Streptozotocin induces renal proximal tubular injury through p53 signaling activation.

Streptozotocin (STZ), an anti-cancer drug that is primarily used to treat neuroendocrine tumors (NETs) in clinical settings, is incorporated into pancreatic ß-cells or proximal tubular epithelial cells through the glucose transporter, GLUT2. However, its cytotoxic effects on kidney cells have been underestimated and the underlying mechanisms remain unclear. We herein demonstrated that DNA damage and subsequent p53 signaling were responsible for the development of STZ-induced tubular epithelial injury. We detected tubular epithelial DNA damage in NET patients treated with STZ. Unbiased transcriptomics of STZ-treated tubular epithelial cells in vitro showed the activation of the p53 signaling pathway. STZ induced DNA damage and activated p53 signaling in vivo in a dose-dependent manner, resulting in reduced membrane transporters. The pharmacological inhibition of p53 and sodium-glucose transporter 2 (SGLT2) mitigated STZ-induced epithelial injury. However, the cytotoxic effects of STZ on pancreatic ß-cells were preserved in SGLT2 inhibitor-treated mice. The present results demonstrate the proximal tubular-specific cytotoxicity of STZ and the underlying mechanisms in vivo. Since the cytotoxic effects of STZ against ß-cells were not impaired by dapagliflozin, pretreatment with an SGLT2 inhibitor has potential as a preventative remedy for kidney injury in NET patients treated with STZ.

Direct evidence of proximal tubular proliferation in early diabetic nephropathy.

Kidney hypertrophy is a common clinical feature in patients with diabetes and is associated with poor renal outcomes. Initial cell proliferation followed by cellular hypertrophy are considered the responsible mechanisms for diabetic kidney hypertrophy. However, whether similar responses against hyperglycemia continue in the chronic phase in diabetes is unclear. We performed lineage tracing analysis of proximal tubular epithelia using novel type 2 diabetic mice with a tamoxifen-inducible proximal tubule-specific fluorescent reporter. Clonal analysis of proximal tubular epithelia demonstrated that the labeled epithelia proliferated in type 2 diabetic mice. Based on the histological analysis and protein/DNA ratio of sorted labeled tubular epithelia, there was no evidence of cellular hypertrophy in type 2 diabetic mice. Lineage tracing and histological analyses of streptozocin-induced type 1 diabetes also revealed that cellular proliferation occurs in the chronic phase of type 1 diabetes induction. According to our study, epithelial proliferation accompanied by SGLT2 upregulation, rather than cellular hypertrophy, predominantly occurs in the hypertrophic kidney in both type 1 and type 2 diabetes. An increased number of SGLT2+ tubular epithelia may be an adaptive response against hyperglycemia, and linked to the hyper-reabsorption of sodium and glucose observed in type 2 diabetes patients.

Prediction of the prognosis of patients with bacteremia caused by encapsulated organisms using spleen volume: A retrospective study.

AIM: The spleen plays an important role in the immune response, and patients with impaired spleen function are at risk of overwhelming post-splenectomy infection. This study investigated whether the spleen volume could predict the prognosis of patients with bacteremia caused by encapsulated organisms. METHODS: This was a single-center, retrospective observational study at Tokyo Medical University Hospital. Twenty patients with encapsulated bacteria (Streptococcus pneumoniae, Haemophilus influenzae, Neisseria meningitidis, and Capnocytophaga canimorsus) detected in blood culture between January 2017 and July 2020 were included in the study and categorized into two groups: survive and nonsurvive groups. We investigated the association between spleen volume (SV), spleen volume index (SVI), and in-hospital mortality. The SVI was defined as: SVI-H, spleen volume cm3/height m; SVI-BW, spleen volume cm3/body weight kg; and SVI-A, spleen volume cm3 × age/100. RESULTS: The number of patients in the survive group was 17, and that of the non-survive group was 3. The SV and SVI were smaller in the nonsurvive group than in the survive group (P < 0.05). The calculated the SV cut-off for the prediction of prognosis was 36 cm3 with a sensitivity of 94.1% and specificity of 66.7% with a positive predictive value of 94.1% and a negative predictive value of 66.7%. CONCLUSIONS: The SV and SVI could be used to predict the prognosis of bacteremia caused by encapsulated organisms. If the spleen volume as measured by computed tomography is small, more intensive treatment should be considered.

Cumulative DNA damage by repeated low-dose cisplatin injection promotes the transition of acute to chronic kidney injury in mice.

Cisplatin is a commonly used anticancer drug, but nephrotoxicity is a dose-limiting adverse effect. Recent experimental and clinical observations have demonstrated that multiple injections of cisplatin induce the transition to chronic kidney disease; however, the underlying mechanisms remain unclear. We found that multiple injections of higher doses of cisplatin in a shorter interval affected the severity of kidney injury, causing kidney fibrosis to develop at a later time point. An additional injection of cisplatin during the recovery period after a prior injury, when proximal tubule epithelia are actively proliferating, induced substantial tubular injury by inducing more severe DNA damage than that induced by a single injection. Lineage tracing analysis of proximal tubular epithelia demonstrated that the tubular epithelia that underwent multiple rounds of cell division after multiple injections of cisplatin existed at the chronic phase, and these populations often expressed vcam1 + , suggesting the induction of proinflammatory failed-repair tubular epithelia. Our study revealed that as cisplatin exerts cytotoxic effects on actively proliferating cells, additional cisplatin injections before the completion of tubular repair exacerbates kidney injury through cumulative DNA damage. Appropriate both the setting of dosage and dosing intervals, with careful monitoring, are essential to prevent nephrotoxicity of repeated cisplatin treatment in cancer patients.

Case report of restless anal syndrome as restless legs syndrome variant after COVID-19.

BACKGROUND: Coronavirus disease 2019 (COVID-19) has a broad spectrum from respiratory and nasopharyngeal symptoms, cerebrovascular diseases, impaired consciousness, and skeletal muscle injury. Emerging evidence has indicated the neural spread of this novel coronavirus. Restless legs syndrome (RLS) is a common neurological, sensorimotor disorder, but highly under diagnosis disorder. Restless anal syndrome as restless legs syndrome variant associated with COVID-19 has been previously not published. We report a case presenting with restless anal syndrome following COVID-19. CASE PRESENTATION: Although a 77-year-old male with COVID-19 improved to normal respiratory function 21 days after admission and treatment of favipiravir 200 mg per day for 14 days and dexamethasone 6.6 mg per day for 5 days, the insomnia and anxiety symptoms remained. Several weeks after discharge, he gradually began to experience restless, deep anal discomfort, approximately 10 cm from the perineal region. The following features were observed in the anal region; urge to move is essential, with worsening with rest, improvement with exercise, and worsening at evening. Colonoscopy revealed internal haemorrhoids without other rectal lesions. Neurological findings including deep tendon reflex, perineum loss of sensory and spinal cord injury, revealed no abnormalities. Diabetes militias, kidney dysfunction and iron deficiency status were not confirmed. Family history of RLS and periodic limb movements were not observed. Clonazepam at 1.5 mg per day resulted in the alleviation restless anal discomfort. CONCLUSIONS: We reported a case presenting with restless anal syndrome following affection of COVID-19 as restless legs syndrome variant. This case fulfilled 4 essential features of RLS, urge to move, worsening with rest, improvement with exercise, and worsening at evening. To date, no case of restless anal syndrome associated with COVID-19 has been previously published. This case report may reflect the associative impacts of COVID-19 on the neuropsychiatric state. The long-term outcomes of neuropsychiatric conditions should continue to be monitored.

Severe Acute Cholangitis and Bacteremia Due to Campylobacter jejuni: A Case Report and Review of the Literature.

Campylobacter jejuni is common cause of enteritis, but biliary infection rarely reported. An 82-year-old woman with pancreatic head cancer underwent endoscopic biliary drainage for malignant biliary obstruction. She was subsequently admitted for management of diarrhea. C. jejuni was identified in stool culture. Her symptoms resolved temporarily without antibiotics but flared up with a fever a few days later. She was diagnosed with acute cholangitis and bacteremia with C. jejuni. Endoscopic biliary drainage and antimicrobial administration improved her symptoms. As complications of C. jejuni diarrhea are rare, antibiotics are not necessarily indicated but sometimes are needed to prevent complications.

Refractory pharyngeal ulceration due to cytomegalovirus in a patient with HIV infection: a case report and literature review.

BACKGROUND: Cytomegalovirus (CMV) is an important pathogen among immunocompromised hosts. Typically, CMV in human immunodeficiency virus (HIV) infection causes diseases of the retina, digestive tract, lungs and liver, but there are few cases of CMV infection of the pharynx and larynx. CASE PRESENTATION: A 57-year-old man with HIV infection was admitted because of pharyngeal pain. Before and after admission, pharyngeal biopsies guided by laryngeal endoscopy were performed four times, but pathological examination showed nonspecific inflammation, and the cause of pharyngeal ulceration was unclear. Additionally, the ulceration deteriorated after initiation of retroviral therapy. Laryngomicrosurgery was conducted under general anesthesia to remove tissue, and pathological diagnosis confirmed CMV infection. Pathological features included enlargement of the cytoplasm and nucleus in infected cells, and intranuclear bodies called owl's eye inclusions. Ganciclovir dramatically improved the symptoms and laryngoscopic findings. CONCLUSIONS: This case was diagnosed as pharyngitis and pharyngeal ulceration caused by CMV infection, related to immune reconstitution inflammatory syndrome. In previous reports of CMV-induced pharyngeal or laryngeal ulceration in HIV infection, we found six cases similar to our present case. All cases were diagnosed by biopsy. The present case indicates the importance of biopsy for definitive diagnosis. CMV infection should be considered as a differential diagnosis of pharyngeal ulceration in patients with HIV infection.

Extraglomerular Vascular Involvement of Glomerulopathy with Fibronectin Deposits.

Glomerulopathy with fibronectin deposits (GFND) is a rare hereditary kidney disease with autosomal dominant inheritance. A 21-year-old woman who had been diagnosed with GFND 10 years ago was admitted for investigation of a rapid decline in her renal function, hemolytic anemia, and cardiac dysfunction. A renal biopsy showed GFND accompanied by extraglomerular vascular lesions. Comprehensive treatments against hypertension and anemia improved the renal function. Although there have been few reports of vascular lesions in GFND, we suspect that endothelial hyperpermeability resulting from hypertension caused the fibronectin deposition and narrowing of the extraglomerular vascular lumens, thereby accelerating hypertension and inducing hemolytic anemia.

Hypertrophic pachymeningitis caused by Schizophyllum sp.: a novel case report.

BACKGROUND: The pathogenic fungus Schizophyllum sp. can cause allergic fungal rhinosinusitis and allergic bronchopulmonary mycosis in humans. Sinus and lung infections due to Schizophyllum sp. have been reported globally; however, no case of hypertrophic pachymeningitis due to this pathogen has been reported yet. Herein, we describe for the first time, a case of hypertrophic pachymeningitis due to Schizophyllum sp. CASE PRESENTATION: A 69-year-old woman visited the hospital with chief complaints of headache, right trigeminal neuralgia (third branch), ataxic gait, and deafness in the right ear. Magnetic resonance imaging revealed a tumor in the right sphenoidal sinus and thickening of the dura mater surrounding the right porus acusticus internus. Endoscopic sinus surgery and neuroendoscopic biopsy were performed to remove sinus lesions and intracranial lesions, respectively. Both pathological specimens showed findings indicative of filamentous fungi on Grocott's staining. DNA sequencing with the sinus specimen revealed Schizophyllum sp. as the causative pathogen, consistent with the diagnosis of fungal sinusitis and hypertrophic pachymeningitis. Intravenous liposomal amphotericin B was started, but owing to lack of improvement, the treatment was switched to intravenous voriconazole. We observed improvements in both radiological findings and symptoms. However, the symptoms exacerbated again when the trough level of voriconazole decreased. Upon increasing the voriconazole dose, a higher trough level was obtained and the symptoms improved. CONCLUSION: Our study suggests that when symptoms of central nervous system infection due to Schizophyllum sp. do not improve with liposomal amphotericin B, voriconazole can be administered at high trough levels to improve the symptoms.

Disseminated Bacillus Calmette-Guérin (BCG) infection and acute exacerbation of interstitial pneumonitis: an autopsy case report and literature review.

BACKGROUND: Intravesical administration of Bacillus Calmette-Guérin (BCG) has proven useful for treatment and prevention of recurrence of superficial bladder cancer and in situ carcinoma. However, fatal side effects such as disseminated infections may occur. Early diagnosis and accurate therapy for interstitial pneumonitis (IP) are important because exacerbation of IP triggered by infections is the major cause of death. Although some fatality reports have suggested newly appeared IP after intravesical BCG treatment, to our knowledge, there are no reports which have demonstrated acute exacerbation of existing IP. Moreover, autopsy is lacking in previous reports. We report the case of a patient with fatal IP exacerbation after BCG instillation and the pathological findings of the autopsy. CASE PRESENTATION: A 77-year-old man with a medical history of IP was referred to our hospital because of fever and malaise. He had received an intravesical injection of BCG 1 day before the admission. His fever reduced after the use of antituberculosis drugs, so he was discharged home. He was referred to our hospital again because of a high fever 7 days after discharge. On hospitalisation, he showed high fever and systemic exanthema. Hepatosplenomegaly and myelosuppression were also observed. Biopsies revealed multiple epithelioid cell granulomas with Langhans giant cells of the liver and bone marrow. Biopsy DNA analyses of Mycobacterium bovis in the bone marrow, sputum, and blood were negative. His oxygen demand worsened drastically, and the ground-glass shadow expanded on the computed tomography scan. He was diagnosed with acute exacerbation of existing IP. We recommenced the antituberculosis drugs with steroid pulse therapy, but he died on day 35 because of respiratory failure. The autopsy revealed a diffuse appearance of multiple epithelioid cell granulomas with Langhans giant cells in multiple organs, although BCG was not evident. CONCLUSIONS: We report the first case of acute exacerbation of chronic IP by BCG infection. This is also the first case of autopsy of a patient with acute exacerbation of existing IP induced by intravesical BCG treatment. Whether the trigger of acute IP exacerbation is infection or hypersensitivity to BCG is still controversial, because pathological evidence confirming BCG infection is lacking. Physicians who administer BCG against bladder cancer should be vigilant for acute exacerbation of IP.

Severe acute respiratory distress syndrome in a patient with AIDS successfully treated with veno-venous extracorporeal membrane oxygenation: a case report and literature review.

CASE: Several successful uses of extracorporeal membrane oxygenation (ECMO) for acute respiratory distress syndrome in patients with novel HIV/AIDS infection have been reported; however, the therapeutic keys have not always been discussed.A 47-year-old man was admitted with progressive shortness of breath. He was in respiratory failure with a PaO2/FIO2 ratio of 110.8 requiring intubation. Chest computed tomography showed diffuse ground glass opacities. An HIV infection was suspected, and a diagnosis of acute respiratory distress syndrome was made. Based on clinical indications, treatment for Pneumocystis jirovecii pneumonia and concomitant bacterial infection was started. OUTCOME: Despite broad-spectrum antibiotics, the patient's oxygenation deteriorated, necessitating ECMO. After 19 days of ECMO therapy, the patient was successfully decannulated and was eventually discharged. CONCLUSION: In acute respiratory distress syndrome in patients with HIV/AIDS refractory to treatment, ECMO should be considered. Post-ECMO antiretroviral therapy could improve outcomes.

A Case of Conjunctival Ulcer and Uveitis Caused by Acrophialophora Sp. in an Immunocompromised Patient: a Case Report and Riterature Review.

We report the first case of invasive ophthalmologic infection by Acrophialophora sp. that was successfully treated using voriconazole (VRCZ). Acrophialophora spp., which has been reported to be an opportunistic pathogen, is a rare thermotolerant soil fungus, but its pathogenicity remains unclear. A 77-year-old man had neutropenia and prostate carcinoma and was receiving hemodialysis. His right eye had been infected for 2 days. His conjunctiva was congested, and it partially formed an abscess. Liposomal amphotericin B (L-AMB) was administered following systemic itraconazole. However, the treatment was changed from L-AMB to systemic VRCZ and VRCZ eye drops because his eye symptoms worsened. Subsequently, his symptoms stabilized and his vision was maintained. Acrophialophora sp. was identified by analyzing regions of internal transcribed spacer and domain 1 and 2 of the ribosomal RNA gene. He completed the 7-week systemic VRCZ course. The mean minimum inhibitory concentration of VRCZ for Acrophialophora spp. has been reported to be the lowest among various antifungal agents, and our results indicated the efficacy of VRCZ treatment for Acrophialophora sp. infection. Our results suggest that invasive Acrophialophora sp. infection may require long-term therapy. Further analysis of the clinical spectrum of Acrophialophora spp. infection and adequate treatment methods are required in the future.

Bacille Calmette-Guérin (BCG) spondylitis with adjacent mycotic aortic aneurysm after intravesical BCG therapy: a case report and literature review.

BACKGROUND: Although intravesical bacille Calmette-Guérin (BCG) therapy is accepted as an effective treatment for bladder cancer, serious complications may occur in rare cases. To date, only 4 cases have been reported in which the patient developed a combination of mycotic aortic aneurysm and BCG spondylitis. Accurate diagnosis of BCG spondylitis is important because it is an iatrogenic disease, and its treatment is different from usual tuberculous spondylitis. However, distinguishing BCG spondylitis from usual tuberculous spondylitis is very difficult and takes a long time. In this study, we were able to suspect BCG spondylitis at an early stage from the result of the interferon-gamma release assay (IGRA). CASE PRESENTATION: We encountered a case of BCG spondylitis with adjacent mycotic aortic aneurysm after intravesical BCG therapy in a 76-year-old man. We performed a 2-stage operation to obtain spine stabilization and replace the aneurysm with a synthetic graft. We started multidrug therapy with antituberculosis medication, excluding pyrazinamide, because the patient's history of BCG therapy, negative IGRA, and positive of tuberculosis-polymerase chain reaction (Tb-PCR) suggested that the pathogenic bacteria of the spondylitis was BCG. Eventually the bacterial strain was identified as BCG by PCR-based genomic deletion analysis. CONCLUSIONS: BCG infection should be considered in patients who have been treated with BCG therapy, even if the treatment was performed several months to several years previously. In the case of a patient with a history of BCG therapy, a positive Tb-PCR result and negative IGRA result probably suggest BCG infections, if the possibility of false-negative IGRA result can be excluded.

Positive fecal occult blood test as a diagnostic cue for Schistosoma mansoni infection in a developed country.

The rise in eco-tourism and travel off the beaten track have increased numbers of tourists with schistosomiasis which is seldom seen in developed countries, although this disease is considered a neglected tropical disease especially in poor communities. A Guinean male living in Japan was seen complaining of severe constipation. He was positive for fecal occult blood (FOB) and underwent colonoscopy. Colonoscopy showed petechiae of the rectal mucosa, with pathologic examination of biopsy tissue showing calcified eggs of the genus Schistosoma. Direct examination of eggs in feces and antibody tests of serum confirmed the diagnosis of schistosomiasis. The patient was administered Praziquantel (400 mg/day for 2 days) and FOB and fecal ova tests were negative after treatment. FOB tests have been reported as a useful assessment of morbidities associated with intestinal schistosomiasis. In developed countries, positive FOB result, which is used as a main examination for bowel malignant disease, are not recognized as being due to schistosomiasis. As this tropical disease is rarely present in developed countries, it may be under-diagnosed. Schistosomiasis should be included in the differential diagnosis of patients with positive FOB tests.

Solitary pulmonary caseating granulomas: A 5-year retrospective single-center analysis.

Solitary pulmonary caseating granulomas (SPCGs) are a characteristic type of tuberculomas associated with infection with non-tuberculous mycobacteria (NTM) and other microbes; however, their significance remains unclear. The aim of the present study was to describe the clinical characteristics of patients with SPCGs in terms of diagnosis, presence of lung cancer and treatment status. A retrospective analysis of 17 immunocompetent patients with histopathologically confirmed caseating granulomas after undergoing video-assisted thoracoscopic surgery (VATS) was conducted at our center between 2011 and 2015. The patients comprised 10 men and 7 women with a mean age of 59.1±14.4 years. Of the 17 patients, 14 (82.4%) were asymptomatic and the lesions were discovered incidentally. In 2 patients the SPCGs were accompanied by a small satellite nodule (SPCG mean diameter, 16.2±5.1 mm). Mycobacteria, including Mycobacterium tuberculosis (11.8%), Mycobacterium avium (11.8%) Mycobacterium kansasii (23.5%) and other Mycobacterium spp. (5.9%), were isolated from 9 of the patients (52.9%). Concurrent lung cancer was present in 3 patients (17.6%). When microbial agents could not be isolated, the interferon-γ release assay was useful for diagnosis. Positron emission tomography was not found to be useful for differentiating SPCGs from lung cancer, or for differentiating tuberculomas from NTM pulmonary nodules (NTMPNs). NTMPNs in cases of SPCGs were diagnosed more frequently in men. The findings indicate that a course of observation may be sufficient for patients in whom an SPCG from NTM (NTMPN) is identified by VATS. However, the presence of concurrent lung cancer in certain cases indicates that malignancy should not necessarily be excluded, particularly in NTMPNs, and highlights the necessity of aggressive diagnosis by VATS.

[Successful Prophylactic Minocycline Treatment for Recurrent Helicobacter Cinaedi Sepsis during Chemotherapy in a Patient with Follicular Lymphoma].

A 63-year-old man with follicular lymphoma was administered standard R-CHOP chemotherapy. Six days after the second course of chemotherapy, the patient developed fever and chills. Blood cultures yielded rod-shaped gram-negative bacteria, but no further identification was obtained. High fever and chills returned on the fifth and sixth days after the third and fourth courses of R-CHOP, respectively. These blood cultures were also positive. Since we detected spiral-shaped gram-negative rods, we performed a prolonged culture during the febrile period after the fourth course of R-CHOP. This revealed the formation of characteristic film-like colonies, and Helicobacter cinaedi(H. cinaedi)bacteria was identified. After final identification, the patient was administered prophylactic minocycline treatment. Subsequent blood cultures were negative, fever did not recur, and we were able to complete 6 courses of R-CHOP. Although H. cinaedi has been reported to be a cause of sepsis in immunocompromised patients, standard correlation has not been established. Our case suggests that H. cinaedi should be considered when recurrent fever is observed after chemotherapy. Prophylactic antibiotic treatment with minocycline may prevent sepsis, as observed in our case.

Totally implantable central venous device-associated blood stream infection in elderly malignant disease patients.

AIM: We investigated the rate of bloodstream infections in elderly malignant disease patients whose totally implantable central venous device (CV ports) had been removed for any reason at our hospital. METHODS: We evaluated 22 elderly malignant disease patients who had had their CV ports removed for any reason between May 2014 to April 2015. RESULTS: The patients were 12 males and 10 females between 62 and 86 years of age with a median age of 75.5 years. The catheter tip cultures were positive in 6 out of 22 cases (27.3%). Gram-positive cocci were detected in 5 cases, and gram-positive bacilli were detected in 1 case. Five of these 6 cases (83%) found to have positive catheter tip cultures were cultured at the time of death. In addition, 5 of the 13 catheters removed at the time of death resulted in positive culture results (38%). The positive culture ratio correlated well with the ratio of death and the age in cases of hematopoietic tumors. CONCLUSION: In cancer patients, the CV port is frequently used for the delivery of anti-cancer medicines. However, CV port infections are underestimated and typically not recognized in a timely manner. Patients suspected of having a CV port infection should be closely observed and the catheter removed immediately. However, it is very difficult to decide to discontinue a CV port, since its removal may render patients more susceptible to blood stream infections due to their poor general health and old age. CV port use should be considered in such cases to prevent future blood stream infections.

The First Case Report of Cerebral Cyst Infection Due to Helicobacter cinaedi.

We report the first case of cerebral cyst infection by Helicobacter cinaedi, a fastidious spiral-shaped gram-negative rod bacterium. A 70-year-old man visited Tokyo Medical University Hospital with persisting fever since 2 weeks. He underwent surgery and radiotherapy for parapharyngeal space squamous cell carcinoma 10 years ago. The radiotherapy resulted in a cerebral cyst as a side effect, and an Ommaya reservoir was inserted into the cyst. Blood culture and analysis of the brain cyst fluid revealed the presence of spiral-shaped gram-negative rod bacteria, which were identified as H. cinaedi by polymerase chain reaction. Initially, we administered clarithromycin (400 mg per day). After H. cinaedi infection was confirmed, the treatment was changed to meropenem (MEPM 6 g per day). The patient was treated for 43 days in the hospital with intravenous meropenem, and his clinical course was satisfactory. On the 44th day, he was discharged and prescribed oral minocycline (MINO 200 mg per day). After discharge, the patient's H. cinaedi infection did not recur. Our case illustrated the wide clinical spectrum of H. cinaedi as well as the effectiveness of antibiotic therapy comprising MERM and MINO for treating central nervous system infection by this organism.