Deficiency of lymph node-resident dendritic cells (DCs) and dysregulation of DC chemoattractants in a malnourished mouse model of Leishmania donovani infection.

Malnutrition is thought to contribute to more than one-third of all childhood deaths via increased susceptibility to infection. Malnutrition is a significant risk factor for the development of visceral leishmaniasis, which results from skin inoculation of the intracellular protozoan Leishmania donovani. We previously established a murine model of childhood malnutrition and found that malnutrition decreased the lymph node barrier function and increased the early dissemination of L. donovani. In the present study, we found reduced numbers of resident dendritic cells (conventional and monocyte derived) but not migratory dermal dendritic cells in the skin-draining lymph nodes of L. donovani-infected malnourished mice. Expression of chemokines and their receptors involved in trafficking of dendritic cells and their progenitors to the lymph nodes was dysregulated. C-C chemokine receptor type 2 (CCR2) and its ligands (CCL2 and CCL7) were reduced in the lymph nodes of infected malnourished mice, as were CCR2-bearing monocytes/macrophages and monocyte-derived dendritic cells. However, CCR7 and its ligands (CCL19 and CCL21) were increased in the lymph node and CCR7 was increased in lymph node macrophages and dendritic cells. CCR2-deficient mice recapitulated the profound reduction in the number of resident (but not migratory dermal) dendritic cells in the lymph node but showed no alteration in the expression of CCL19 and CCL21. Collectively, these results suggest that the malnutrition-related reduction in the lymph node barrier to dissemination of L. donovani is related to insufficient numbers of lymph node-resident but not migratory dermal dendritic cells. This is likely driven by the altered activity of the CCR2 and CCR7 chemoattractant pathways.

An Exuberant Case of Ulceronodular-Rupioid (Malignant) Syphilis in an HIV Patient: A Proposal for New Diagnostic Criteria.

We report the case of a 28-year-old male with uncontrolled human immunodeficiency virus (HIV) infection who presented with extensive ulcerated lesions with dark lamellated crusting on his face, torso, and limbs. The patient had a rapid plasma reagin (RPR) titer of 1:512, indicative of syphilis. A skin biopsy revealed granulomata surrounded by lymphocytes, histiocytes, and plasma cells, with spirochetes visible on immunohistochemical staining. The patient's rash resolved with hyperpigmented scarring after penicillin and doxycycline treatment. This severe form of secondary syphilis has been termed malignant syphilis, lues maligna, ulceronodular syphilis, or rupioid syphilis. We propose a single descriptive name for this entity, ulceronodular-rupioid syphilis. In 1969, Fisher proposed criteria for malignant syphilis based on lesion appearance, histopathologic findings, high RPR values, and rapid response to treatment. We found that the Fisher criteria were imprecise with respect to specific histopathologic findings, the quantitation of RPR values, and what constitutes rapid response to treatment. Thus, we examined an additional 74 cases from the literature and propose new diagnostic criteria based on rash appearance, histopathologic characteristics, non-treponemal and treponemal test positivity, and response to therapy. We also found that uncontrolled viremia, and not a low CD4 count, is a major risk factor for ulceronodular-rupioid syphilis in HIV patients.

Flea-Borne Typhus as a COVID-19 Mimic: A Report of Four Cases.

Flea-borne typhus (FBT), due to Rickettsia typhi and R. felis, is an infection causing fever, headache, rash, hepatitis, thrombocytopenia, and diverse organ manifestations. Cough occurs in about 30% of patients with FBT, and chest X-ray abnormalities are seen in 17%. Severe pulmonary manifestations have also been reported in FBT, including adult respiratory distress syndrome and pulmonary embolism. Because of these pulmonary manifestations, FBT can mimic Coronavirus Illness 2019 (COVID-19), a febrile illness with prominent respiratory involvement. Flea-borne typhus and COVID-19 may also have similar laboratory abnormalities, including elevated ferritin, C-reactive protein, and D-dimer. However, elevated transaminase levels, rash, and thrombocytopenia are more common in FBT. Herein, we present four cases of patients with FBT who were initially suspected to have COVID-19. These cases illustrate the problem of availability bias, in which the clinician thinks a particular common condition (COVID-19 in this case) is more prevalent than it actually is.

Pseudopropionibacterium propionicum as a Cause of Empyema; A Diagnosis with Next-Generation Sequencing.

Pseudopropionibacterium propionicum (P.p.) is an anaerobic, Gram-positive, branching beaded rod that is a component of the human microbiome. An infection of the thoracic cavity with P.p. can mimic tuberculosis (TB), nocardiosis, and malignancy. We present a case of a 77-year-old male who presented with dyspnea and a productive cough who was initially misdiagnosed with TB based on positive acid-fast staining of a pleural biopsy specimen and an elevated adenosine deaminase level of the pleural fluid. He was then diagnosed with nocardiosis based on the Gram stain of his pleural fluid that showed a Gram-positive beaded and branching rod. The pleural fluid specimen was culture-negative, but the diagnosis of thoracic P.p. infection was determined with next-generation sequencing (NGS). The patient was initially treated with imipenem and minocycline, then ceftriaxone and minocycline, and later changed to minocycline only. This report shows the utility of NGS in making a microbiological diagnosis when other techniques either failed to provide a result (culture) or gave misleading information (histopathologic exam, pleural fluid adenosine deaminase determination, and organism morphology on Gram stain).

Flea-Borne Typhus Causing Hemophagocytic Lymphohistiocytosis: An Autopsy Case.

Infection with members of the order Rickettsiales (the genera Rickettsia, Anaplasma, Orientia, and Ehrlichia) is known to cause hemophagocytic lymphohistiocytosis (HLH). The literature is scant on flea-borne typhus (FBT) being implicated in this process. We present a case of autopsy-proven HLH caused by FBT in a 71-year-old diabetic female who was initially suspected of having diabetic ketoacidosis who rapidly suffered decompensated multi-organ failure. Although she was suspected of having FBT and HLH pre-mortem, due to her rapid progression to multi-organ failure, she was transitioned to comfort care by her family five days after admission. A literature search yielded five other cases of HLH secondary to FBT, which are analyzed in this review. The literature on HLH occurring with infection due to other members of the order Rickettsiales is also surveyed.

Adiaspiromycosis causing respiratory failure and a review of human infections due to Emmonsia and Chrysosporium spp.

We report a case of a 27-year-old male who presented with respiratory distress that required mechanical ventilation. Transbronchial biopsy revealed adiaspores of the fungus Emmonsia crescens within granulomata, a condition known as adiaspiromycosis. The patient received amphotericin products and corticosteroids, followed by itraconazole, and made a full recovery. Emmonsia crescens is a saprobe with a wide distribution that is primarily a rodent pathogen. The clinical characteristics of the 20 cases of human pulmonary adiaspiromycosis reported since the last comprehensive case review in 1993 are described here, as well as other infections recently reported for the genus Emmonsia. Pulmonary adiaspiromycosis has been reported primarily in persons without underlying host factors and has a mild to severe course. It remains uncertain if the optimal management of severe pulmonary adiaspiromycosis is supportive or if should consist of antifungal treatment, corticosteroids, or a combination of the latter two. The classification of fungi currently in the genus Emmonsia has undergone considerable revision since their original description, including being grouped with the genus Chrysosporium at one time. Molecular genetics has clearly differentiated the genus Emmonsia from the Chrysosporium species. Nevertheless, there has been a persistent confusion in the literature regarding the clinical presentation of infection with fungi of these two genera; to clarify this matter, the reported cases of invasive Chrysosporium infections were reviewed. Invasive Chrysosporium infections typically occur in impaired hosts and can have a fatal course. Based on limited in vitro susceptibility data for Chrysosporium zonatum, amphotericin B is the most active drug, itraconazole susceptibility is strain-dependent, and fluconazole and 5-fluorocytosine are not active.

Septic arthritis due to Nocardia brasiliensis and a review of nocardiosis as a cause of arthritis.

Bacteria of the genus Nocardia are implicated in several disease processes but are a rare cause of septic arthritis. Typically, the cause of Nocardia septic arthritis is dissemination from a pulmonary infection in an immunocompromised host. Herein we present a case of a 64-year-old male who had received a long course of prednisone for membranous nephropathy and developed a septic arthritis due to Nocardia brasiliensis. He was treated sequentially with trimethoprim-sulfamethoxazole and amoxicillin-clavulanate, linezolid and amoxicillin-clavulanate, tigecycline and amoxicillin-clavulanate, and omadacycline and amoxicillin-clavulanate. To our knowledge, only two prior cases of Nocardia brasiliensis septic arthritis without antecedent trauma to the joint or local skin breakdown have been reported. A review of the literature identified 19 other cases of Nocardia septic arthritis. This case reinforces the need to consider Nocardia infection in the differential diagnosis in the immunocompromised patient with concurrent pulmonary infection and septic arthritis.

Fatal coccidioidomycosis involving the lungs, brain, tongue, and adrenals in a cirrhotic patient. An autopsy case.

In this paper, we describe a case of fatal disseminated coccidioidomycosis (CM). The patient was a 44-year old male with a history of cirrhosis who presented with altered mental status, cough, and an enlarged, ulcerated tongue. On evaluation, the patient was found to have coccidioidal infection of the tongue, lungs, and brain. Despite over two months of antifungal treatment, the patient died from aspiration pneumonia and at autopsy was found to have persistent infection of the tongue and lungs, extensive mycosis of the brain, and involvement of both adrenal glands. The fulminant course of coccidioidomycosis in this patient is ascribed to his baseline cirrhosis and lymphocytopenia. There are few autopsy cases of CM that have been described in the post-antifungal era and few published cases of CM with either tongue or adrenal involvement.

A Surprising Cause of Liver Abscesses in a Post-Chemotherapy Patient: Herpes Simplex Virus.

Herpes simplex virus (HSV) hepatitis is a rare complication of HSV infection, and a rare cause of hepatitis. It is often fatal, especially if the diagnosis and treatment are delayed. Herein, we describe the case of a 31-year-old female with a history of receiving cytotoxic cancer chemotherapy five months prior who presented with a one-week history of worsening abdominal pain and fever. She was noted to have an outbreak of genital herpes at the time of presentation. Computed tomography (CT) scan of the abdomen showed innumerable hypodensities compatible with hepatic micro-abscesses. A specimen from a subsequent liver biopsy revealed HSV-type cytopathic changes and nuclear staining with an anti-HSV immunohistochemical stain. She was initially started on high-dose oral valacyclovir for genital herpes and was noted to have rapid clinical improvement prior to the histopathologic diagnosis of HSV hepatitis. She achieved full recovery while on oral valacyclovir. This is the first reported case of HSV hepatitis treated with oral valacyclovir and the third reported case of HSV hepatitis mimicking pyogenic abscesses on abdominal imaging. With the high mortality rate associated with HSV hepatitis, one should consider the diagnosis in all patients with multifocal liver lesions of unknown etiology, especially if genital herpes is present at the time of presentation, or in patients who are immunocompromised.

Pandora's Box: Disseminated Coccidioidomycosis Associated with Self-Medication with an Unregulated Potent Corticosteroid Acquired in Mexico.

Coccidioidomycosis (CM), caused by the dimorphic fungi Coccidioides immitis and C. posadasii, typically presents as acute or chronic pulmonary disease. However, disseminated disease occurs in about 1% of patients. Disseminated CM may affect multiple organ systems, including cutaneous, osteoarticular, and central nervous system sites. Here, we present a case of disseminated CM in a patient from a border city in Texas. The patient had a history of uncontrolled diabetes mellitus and was also taking an over-the-counter medication acquired in Mexico that contained a potent corticosteroid. The patient presented with seizures and was found to have a brain infarct, cavitary lung lesions, synovitis of the knee, multiple skin lesions, and chorioretinitis. The patient had a very high complement fixation titer for Coccidioides; fungal spherules were seen in a skin biopsy specimen, and Coccidioides grew in culture from a sample of synovial fluid and the skin biopsy specimen. This case illustrates the dissemination potential of Coccidioides, the danger of unregulated pharmaceuticals, the importance of thorough history taking, and recognizing risk factors that contribute to disseminated CM.

History, Rats, Fleas, and Opossums. II. The Decline and Resurgence of Flea-Borne Typhus in the United States, 1945-2019.

Flea-borne typhus, due to Rickettsia typhi and R. felis, is an infection causing fever, headache, rash, and diverse organ manifestations that can result in critical illness or death. This is the second part of a two-part series describing the rise, decline, and resurgence of flea-borne typhus (FBT) in the United States over the last century. These studies illustrate the influence of historical events, social conditions, technology, and public health interventions on the prevalence of a vector-borne disease. Flea-borne typhus was an emerging disease, primarily in the Southern USA and California, from 1910 to 1945. The primary reservoirs in this period were the rats Rattus norvegicus and Ra. rattus and the main vector was the Oriental rat flea (Xenopsylla cheopis). The period 1930 to 1945 saw a dramatic rise in the number of reported cases. This was due to conditions favorable to the proliferation of rodents and their fleas during the Depression and World War II years, including: dilapidated, overcrowded housing; poor environmental sanitation; and the difficulty of importing insecticides and rodenticides during wartime. About 42,000 cases were reported between 1931-1946, and the actual number of cases may have been three-fold higher. The number of annual cases of FBT peaked in 1944 at 5401 cases. American involvement in World War II, in the short term, further perpetuated the epidemic of FBT by the increased production of food crops in the American South and by promoting crowded and unsanitary conditions in the Southern cities. However, ultimately, World War II proved to be a powerful catalyst in the control of FBT by improving standards of living and providing the tools for typhus control, such as synthetic insecticides and novel rodenticides. A vigorous program for the control of FBT was conducted by the US Public Health Service from 1945 to 1952, using insecticides, rodenticides, and environmental sanitation and remediation. Government programs and relative economic prosperity in the South also resulted in slum clearance and improved housing, which reduced rodent harborage. By 1956, the number of cases of FBT in the United States had dropped dramatically to only 98. Federally funded projects for rat control continued until the mid-1980s. Effective antibiotics for FBT, such as the tetracyclines, came into clinical practice in the late 1940s. The first diagnostic test for FBT, the Weil-Felix test, was found to have inadequate sensitivity and specificity and was replaced by complement fixation in the 1940s and the indirect fluorescent antibody test in the 1980s. A second organism causing FBT, R. felis, was discovered in 1990. Flea-borne typhus persists in the United States, primarily in South and Central Texas, the Los Angeles area, and Hawaii. In the former two areas, the opossum (Didelphis virginiana) and cats have replaced rats as the primary reservoirs, with the cat flea (Ctenocephalides felis) now as the most important vector. In Hawaii, 73% of cases occur in Maui County because it has lower rainfall than other areas. Despite great successes against FBT in the post-World War II era, it has proved difficult to eliminate because it is now associated with our companion animals, stray pets, opossums, and the cat flea, an abundant and non-selective vector. In the new millennium, cases of FBT are increasing in Texas and California. In 2018-2019, Los Angeles County experienced a resurgence of FBT, with rats as the reservoir.

History, Rats, Fleas, and Opossums: The Ascendency of Flea-Borne Typhus in the United States, 1910-1944.

Flea-borne typhus, due to Rickettsia typhi and Rickettsia felis, is an infection causing fever, headache, rash, hepatitis, thrombocytopenia, and diverse organ manifestations. Although most cases are self-limited, 26%-28% have complications and up to one-third require intensive care. Flea-borne typhus was recognized as an illness similar to epidemic typhus, but having a milder course, in the Southeastern United States and TX from 1913 into the 1920s. Kenneth Maxcy of the US Public Health Service (USPHS) first described the illness in detail and proposed a rodent reservoir and an arthropod vector. Other investigators of the USPHS (Eugene Dyer, Adolph Rumreich, Lucius Badger, Elmer Ceder, William Workman, and George Brigham) determined that the brown and black rats were reservoirs and various species of fleas, especially the Oriental rat flea, were the vectors. The disease was recognized as a health concern in the Southern United States in the 1920s and an increasing number of cases were observed in the 1930s and 1940s, with about 42,000 cases reported between 1931-1946. Attempts to control the disease in the 1930s by fumigation and rat proofing and extermination were unsuccessful. The dramatic increase in the number of cases from 1930 through 1944 was due to: the diversification of Southern agriculture away from cotton; the displacement of the smaller black rat by the larger brown rat in many areas; poor housing conditions during the Great Depression and World War II; and shortages of effective rodenticides and insecticides during World War II.

Parinaud's Oculoglandular Syndrome: A Case in an Adult with Flea-Borne Typhus and a Review.

Parinaud's oculoglandular syndrome (POGS) is defined as unilateral granulomatous conjunctivitis and facial lymphadenopathy. The aims of the current study are to describe a case of POGS with uveitis due to flea-borne typhus (FBT) and to present a diagnostic and therapeutic approach to POGS. The patient, a 38-year old man, presented with persistent unilateral eye pain, fever, rash, preauricular and submandibular lymphadenopathy, and laboratory findings of FBT: hyponatremia, elevated transaminase and lactate dehydrogenase levels, thrombocytopenia, and hypoalbuminemia. His condition rapidly improved after starting doxycycline. Soon after hospitalization, he was diagnosed with uveitis, which responded to topical prednisolone. To derive a diagnostic and empiric therapeutic approach to POGS, we reviewed the cases of POGS from its various causes since 1976 to discern epidemiologic clues and determine successful diagnostic techniques and therapies; we found multiple cases due to cat scratch disease (CSD; due to Bartonella henselae) (twelve), tularemia (ten), sporotrichosis (three), Rickettsia conorii (three), R. typhi/felis (two), and herpes simplex virus (two) and single cases due to tuberculosis, paracoccidioidomycosis, Yersinia enterocolitica, Pasteurella multocida, Chlamydia trachomatis, Epstein-Barr virus, and Nocardia brasiliensis. Preauricular lymphadenopathy is a common clinical clue for POGS and is unusual in viral and bacterial conjunctivitis. For POGS, the major etiological consideration is B. henselae, which is usually diagnosed by the indirect immunofluorescence serologic technique. Although CSD POGS is usually self-limited, oral azithromycin may hasten resolution. However, other possible etiologies of POGS may also arise from cat or cat flea contact: sporotrichosis, tularemia, Pasteurella multocida, or FBT. If there is no cat contact, other epidemiologic and clinical findings should be sought, because several of these conditions, such as tularemia, paracoccidioidomycosis, and tuberculosis, may have grave systemic complications. Although there are usually no long-term ocular sequelae if POGS is properly diagnosed, it still may cause prolonged ocular discomfort and require multiple physician contacts.

Case Report: Early Doxycycline Therapy for Potential Rickettsiosis in Critically Ill Patients in Flea-Borne Typhus-Endemic Areas.

Flea-borne typhus (FBT), although usually perceived as a self-resolving febrile illness, actually encompasses a wide spectrum of disease severity, including fulminant sepsis with multi-organ failure. In endemic Texas and California, the incidence of FBT has more than doubled over the last decade. Clinicians remain unfamiliar with severe septic presentations of FBT when considering the etiologies of acute undifferentiated febrile syndromes. The diagnostic challenges of FBT include the nonspecific and variable nature of both history and physical examination and the lack of diagnostic testing that can provide clinically relevant information early in the course of infection. These barriers perpetuate misdiagnoses in critically ill patients and lead to delay in initiating appropriate antibiotics, which may contribute to preventable morbidity and mortality. This case series describes the clinical and diagnostic trajectories of three patients who developed FBT-associated multi-organ dysfunction. These patients achieved resolution of infection after receiving doxycycline in the context of a high clinical suspicion. Patients residing in FBT-endemic areas presenting with a febrile illness of unknown etiology with a suggestive constellation of hyponatremia, elevated transaminase levels, and thrombocytopenia should be suspected of having FBT. Clinicians should proceed to serologic testing with early doxycycline therapy for potential rickettsiosis. Familiarizing clinicians with the presentation of rickettsiosis-associated septic syndromes and its early and appropriate antibiotic treatment can provide lifesaving care and reduce health-care costs through prevention of the morbidity associated with FBT.

Hemoptysis in the Immunocompromised Patient: Do Not Forget Strongyloidiasis.

Strongyloidiasis, due to infection with the nematode Strongyloides stercoralis, affects millions of people in the tropics and subtropics. Strongyloides has a unique auto-infective lifecycle such that it can persist in the human host for decades. In immunosuppressed patients, especially those on corticosteroids, potentially fatal disseminated strongyloidiasis can occur, often with concurrent secondary infections. Herein, we present two immunocompromised patients with severe strongyloidiasis who presented with pneumonia, hemoptysis, and sepsis. Both patients were immigrants from developing countries and had received prolonged courses of corticosteroids prior to admission. Patient 1 also presented with a diffuse abdominal rash; a skin biopsy showed multiple intradermal Strongyloides larvae. Patient 1 had concurrent pneumonic nocardiosis and bacteremia with Klebsiella pneumoniae and Enterococcus faecalis. Patient 2 had concurrent Aspergillus and Candida pneumonia and developed an Aerococcus meningitis. Both patients had negative serologic tests for Strongyloides; patient 2 manifested intermittent eosinophilia. In both patients, the diagnosis was afforded by bronchoscopy with lavage. The patients were successfully treated with broad-spectrum antibiotics and ivermectin. Patient 1 also received albendazole. Strongyloidiasis should be considered in the differential diagnosis of hemoptysis in immunocompromised patients with possible prior exposure to S. stercoralis.

Plastic Bronchitis in an AIDS Patient with Pulmonary Kaposi Sarcoma.

Plastic bronchitis is the expectoration of bronchial casts in the mold of the tracheobronchial tree. It is a rare occurrence of unknown etiology that has been primarily described in children with congenital heart disease. In this case report, we present the first reported case of plastic bronchitis in a patient with pulmonary Kaposi sarcoma and underlying HIV infection.

Case Report: Fulminant Murine Typhus Presenting with Status Epilepticus and Multi-Organ Failure: an Autopsy Case and a Review of the Neurologic Presentations of Murine Typhus.

Murine typhus (MT) is an important cause of febrile illness in endemic areas, and there is an epidemiologic resurgence of this infection currently transpiring in Texas and California. Fatal cases and severe neurological complications are rare. A fatal case of MT in a middle-aged man is reported with a course culminating in multi-organ failure and refractory status epilepticus. An autopsy revealed hemorrhagic pneumonia, acute tubular necrosis, and ischemic necrosis in the liver, adrenals, and brain. We have also reviewed the neurologic complications of MT.

Posaconazole for the treatment of azole-refractory oropharyngeal and esophageal candidiasis in subjects with HIV infection.

BACKGROUND: We evaluated the efficacy and safety of oral posaconazole for human immunodeficiency virus (HIV)-infected subjects with oropharyngeal candidiasis (OPC) and/or esophageal candidiasis (EC) who were clinically refractory to treatment with oral fluconazole or itraconazole. METHODS: Subjects with confirmed OPC or EC who did not improve after receiving standard courses of fluconazole or itraconazole treatment were eligible for study enrollment. Subjects received either oral posaconazole (400 mg twice daily) for 3 days followed by oral posaconazole (400 mg once daily) for 25 days (regimen A; 103 patients) or oral posaconazole (400 mg twice daily) for 28 days (regimen B; 96 patients). The primary end point was cure or improvement after 28 days. Primary efficacy analyses were performed on the subset of treated subjects with refractory disease (e.g., baseline culture positive for fluconazole- or itraconazole-resistant Candida species or persistent or progressive clinical signs or symptoms consistent with treatment failure). RESULTS: Of the modified intent-to-treat population, 132 (75%) of 176 subjects achieved a clinical response to posaconazole treatment. Clinical response rates were similar between regimen A recipients (75.3%) and regimen B recipients (74.7%). Clinical responses occurred in 67 (73%) of 92 subjects with baseline isolates resistant to fluconazole, 49 (74%) of 66 subjects with baseline isolates resistant to itraconazole, and 42 (74%) of 57 subjects with isolates resistant to both. Clinical response was achieved in 32 (74.4%) of 43 subjects with endoscopically documented EC. The most common treatment-related adverse events were diarrhea (11%), neutropenia (7%), flatulence (6%), and nausea (6%). Eight subjects (4%) discontinued therapy as a result of a treatment-related adverse event. CONCLUSIONS: Posaconazole offers a safe and effective treatment option for HIV-infected subjects with azole-refractory OPC and/or EC.

Posaconazole therapy for chronic refractory coccidioidomycosis.

BACKGROUND: Coccidioides infections often result in chronic relapsing disease that presents a challenge to the currently available therapy. Posaconazole, an oral extended-spectrum triazole agent, has been shown in vitro and in vivo to have potent activity against this fungus. METHODS: An open-label multinational study of posaconazole, 800 mg/d, administered in divided doses for the treatment of invasive fungal infection that has been refractory to previous therapy was conducted. The data were reviewed by an independent data review committee (DRC). Fifteen patients met the criteria for proven coccidioidal infection and disease refractory to previous therapy. Success was a complete or partial response; nonsuccess was stable disease, lack of response to therapy, or undetermined response. RESULTS: The sites of coccidioidal infection were pulmonary (seven patients) and disseminated (eight patients). Patients were refractory to previous therapy (including amphotericin B with or without an azole) for a median duration of 306 days. At the end of treatment (posaconazole treatment duration, 34 to 365 days), therapy for 11 of 15 patients (73%) was considered to be successful by the DRC. Four responses were complete and seven were partial; these included five patients with pulmonary sites and six patients with disseminated sites. In responders, improvement was seen within months of the initiation of therapy. Five patients received therapy for >or= 12 months. The side effects were minimal. CONCLUSIONS: Therapy for coccidioidomycosis remains a clinical challenge, especially when patients have not responded to therapy with drugs that were recommended in treatment guidelines. The success rate (73%) achieved in this case series suggests that oral posaconazole should be considered as an important agent for the treatment of refractory coccidioidomycosis.

Treatment of infections caused by resistant Staphylococcus aureus.

We review data on the treatment of infections caused by drug-resistant Staphylococcus aureus, particularly methicillin-resistant S. aureus (MRSA). In this review, we cover findings reported in the English language medical literature up to February 2006. Despite the emergence of resistant and multidrug resistant S. aureus, five effective drugs for which little resistance has been observed are in clinical use: vancomycin, quinupristin-dalfopristin, linezolid, tigecycline, and daptomycin. However, vancomycin is less effective for infections with MRSA isolates that have a high minimum inhibitory concentration in the susceptible range. Linezolid looks promising in the treatment of MRSA pneumonia and skin and soft-tissue infections (SSTIs). Daptomycin displays rapid bactericidal activity in vitro, and it has been shown to be noninferior to comparator agents in the treatment of SSTIs and bacteremia. Tigecycline was also noninferior to comparator drugs in the treatment of SSTIs. Clindamycin, trimethoprim-sulfamethoxazole, doxycycline, and minocycline are oral antistaphylococcal agents that may have utility in the treatment of SSTIs and osteomyelitis, but the clinical data for their efficacy is limited. There are four drugs with broad-spectrum activity against Gram-positive organisms at an advanced stage of clinical testing: ceptobiprole and three new glycopeptides with potent bactericidal activity, oritavancin, dalbavancin, and telavancin. Thus, there are currently many effective drugs to treat resistant S. aureus infections and many promising agents in the pipeline. Nevertheless, S. aureus remains a formidable adversary against which there are frequent treatment failures. The next goals are to determine the most appropriate indications and cost-effectiveness of each of these drugs in the treatment strategy against S. aureus.