The outbreak of multispecies carbapenemase-producing Enterobacterales associated with pediatric ward sinks: IncM1 plasmids act as vehicles for cross-species transmission.

BACKGROUND: This study describes an outbreak caused by multispecies carbapenemase-producing Enterobacterales (CPE) occurring in a pediatric ward at an academic medical center in Tokyo. METHODS: The index case involved a 1-year-old boy with Klebsiella variicola (CPE) detected in anal swabs in June 2016. The second case was Klebsiella quasipneumoniae (CPE) occurred in March 2017 followed by further spread, leading to the declaration of an outbreak in April 2017. Extensive environmental and patient microbiological sampling was performed. The relatedness of the isolates was determined using draft-whole-genome sequencing. RESULTS: CPE surveillance cultures of patients and environments were positive in 19 patients and 9 sinks in the ward. The sinks in hospital rooms uninhabited by CPE patients exhibited no positive CPE-positive specimen during the outbreak. All CPE strains analyzed using draft-whole-genome sequencing harbored blaIMP-1, except for one harboring blaIMP-11; these strains harbored identical blaIMP-1-carrying IncM1 plasmids. CPE was detected even after sink replacement; infection-control measures focused on sinks were implemented and the CPE outbreak ended after 7 months. CONCLUSIONS: Multiple bacterial species can become CPE via blaIMP-1-carrying IncM1 plasmids of the same origin and spread through sinks in a hospital ward. Thorough infection-control measures implemented as a bundle might be crucial.

Clinical Efficacy of Therapeutic Agents for Clostridioides difficile Infection Based on Four Severity Classifications.

The Japanese guidelines for the management of Clostridioides difficile infection (CDI) recommend metronidazole (MNZ) for non-severe cases and vancomycin (VCM) for severe cases. Here, we investigated the use of CDI antimicrobials and evaluated their clinical efficacy in four severity classifications and the validity of these classifications. A retrospective chart review was conducted on 137 inpatients with an initial positive C. difficile toxin test and initiation of CDI antimicrobials between April 2015 and March 2019. For the clinical efficacy analysis of the CDI antimicrobials and validation of the severity classifications, patients treated with VCM or oral MNZ were included. The endpoints were CDI recurrence rate, 30-day mortality rate, and diarrhea cure rate. No significant differences were found between the VCM and oral MNZ groups regarding the CDI recurrence rate (10.4% vs. 12.7%, p = 0.707), 30-day mortality rate (12.5% vs. 5.6%, p = 0.162), and diarrhea cure rate (61.9% vs. 72.7%, p = 0.238), regardless of the severity. Treatment with oral MNZ for non-severe cases was promising, confirming the usefulness of treatment according to Japanese guidelines. Further investigation of the clinical efficacy of oral MNZ in patients with first-episode CDI and evaluation of the preferable severity classification are warranted.

Pseudomonas otitidis bacteremia in an immunocompromised patient with cellulitis: case report and literature review.

BACKGROUND: Pseudomonas otitidis belongs to the genus Pseudomonas and causes various infections, including ear, skin, and soft tissue infections. P. otitidis has a unique susceptibility profile, being susceptible to penicillins and cephalosporins but resistant to carbapenems, due to the production of the metallo-ß-lactamase called POM-1. This revealed genetic similarities with Pseudomonas aeruginosa, which can sometimes lead to misidentification. CASE PRESENTATION: We report the case of a 70-year-old Japanese male who developed cellulitis and bacteremia during chemotherapy for multiple myeloma. He was initially treated with meropenem, but blood culture later revealed gram-negative bacilli identified as P. otitidis using matrix-assisted laser desorption ionization-time of flight mass spectrometry (MALDI-TOF MS). Carbapenem resistance was predicted from previous reports; therefore, we switched to dual therapy with levofloxacin and cefepime, and favorable treatment results were obtained. CONCLUSION: This is the first reported case of P. otitidis cellulitis and bacteremia in an immunocompromised patient. Carbapenems are typically used in immunocompromised patients and P. otitidis is often resistant to it. However, its biochemical properties are similar to those of Pseudomonas aeruginosa; therefore, its accurate identification is critical. In the present study, we rapidly identified P. otitidis using MALDI-TOF MS and switched from carbapenems to an appropriate antimicrobial therapy, resulting in a successful outcome.

Impact of inhaled ciclesonide on asymptomatic or mild COVID-19: A randomized trial.

The aim of this study was to determine the efficacy and safety of ciclesonide in the treatment of novel coronavirus disease 2019 (COVID-19) as gauged by pneumonia progression. This multi-center, open-label randomized trial was conducted with patients recruited from 22 hospitals across Japan. Participants were patients admitted with mild or asymptomatic COVID-19 without signs of pneumonia on chest X-rays. Asymptomatic participants were diagnosed after identification through contact tracing. Trial participants were randomized to either the ciclesonide or control arm. Participants in the treatment arm were administered 400 µg of ciclesonide three times a day over seven consecutive days. The primary endpoint was exacerbated pneumonia within seven days. Secondary outcomes were changes in clinical findings, laboratory findings, and changes over time in the amount of the viral genome. In the treatment group, 16 patients (39.0%) were classified as having exacerbated pneumonia compared to 9 (18.8%) in the control group. The risk ratio (RR) was 2.08 (95% confidence interval (CI): 1.15-3.75), indicating a worsening of pneumonia in the ciclesonide group. Significant differences were noted in participants with a fever on admission (RR: 2.62, 90% CI: 1.17-5.85, 95% CI: 1.00-6.82) and individuals 60 years of age or older (RR: 8.80, 90% CI: 1.76-44.06, 95% CI: 1.29-59.99). The current results indicated that ciclesonide exacerbates signs of pneumonia on images in individuals with mild or asymptomatic symptoms of COVID-19 without worsening clinical symptoms.

Oral fidaxomicin versus vancomycin for the treatment of Clostridioides difficile infection: A systematic review and meta-analysis of randomized controlled trials.

BACKGROUND: Fidaxomicin (FDX) has received considerable attention as a novel therapeutic alternative agent to vancomycin (VCM) for Clostridioides difficile infection (CDI). However, the superiority and efficacy profile of FDX are not sufficiently determined by high-quality evidence. This study aimed to clarify the superiority of FDX for CDI treatment through a systematic review and meta-analysis. METHODS: We conducted a meta-analysis of randomized controlled trials (RCTs) which evaluated the efficacy and safety of FDX and VCM in patients with CDI. Electronic databases (PubMed, Cochrane Library, Web of Science, and Clinicaltrials.gov) were searched for studies published until October 15, 2021. The primary endpoint was global cure. The secondary endpoints were clinical cure, recurrence, and adverse event. Risk ratios (RRs), risk differences (RDs), and 95% confidence intervals were calculated using Mantel-Haenszel random-effects model. The risk of bias was assessed using Cochrane Handbook for Systematic Reviews of Interventions and Assessment Criteria. RESULTS: Six RCTs were included in this meta-analysis. Compared to VCM, FDX was associated with significantly higher global cure rates (RR = 1.18, P < 0.00001; RD = 0.11, 95% CI = 0.07-0.16). In addition, clinical cure rates were comparable between FDX and VCM (P = 0.31). FDX was associated with significantly lower recurrence rates compared to VCM (RR = 0.59, P < 0.0001). In addition, adverse event rates were not significantly different between the drugs (P = 0.41). CONCLUSION: FDX achieves significantly higher global cure rates and lower recurrence rates and is comparable to VCM in clinical cure rates and adverse event rates in patients with CDI. Collectively, FDX is superior to VCM as a therapeutic agent for CDI.

Evaluation of risk factors for uric acid elevation in COVID-19 patients treated with favipiravir.

The objective of this retrospective study was to identify the clinical risk factor associated with uric acid elevation in coronavirus disease (COVID-19) patients treated with favipiravir. Uric acid elevation was defined as an unexplained increase of ≥1.5 times in the patient's uric acid level from baseline. Twenty-nine COVID-19 patients were included in the study. Uric acid elevation developed during favipiravir therapy in 12 (41.4%) patients and the median onset time was 4.5 days after starting favipiravir. In multiple logistic regression analysis, the favipiravir dosage (adjusted OR = 1.69 [1.02-2.81], P = 0.044) and younger patient age (adjusted OR = 0.91 [0.83-0.99], P = 0.040) were significant clinical risk factors for uric acid elevation. No significant between-group difference was noted in the uric acid elevation and non-elevation groups in the clinical recovery after favipiravir therapy. The uric acid levels of patients administered with favipiravir should be monitored closely.

Early Anti-SARS-CoV-2 Immunoglobulin G Response May Be Associated with Disease Severity in Patients with COVID-19.

Most coronavirus disease 2019 (COVID-19) cases are mild or asymptomatic, and a substantial minority of patients have severe or critical diseases. There are several reports on the potential risk factors of severe disease, but few reports have reported a relationship between antibody titer and severity in Japan. Antibody-dependent enhancement affects disease progression. We evaluated the IgG responses in COVID-19 patients at our tertiary hospital. The IgG index was the measure of interest. We assigned 1.4 as the cutoff value for a positive result based on the specifications by the manufacturer and observed that patients could be categorized into two groups: the early elevation of IgG and late elevation of IgG (IgG elevated in the first 7 days ± 2 days or more than 10 days after symptom onset) groups. The former comprised early IgG responders (n = 7) and the latter comprised late IgG responders (n = 14), and they were compared. The C-reactive protein and D-dimer concentrations were significantly higher in the early IgG responders on admission (HD 0). The respiratory rate was also higher. The lymphocytes were significantly fewer on day 7 of hospitalization (HD 7). These results suggest that early production of anti-severe acute respiratory syndrome coronavirus 2 IgG may be associated with clinical indicators of severity.

Clinical validation of quantitative SARS-CoV-2 antigen assays to estimate SARS-CoV-2 viral loads in nasopharyngeal swabs.

BACKGROUND: Expansion of the testing capacity for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is an important issue to mitigate the pandemic of coronavirus disease-2019 (COVID-19) caused by this virus. Recently, a sensitive quantitative antigen test (SQT), Lumipulse® SARS-CoV-2 Ag, was developed. It is a fully automated chemiluminescent enzyme immunoassay system for SARS-CoV-2. METHODS: In this study, the analytical performance of SQT was examined using clinical specimens from nasopharyngeal swabs using reverse transcription polymerase chain reaction (RT-PCR) as a control. RESULTS: Receiver operating characteristic analysis of 24 SARS-CoV-2-positive and 524 -negative patients showed an area under the curve of 0.957 ± 0.063. Using a cut-off value of 1.34 pg/ml, the sensitivity was 91.7%, the specificity was 98.5%, and the overall rate of agreement was 98.2%. In the distribution of negative cases, the 99.5 percentile value was 1.03 pg/ml. There was a high correlation between the viral load calculated using the cycle threshold value of RT-PCR and the concentration of antigen. The tendency for the antigen concentration to decrease with time after disease onset correlated with that of the viral load. CONCLUSIONS: Presented results indicate that SQT is highly concordant with RT-PCR and should be useful for the diagnosis of COVID-19 in any clinical setting. Therefore, this fully automated kit will contribute to the expansion of the testing capability for SARS-CoV-2.

Immunochromatographic test for the detection of SARS-CoV-2 in saliva.

We evaluated the rapid immunochromatographic test for severe acute respiratory coronavirus 2 (SARS-CoV-2) antigen detection using 16 saliva specimens collected from 6 COVID-19 hospitalized patients, and detected N-antigen in 4 of 7 RT-PCR positive specimens. This POCT detected SARS-CoV-2 antigen in saliva and would be useful for COVID-19 diagnosis.

IgG Antibodies, SARS-CoV-2 Load, and Prognostic Indicators in Patients with Severe and Mild COVID-19 in Japan.

We assessed the association of severity of coronavirus disease 2019 (COVID-19) with acute respiratory syndrome coronavirus 2 (SARS-CoV-2) load, IgG antibody level, and prognostic indicators.Twenty-one patients hospitalized with COVID-19 were classified as having severe or mild disease on the basis of average respiratory rate during hospitalization (severe: ≥22 breaths/min; mild: <22 breaths/min). Viral load in nasopharyngeal samples, blood levels of C-reactive protein (CRP), lymphocytes, and D-dimer on admission and plasma immunoglobulin G (IgG) index on Day 7±2 after symptom onset were compared in relation to disease severity. Seven patients had severe disease and 14 had mild disease. Those with severe disease had a significantly higher IgG index (median: 3.75 vs 0.56, p=0.01) and CRP (median: 8.6 vs 1.0 mg/dL, p<0.001) and D-dimer levels (median: 1.65 vs 0.75 µg/mL; p=0.002) and a significantly lower lymphocyte count (median: 1,176 vs 666 cells/µL, p=0.005) and viral load (median: 8.7×106 vs 2.3×104 copies/mL, p=0.005). Furthermore, time from symptom onset to virus disappearance was significantly longer in severe patients (median: 24 vs 17 days, p=0.03). A high IgG index in the early phase of the disease was associated with severe disease and might serve as a prognostic indicator.

Streptococcal toxic shock syndrome caused by ß-hemolytic streptococci: Clinical features and cytokine and chemokine analyses of 15 cases.

OBJECTIVES: ß-Hemolytic streptococci occasionally cause severe infections such as necrotizing fasciitis and streptococcal toxic shock syndrome (STSS). Here, we conducted a prospective study to investigate the production of cytokines and chemokines in patients with STSS to explore its pathogenesis in survivors and fatal cases. METHODS: From January 2013 through August 2015, all culture results from normally sterile sites were prospectively followed and screened for STSS. Clinical characteristics of the patients with STSS were evaluated and compared between survivors and fatal cases. Serum samples were collected on admission for quantification of various cytokines and chemokines. Bacterial strains were categorized by Lancefield grouping and analyzed for the emm type, and presence of speA, speB, speC, and speF. RESULTS: Fifteen patients received diagnosis of STSS. The median age of the patients was 60-year-old, and the mortality rate was 40% despite intensive treatment. Nine strains were categorized as group A, two belonged to group G, and four to group B. Group A contained various emm genotypes. Unexpectedly, potent proinflammatory cytokine levels such as TNF-α and IL-1ß were not significantly elevated, and comparison with surviving patients showed that IL-6, IL-8, and MCP-1 levels were significantly decreased and creatine kinase level was significantly elevated in fatally ill cases. CONCLUSION: Our results indicate that reduced production of proinflammatory cytokines and chemokines may be involved in STSS pathogenesis and critical for prognosis of patients with STSS.

Oral vancomycin versus metronidazole for the treatment of Clostridioides difficile infection: Meta-analysis of randomized controlled trials.

At present, vancomycin (VCM) and metronidazole (MNZ) are used for the first-line standard treatment of Clostridioides difficile infection (CDI). However, their differential use has not been sufficiently investigated. In this study, a meta-analysis on differences in the efficacy for CDI between VCM and MNZ was performed. Reports of randomized controlled studies using VCM or MNZ to treat CDI were surveyed. Meta-analysis was performed using the Mantel-Haenszel method and random-effects model, and the risk ratio and 95% confidence interval were calculated. Excluding overlapping reports, 1043 reports were extracted and 5 randomized controlled studies were extracted. There was no difference in therapeutic effects for CDI between VCM and MNZ (RR = 1.08, 95% CI (0.99-1.17), p = 0.09, I2 = 37%). On subgroup analysis by the severity, there was no difference in the clinical effects for CDI between VCM and MNZ in non-severe cases (risk ratio: 1.09, 95% confidence interval: 1.00-1.19, p = 0.06), but the clinical effects of VCM were significantly higher than those of MNZ in severe cases (risk ratio: 1.19, 95% confidence interval: 1.02-1.39, p = 0.03). No significant difference was noted in the recurrence rate, incidence of adverse event, time to exhibit therapeutic effects, or judgment of the bacteriological effects. As the therapeutic effects of VCM were superior in severe CDI cases, VCM should be considered first in severe cases.

Staphylococcus aureus surface contamination of mobile phones and presence of genetically identical strains on the hands of nursing personnel.

We investigated the genetic relatedness of Staphylococcus aureus isolates recovered from mobile phones and palms and fingers of users. Genetically identical isolates were detected from mobile phones and their user and multiple users, which is consistent with mobile phones serving as reservoirs of infection in the health care environment. These findings reinforce the need for hand hygiene prior to patient contact as the most effective intervention for preventing health care-associated infection.

Worldwide Lineages of Clinical Pneumococci in a Japanese Teaching Hospital Identified by DiversiLab System.

Pneumococcal Molecular Epidemiology Network (PMEN) clones are representatives of worldwide-spreading pathogens. DiversiLab system, a repetitive PCR system, has been proposed as a less labor-and time-intensive genotyping platform alternative to conventional methods. However, the utility and analysis parameters of DiversiLab for identifying worldwide lineages was not established. To evaluate and optimize the performance of DiversiLab for identifying worldwide pneumococcal lineages, we examined 245 consecutive isolates of clinical Streptococcus pneumoniae from all age-group patients at a teaching hospital in Japan. The capsular swelling reaction of all isolates yielded 24 different serotypes. Intensive visual observation (VO) of DiversiLab band pattern difference divided all isolates into 73 clusters. Multilocus sequence typing (MLST) of representative 73 isolates from each VO cluster yielded 51 different STs. Among them, PMEN-related lineages accounted for 63% (46/73). Although the serotype of PMEN-related isolates was identical to that of the original PMEN clone in 70% (32/46), CC156-related PMEN lineages, namely Greece(6B)-22 and Colombia(23F)-26, harbored various capsular types discordant to the original PMEN clones. Regarding automated analysis, genotyping by extended Jaccard (XJ) with a 75% similarity index cutoff (SIC) showed the highest correlation with serotyping (adjusted Rand's coefficient, 0.528). Elevating the SIC for XJ to 85% increased the discriminatory power sufficient for distinguishing two major PMEN-related isolates of Taiwan(19F)-14 and Netherlands(3)-31. These results demonstrated a potential utility of DiversiLab for identifying worldwide lineage of pneumococcus. An optimized parameters of automated analysis should be useful especially for comparison for reference strains by "identification" function of DiversiLab.

Neurosyphilis Mimicking Ramsay Hunt Syndrome.

A 36-year-old man presented with facial nerve palsy, hearing loss, vertigo and headache. He was initially diagnosed with Ramsay Hunt syndrome and treated with a systemic steroid and valaciclovir; however, his symptoms deteriorated. Serum rapid plasma reagin (RPR) and treponema pallidum hemagglutination tests were positive. Cerebrospinal fluid analysis revealed an elevated white blood cell count and positive RPR, confirming the diagnosis of neurosyphilis. Penicillin G (PCG) was administered, and his facial nerve function and headache improved. However, left-side hearing loss worsened temporarily, which was assumed to be a Jarisch-Herxheimer reaction. Betamethasone was administered along with PCG, and he recovered completely.

[Usefulness of Immunochromatography Method for Malaria and Dengue Fever Diagnosis].

There are three major differential diagnosis of febrile patients with history of travels to the tropical countries i.e., malaria, typhoid fever and dengue fever. Diagnosis of malaria patients undergoes sometimes arduous process due to the variable skills of laboratory technician, and more convenient method is warranted. Immunochromatography (IC) method is simple method and recently used for diagnosis of several infectious diseases. Here, we reported usefulness of IC method for malaria and dengue fever diagnosis. Forty-seven samples from 46 patients were retrospectively analyzed by both malaria IC method and microscopic examination. Furthermore, three patients were undergone dengue IC method followed by PCR and antibody examination (ELISA) if the results were positive. Several factors such as rheumatoid factor (RF) are known to affect the results of IC method. We also checked malaria and dengue IC method using serum known to be high RF results without malaria infection. Totally six patients were diagnosed as malaria i.e., 1 vivax malaria and 5 falciparum malaria. Sensitivity and specificity of the malaria IC method were excellent, 100% and 97.6%, respectively. Among three patients, one patient revealed false-negative results of dengue IC method, however, results of the other two patients revealed good correlation between IC method and PCR/ELISA results. Among four RF positive serums, 2 malaria IC method and 4 dengue IC method revealed false-positive results. In summary, IC method for malaria and dengue fever might be quick and convenient method and considered to be used as an adjunctive diagnostic tool.

Incorrect diagnosis of Clostridium difficile infection in a university hospital in Japan.

Physicians often fail to suspect Clostridium difficile infection (CDI) and many microbiology laboratories use suboptimal diagnostic techniques. To estimate the extent of and reasons for incorrect diagnosis of CDI in Japan, we investigated toxigenic C. difficile isolated from all stool culture samples and clinical course. Over a 12-month period in 2010, all stool culture samples (n = 975) submitted from inpatients in a university hospital in Japan were cultured for C. difficile and routine microbiological testing was conducted. In total, 177 C. difficile isolates were recovered, and 127 isolates were toxigenic. Among the toxin-A-positive/toxin-B-positive isolates, 12 were also positive for the binary toxin gene. However, clinically important ribotypes, such as 027 and 078, were not identified. A total of 58 (45.7%) cases with toxigenic C. difficile had unformed stool, and the incidence CDI was 1.6 cases per 10,000 patient-days. Of these 58 cases, 40 were not diagnosed in routine testing due to a lack of clinical suspicion (24.1%, 14/58) or a negative C. difficile toxin assay result (44.8%, 26/58). A stool toxin assay was performed in 54 patients (78.2%, 54/69) who did not have unformed stool. The present study demonstrated that a significant number of CDI cases in Japan might be overlooked or misdiagnosed in clinical practice due to a lack of clinical suspicion and limitations of microbiological testing for CDI in Japan. Providing education to promote awareness of CDI among physicians is important to improve the accuracy of diagnosis in Japan.

Protective effect of procysteine on Acinetobacter pneumonia in hyperoxic conditions.

OBJECTIVES: Ventilator-associated pneumonia (VAP) is an important cause of morbidity and mortality in critical care settings. Acinetobacter has become a leading cause of VAP. In particular, the appearance and spread of multidrug-resistant Acinetobacter is of great concern. In this study, we examined the effect of the antioxidant procysteine on Acinetobacter murine pneumonia in hyperoxic conditions in order to simulate VAP. METHODS: Acinetobacter was administered intranasally to BALB/c mice kept in hyperoxic conditions. At designated timepoints, bacterial number, cytokine production and histopathological findings in the lungs were examined. The effects of procysteine on survival rates, lung bacterial burdens and the phagocytic activities of alveolar macrophages were evaluated. RESULTS: Drastic decreases in survival were observed when the infected mice were kept in hyperoxic conditions (P < 0.001). Significant differences in pulmonary bacterial number and neutrophil accumulation were observed between mice kept in hyperoxic or normoxic conditions on day 3. Although all mice infected with Acinetobacter spp. and kept in hyperoxic conditions died by day 3, procysteine treatment significantly improved survival (60% survival on day 7, P < 0.01). Procysteine treatment decreased the lung bacterial burden on days 2 and 3. Finally, improved uptake of FITC-labelled beads by alveolar macrophages from mice treated with procysteine and kept in hyperoxic conditions was noted. CONCLUSIONS: These results suggest that hyperoxia increases mortality in mice with Acinetobacter pneumonia and that procysteine improves survival by increasing the phagocytic activity of alveolar macrophages in mice kept in hyperoxic conditions.