a period of profound neutropenia following cytotoxic chemotherapy for acute lymphoblastic leukaemia.

Cancrum oris (noma) in a patient with acute lymphoblastic leukaemia. A complication of chemotherapy induced neutropenia

Cancrum oris (noma) has been most commonly described in malnourished debilitated children with poor oral hygiene following systemic childhood infections such as measles, pertussis or scarlet fever. We describe a patient who developed this condition during a period of profound neutropenia following cytotoxic chemotherapy for acute lymphoblastic leukaemia(AU)

Cancrum oris (noma) in a patient with acute lymphoblastic leukaemia. A complication of chemotherapy induced neutropenia

Cancrum oris (noma) has been most commonly described in malnourished debilitated children with poor oral hygiene following systemic childhood infections such as measles, pertussis or scarlet fever. We describe a patient who developed this condition during a period of profound neutropenia following cytotoxic chemotherapy for acute lymphoblastic leukaemia.

Bone marrow suppression and klebsiella pneumonia septicemia due to ticlopidine and successful treatment with filgrastim; a case report.

In this report we describe an elderly lady, who after 27 days of ticlopidine treatment developed severe pancytopenia and gram (-) septicemia. No clinical response was obtained with an eight days course of empirical broad spectrum antibiotics, after which granulocyte colony stimulating factor (G-CSF, filgrastim) added to her regimen. In a period of seven days her neutrophil count was normal and she had recovered from septicemia. Twelve weeks after discharge she is fine and her blood parameters are all normal.