[Rhodococcus equi infections in humans: an emerging zoonotic pathogen].

Rhodococcus equi is a facultative intracellular gram-positive coccobacillus which is a well-known cause of foal pneumonia and/or enteritis in equine veterinary medicine. More than 300 cases of R. equi infection have been reported since the first description of human disease in 1968. Most patients who become infected with R equi are immunocompromised, such as those infected with human immunodeficiency virus (HIV), recipients of organ transplantation, and patients receiving cancer treatment. However, there are increasing reports of the immunocompetent hosts. The pathogenicity of R. equi has been attributed to the presence of plasmid-encoded virulence-associated proteins (Vap). To date, three host-associated virulence plasmid types of R. equi have been identified as follows: the circular pVAPA and pVAPB, related, respectively, to equine and porcine isolates in 1991 and 1995, and a recently described linear pVAPN plasmid associated with bovine and caprine strains in 2015. More recently, these three plasmid types have been re-found in the human isolates which were isolated during 1980s to 1990s. Not only horses, but also pigs, goats, cattle and their environment should be considered as a potential source of R. equi for humans. In this review, we shed light on the current understanding of R. equi as an emerging zoonotic pathogen.

An attempt to support by the Japanese society of travel and health for increasing travel clinics.

In recent years, both the number of Japanese travelers to foreign countries and foreign travelers who visit Japan have increased remarkably, and the risk of travelers suffering various infectious diseases is also increasing. In many western countries travel clinics commonly perform medical consultations, vaccinations, and issue prescriptions. However, travel clinics are not yet popular in Japan. In 2011, Japanese society of travel and health (JSTH) began a support project for travel clinic with a goal of increasing their number throughout the country. The project included the release of a manual for education, training, equipment, details of medical treatment, sources of information for travel clinic opening on the JSTH website (http://jstah.umin.jp/20TravelClinicSupport/manual_20120726.pdf), and mediation of short-term visitation to experienced travel clinics registered in the JSTH to facilitate learning above information and aftercare services. JSTH accepted requests for visitation to travel clinics from 39 medical institutions between 2011 and 2018. By 2018, 26 (66.7%) of the 39 medical institutions had opened travel clinics within two years and the 25 travel clinics had registered in the JSTH and one was a campus-limited clinic, while most of the remaining institutions are still in preparation stages. The number of travel clinics registered in the JSTH has increased from 45 in 2011 to 108 in 2018. Twenty-five travel clinics registered in the JSTH between 2011 and 2018 were eventually receiving support from JSTH. Our data indicates travel clinics in Japan have gradually increased and establishment areas are expanding after the beginning of support project for travel clinics by JSTH.

Retrospective observational study of the use of artemether-lumefantrine in the treatment of malaria in Japan.

BACKGROUND: The Research Group on Chemotherapy of Tropical Diseases, Japan, introduced artemether-lumefantrine (AL) in late 2002, mainly for treating uncomplicated Plasmodium falciparum malaria. Because AL was on the market in Japan in March 2017, the effectiveness and safety of AL were analyzed to help medical personnel use AL optimally. METHODS: Case report forms submitted by the attending physicians were analyzed. When necessary, direct contact with the attending physicians was made to obtain detailed information. RESULTS: Effectiveness analysis was performed for 62 cases and safety analysis was performed for 66 cases. In P. falciparum malaria, the overall cure rate was 91.1% (51/56), of which the cure rates for Japanese and non-Japanese patients were 82.1% (23/28) and 100% (28/28), respectively. The successfully treated cases included severe P. falciparum malaria, with parasite densities exceeding 500,000/µL. Adverse events were reported in 14 patients, including delayed hemolytic anemia which occurred in the top four highest parasitemic cases. CONCLUSIONS: AL treatment failure in P. falciparum malaria may not be rare among non-immune individuals, including Japanese. The possibility of delayed hemolytic anemia, which occurs preferentially in high parasitemic cases, should be considered following AL treatment.

Extended-spectrum ß-lactamase-producing Enterobacteriaceae colonisation in long-term overseas business travellers.

BACKGROUND: International travel is considered a risk for colonisation with extended-spectrum ß-lactamase-producing Enterobacteriaceae (ESBL-PE). To our knowledge, no studies to date have focused on ESBL-PE colonisation among long-term business travellers. Therefore this study aimed to clarify the characteristics associated with ESBL-PE colonisation in Japanese long-term business travellers. METHODS: Japanese business travellers planning to stay abroad for ≥6 months were enrolled. Of the 192 travellers, 135 provided only post-travel stool samples and 57 provided both pre- and post-travel stool samples. Additionally, microbiological analyses of ESBL-PE strains, including susceptibility tests and polymerase chain reaction amplification of CTX-M genes and their sequencing were performed. RESULTS: A post-travel survey showed that of the 55 travellers (40.7%) who tested positive for ESBL-PE after travel, the highest proportion was travellers returning from East and Central Asia. CTX-M gene analyses showed that CTX-M-15 was the most frequently observed (55.0%). A pre- and post-travel survey showed that of the 22 travellers (44.9%) acquired ESBL-PE during their travel, with acquisition most frequently observed in travellers returning from South Asia. CONCLUSION: Risk-based evaluations of ESBL-PE colonisation should be performed not only for regular tourists but also for long-term business travellers.

Strongyloides stercoralis Infection Causing Obstructive Jaundice and Refractory Pancreatitis: A Lesson Learned from a Case Study.

A 58-year-old Japanese woman came to our institution because of leg edema and abdominal distention. She had developed acute pancreatitis 5 times in the past 3 years. Dilation of the bile duct and main pancreatic duct without obstruction was observed on computed tomography and magnetic resonance cholangiopancreatography. The presence of Strongyloides stercoralis was highly suspected from the biopsy sample from the duodenal papilla. Polymerase chain reaction amplification and sequencing of small subunit rDNA from paraffin-embedded specimens identified the worm as S. stercoralis. All of the symptoms were considered to be associated with S. stercoralis infection. Therefore, the patient was treated with oral administration of ivermectin. Subsequently, symptoms and laboratory data improved. There has been no recurrence of the symptoms to date.

Case Series of Imported Enteric Fever at a Referral Center in Tokyo, Japan: Antibiotic Susceptibility and Risk Factors for Relapse.

Owing to the increase in Salmonella strains with decreased fluoroquinolone susceptibility in the endemic areas, we have been treating enteric fever with intravenous ceftriaxone empirically since 2007. In this study, we reevaluated our treatment protocol. This retrospective cohort study was conducted at a single institute in Tokyo, Japan, between January 2006 and December 2013. Enteric fever was defined as isolation of Salmonella Typhi or Salmonella Paratyphi A, B, and C from the blood and/or stool of patients with fever. Of the 35 patients with imported enteric fever, 28 (80%) had returned from south Asia. Ciprofloxacin-susceptible strains were detected in only 12% of the cases. The isolates showed excellent susceptibility to ampicillin (91%), chloramphenicol (94%), ceftriaxone (97%), and azithromycin (97%). One case of Salmonella Paratyphi B was excluded, and of the remaining 34 patients, 56% were treated with ceftriaxone alone, 26% with ceftriaxone then fluoroquinolone, and 9% with levofloxacin alone. The overall relapse rate was 6.1%; however, among those receiving ceftriaxone monotherapy, the relapse rate was 11% (N = 2). The relapse group was characterized by longer times to treatment initiation (P = 0.035) and defervescence (> 7 days) after treatment initiation (P = 0.022). In such cases, we recommend that ceftriaxone treatment be continued for > 4 days after defervescence or be changed to fluoroquinolone if the strains are found to be susceptible to prevent relapse. Furthermore, ampicillin and chloramphenicol, which are no longer prescribed, may be reconsidered as treatment options in Asia.

Neurocysticercosis with Diplopia Responds Well to Albendazole.

We report a case of neurocysticercosis concurrent with taeniasis in a 31-year-old woman. The patient presented with a headache and diplopia. Oculomotor disturbances with a left adduction deficit were observed. Fundoscopy revealed papilledema. Additionally, computed tomography of the brain revealed more than 20 small cysts within the parenchyma, most of which were associated with ring enhancement. Moreover, serum antibody testing (Western blotting) for Taenia solium-cysticerci was positive. The patient received albendazole and corticosteroids, and progressive resolution of the neurological symptoms and papilledema was observed starting approximately three days after administration. This patient has been asymptomatic for more than one year.

[Intravenous Minocycline and Levofloxacin for Treatment of Two Cases of Japanese Spotted Fever].

We report herein on two cases of Japanese spotted fever (JSF) treated with intravenous minocycline (MINO) and levofloxacin (LVFX). An 80 year-old woman (Case1) and a 63 year-old man (Case2) with high fever (> 39 degrees C) and wide-spread skin erythema were admitted because they were suspected of having developed JSF. After admission, we treated them with intravenous MINO and LVFX. The patients' fevers were resolved within 36 hours after antibiotics. They were diagnosed as having JSF based on the serological test, and Rickettsia japonica was detected from the genetic findings (PCR analysis from eschar) only in case 1. In the treatment of fulminant JSF (body temperature > 39 degrees C) the prompt administration of a combination of tetracycline and new quinolone has been recommended. The number of cases of JSF and its endemic area are gradually increasing in Japan. As for new quinolones, ciprofloxacin and tosufloxacin have been used against to JSF in Japan, but LVFX may become a new option.

A first case of New Delhi metallo-ß-lactamase-7 in an Escherichia coli ST648 isolate in Japan.

We report a first identification case of an Escherichia coli ST648 isolate producing a variant New Delhi metallo-ß-lactamase (NDM) -7 in Japan, which was recovered from a patient hospitalized in India. Although the first isolate, NDM-1, was identified in Japan in 2010, NDM-producing bacteria have only been isolated from seven patients to date, and no other variant of NDM producing organism has been reported yet. The emergence of NDM variants in Enterobacteriaceae is of great concern, and the use of rigorous screening tests and preventive measures against infection is imperative.

First case report of vancomycin-intermediate sequence type 72 Staphylococcus aureus with nonsusceptibility to daptomycin.

BACKGROUND: Sequence type 72 methicillin-resistant Staphylococcus aureus (MRSA) SCCmec type IV (ST72-MRSA-IV) is the most common community-acquired MRSA clone in Korea. Resistance to daptomycin or vancomycin among community-acquired MRSA clones is not well described in the literature. We herein report the first case of vancomycin-intermediate, daptomycin-nonsusceptible ST72-MRSA-IV. CASE PRESENTATION: A 45-year-old Japanese man underwent aortic arch prosthesis implantation for treatment of a dissecting aortic aneurysm. Fourteen months later, he developed a prosthetic graft infection of the aortic arch and an anterior mediastinal abscess caused by ST72-MRSA-IV. First-line treatment with vancomycin and rifampicin failed, and daptomycin was thus administered. After several days, the treatment was changed to linezolid because of the re-emergence of fever. The patient's condition resolved and no recurrence or other problems were seen for 1 year post-treatment. The infectious agent was definitively identified as vancomycin-intermediate, daptomycin-nonsusceptible, rifampicin-resistant ST72-MRSA-IV based on culture results and minimum inhibitory concentration testing. CONCLUSION: This case report illustrates the importance of fully understanding the changing epidemiology of infectious agents and the risk factors for the development of antibiotic resistance. Such information will help to minimize the emergence and spread of antibiotic-resistant strains. This report concerns one particular bacterial strain; however, the basic concepts involved in this case translate to all infectious disease fields.

Fulminant colitis from Clostridium difficile infection, the epidemic strain ribotype 027, in Japan.

In December 2012, a 32-year-old woman with no previous medical history and no previous antibiotic treatment had a fever and diarrhea 2 days after a cesarean section in which cefazolin was used as a prophylactic antimicrobial agent. She was transferred to our hospital 5 days after the cesarean for severe colitis. A rapid test of stool for Clostridium difficile toxin A and B was positive. Although oral vancomycin (0.5-2.0 g/day) and intravenous immunoglobulin (5 g/day) were administered after her transfer, 7 days after admission emergency exploratory surgery was performed because of poor response to therapy. Bowel perforation was noted and a temporary colostomy was created without colectomy. Vancomycin (2.0 g/day) was administered via the colostomy, in addition to a vancomycin enema (2.0 g/day), oral metronidazole (1500 mg/day), and oral vancomycin (2.0 g/day). Three days after the operation, linezolid (1200 mg/day IV) was added. She was treated with antibiotics against C. difficile for a total of 18 days after the operation. The same strain was not isolated from other patients in the same ward. Microbiological analysis of the isolate revealed housekeeping gene (tpi), toxin A gene (tcdA), toxin B gene (tcdB), and binary toxin gene (cdtA and cdtB). DNA sequencing of tcdC revealed a base 117 deletion and contained an 18-bp tcdC deletion. PCR ribotyping showed ribotype 027 patterns. The MIC of moxifloxacin was >32 µg/ml, indicating resistance to fluoroquinolones. This isolate was considered as the epidemic strain. Our case of fulminant colitis is apparently the first case involving the epidemic strain ribotype 027 in Japan.

Effectiveness of antibiotic combination therapy as evaluated by the Break-point Checkerboard Plate method for multidrug-resistant Pseudomonas aeruginosa in clinical use.

Multidrug-resistant Pseudomonas aeruginosa (MDRP) strains are defined as having resistance to the following 3 groups of antibiotics: carbapenems, aminoglycosides, and fluoroquinolones. Antibiotic combinations have demonstrated increased activity in vitro compared with a single agent. As an in vitro method of determining the combination activity of antibiotics, the Break-point Checkerboard Plate (BC-plate) can be used routinely in clinical microbiology laboratories. We evaluated the effectiveness of the BC-plate for MDRP infections in clinical settings. We retrospectively selected cases of MDRP infection treated with combination therapy of antibiotics in Tokyo Medical University Hospital (1015 beds), Tokyo, Japan, from November 2010 to October 2012. A total of 28 MDRP strains were clinically isolated from 28 patients during the study period. This study design is a case series of MDRP infection. Six infections among the 28 patients were treated based on the results of the BC-plate assay, and the 6 strains tested positive for MBL. One patient had pneumonia, 3 had urinary tract infections, 1 had vertebral osteomyelitis, and 1 had nasal abscess. The combination of aztreonam with amikacin demonstrated the most frequently recognized in vitro effect (5 patients). Next, aztreonam with ciprofloxacin and piperacillin with amikacin revealed equivalent in vitro effects (3 patients, respectively). The clinical cure rate was 83.3% (5/6 patients). Antibiotic combination therapy based on the results of the BC-plate assay might indicate the effective therapy against MDRP infection in clinical settings.

Immunogenicity of single-dose Vero cell-derived Japanese encephalitis vaccine in Japanese adults.

In Japan, intensive immunization against Japanese encephalitis (JE) was performed from 1967 to 1976, and regular JE immunization was performed thereafter. However, for Japanese adults facing JE risk, dates of vaccination with new inactivated Vero cell-derived JE vaccine are unavailable. This study investigated how a single dose of Vero cell-derived JE vaccine affects Japanese adults. Neutralizing antibodies were measured pre- and post-JE vaccination in 79 participants (age 40.7 ± 9.4 years), enrolled between October 2009 and March 2011, whose JE-vaccination data were gathered from vaccination records and history taking. Before vaccination, the participants' seroprotection rate (SPR) was 51.9%, whereas SPR after vaccination was 93.7%. The seroconversion rate (SCR), which measures seronegative cases that turn seropositive after vaccination, was 86.8%. The geometric mean titer (GMT) was 14.7 before vaccination and 70.1 after vaccination. Age was a significant difference between seroprotected (42.8 years) and non-seroprotected (38.7 years) groups before vaccination. Then the difference of age, SCR, pre-vaccination GMT, post-vaccination GMT and sex ratio were also significant in participants aged 25-39 years and ≥40 years, who represent generations born when Japan's JE-vaccination policy changed. SCR was 100% in participants aged 25-39 years with a vaccination recorded 55.6% in participants aged 25-39 without a vaccination record, and 96.0% in participants aged ≥40 years. Thus, more participants aged 25-39 years were seroprotected before vaccination, but SCR was higher in those aged ≥40 years. Most Japanese adults can be protected after one-dose vaccination, but this may be insufficient for people aged 25-39 years without recorded JE vaccination.

Seroprevalence of tetanus toxoid antibody and booster vaccination efficacy in Japanese travelers.

Tetanus can be prevented by vaccination, which is especially important for overseas travelers. However, despite booster vaccination every 10 years being recommended, most Japanese adults do not receive it in the absence of physical injury or overseas travel. We aimed to investigate the level of protective immunity against tetanus among Japanese travelers, which may provide valuable information for formulating booster vaccination recommendations. 113 Japanese travelers given tetanus toxoid were recruited. The collected samples included paired samples prior to and 3-5 weeks after receiving the booster vaccination. Travelers who did not return and those lacking sample collection at the second visit were excluded. Finally, 96 paired blood samples were collected. History of immunization against tetanus, including DPT and DT vaccines, was determined from interviews or immunization records. The pre-vaccination geometric mean titer for the 96 participants was 1.07 IU/mL; 76% had a protective antitoxin level (>0.1 IU/mL), and 50% had a long-term protective antitoxin level (>1.0 IU/mL). Most participants <40 years old had protective immunity without receiving booster vaccination, whereas only 30.8% of those >50 years of age had protective immunity. Among the 23 participants without protective antitoxin levels (<0.1 IU/mL), booster vaccination was efficient in 100% of those <40 years but in only 28.6% of those >50 years of age. Although the tetanus antitoxin level decreases with age, booster vaccination helped to achieve an adequate protective antitoxin levels in Japanese travelers <40 years of age. Furthermore, the individuals who have never been vaccinated against tetanus especially in those >50 years old need to obtain protective immunity against tetanus according to a basic immunization schedule to prevent tetanus in travelers and residents of Japan.

[Malaria cases treated with artemether/lumefantrine in Japanese travelers].

Artemisinin-based combination therapy (ACT) has been the standard treatment for uncomplicated malaria. Although not licensed in Japan, artemether/lumefantrine (AL), one type of ACT, has been administered to patients with malaria since 2002 by the Research Group on Chemotherapy of Tropical Diseases. Herein, we reviewed malaria cases treated with AL in Japanese travelers. A retrospective study was conducted at the National Center for Global Health and Medicine from October 2005 to March 2013. There were 19 malaria patients treated with AL, and 10 falciparum malaria patients treated with AL only. In these 10 patients treated with AL only, the median time of fever clearance was 25.0 hours (range:14-66 hours), and the median time of parasite clearance was 36.0 hours (range:16-62 hours). There was a positive correlation between parasitemia and time from the start of therapy to the disappearance of the parasites. Parasitemia was higher (4.05% vs. 0.24%; p = 0.044) and parasite clearance time was longer (55.5 hours vs. 31.5 hours; p = 0.044) in the cases of recrudescence than non-recrudescence, respectively. Three of the 19 malaria patients showed recrudescence of malaria after treatment with AL. The reason that treatment failure was more frequently observed in this study than in previous reports may be related to poor absorption of lumefantrine owing to gastrointestinal symptoms, insufficiently ingested fatty foods, or high parasitemia on admission. The World Health Organization recommends that intravenous antimalarials should be administered in cases of severe malaria however, this is not applicable in Japan. Further studies are needed to distinguish patients with malaria who are treatable with ACT from those who should be treated initially with other intravenous antimalarials.

Clinical aspects of infection with methicillin-resistant Staphylococcus aureus USA300 strain, generally regarded as community-acquired, in Japan.

The characteristics of community-acquired methicillin-resistant Staphylococcus aureus (CA-MRSA) infection in Japan have not yet been completely established compared with those in Europe and the United States. CA-MRSA infections with the USA300 clone are very rare in Japan. In this study, we describe 4 cases of CA-MRSA infections, particularly the USA300 clone. Case 1 involved a 21-year-old man without any remarkable medical history or risk factors of CA-MRSA who suffered from a rapidly progressive infection in his left arm. Case 2 involved a 34-year-old man and Case 3 a 22-year-old man who presented with recurrent and refractory furuncles. Both men were members of a combat sports gym where other members also had skin infections. Case 4 involved a 60-year-old man with lumbar canal stenosis who suffered from surgical site infection 7 days after lumbar laminectomy and posterolateral fusion. Only 5 cases of USA300 infections were reported in Japan from 2007 to 2009, and 4 cases were detected at Tokyo Medical University Hospital from 2010 to 2011. The diversity of the routes of infection in these cases may indicate the possible spread of the USA300 clone in Japan.

[Clinical experience of primaquine use for treatment of vivax and ovale malaria in Japanese travelers].

Primaquine phosphate has been used to prevent relapse as a radical cure after the acute-phase treatment of vivax and ovale malaria however. Many vivax malaria relapses have been reported following a standard dose of primaquine (15 mg/day for 14 days). A higher dose of primaquine (30 mg/day for 14 days) decreases the relapse rate, and the concomitant risk of gastrointestinal side effects tends to disappear when the drug is administered with food. G6PD deficiency is rare in the Japanese population. Although the relapsed phenomenon is reported globally, the higher dose of primaquine is currently recommended in Japan only for those returning from Southeast Asia or Papua New Guinea. Cases of 18 Japanese, including 13 vivax malaria and 5 ovale malaria, prescribed primaquine at a referral center in Japan, were analyzed retrospectively from 2007-2011. Data on diagnosis, treatment, and outcome were extracted from medical records. Of the 18, 10 with vivax malaria were administered the higher dose of primaquine. We found that only one suffered relapse-a vivax malarial case returning from Brazil and treated with the standard dose of primaquine. No ovale malarial case suffered relapse. None, including the 10 prescribed the higher primaquine dose, experienced any adverse side effects. Based on our findings, we recommend a higher dose of primaquine be used to prevent relapse when treating Japanese suffering from vivax malaria.

Vertebral osteomyelitis caused by non-tuberculous mycobacteria: case reports and review.

There are currently few reports of vertebral osteomyelitis caused by non-tuberculous mycobacteria. To date, only 38 cases, excluding human immunodeficiency virus patients, have been reported. We describe 3 patients with vertebral osteomyelitis caused by Mycobacterium avium-intracellulare complex or Mycobacterium kansasii, and review previous reports of vertebral osteomyelitis caused by non-tuberculous mycobacteria. Case 1 is a 50-year-old man who presented with lower back pain. Radiologic examination revealed L1-L5 enhancement and paravertebral abscess. The surgical specimen was positive for Mycobacterium avium-intracellulare complex. The patient was successfully treated by surgical excision and antibiotic administration. Case 2 is a 68-year-old woman who presented with upper back pain. Spine MRI revealed multiple lesions at T9-T12, L2, L4, and L5. Her back pain worsened, and repeated MRI revealed extensive bone lesions. Mycobacterium kansasii was isolated from a T5 vertebral body specimen. Surgery was not performed. Case 3 is a 38-year-old woman who had been taking prednisolone for systemic lupus erythematosus. We diagnosed her condition as suppurative knee arthritis caused by M. avium-intracellulare complex. Vertebral MRI revealed T9 vertebral body enhancement and a paravertebral abscess at T8-T9. Tissue culture of a T9 specimen yielded M. avium-intracellulare complex. Her clinical condition improved following posterior thoracic spinal fusion. In conclusion, vertebral osteomyelitis caused by non-tuberculous mycobacteria should be included in the differential diagnosis, even in immunocompetent patients.