Serologic tests have assisted in the diagnosis and prognosis of coccidioidomycosis for a half-century. The causative agent, Coccidioides immitis, is a dimorphic fungus existing in a hyphal form with arthroconidia in nature and in the usual culture. The arthroconidia represent the inhaled infective forms which in vivo and under special laboratory conditions form spherules which endosporulate. The culture filtrate/autolysate (coccidioidin) from the hyphal phase has provided antigens of suitable reliability for currently used serologic tests. These tests are primarily to determine the two major antibody responses: the early immunoglobulin M (IgM) response is useful in the diagnosis of acute primary coccidioidomycosis. Later, IgG is produced and usually outlasts the IgM, persisting in chronic coccidioidomycosis. The IgM is detectable by tube precipitin, a corresponding immunodiffusion, or latex particle agglutination tests. The pertinent antigen(s) is heat stable and pronase resistant and appears to be largely carbohydrate, mainly mannose with some 3-O-methyl mannose. The IgG detectable in the serum and other body fluids by complement fixation and a corresponding immuno-diffusion is useful in diagnosis, and its quantitation provides an indicator of progression of disease (increasing titer) or regression (decreasing titer). The pertinent antigen appears to be a heat-labile, pronase-sensitive protein which in an unreduced form has a molecular weight of 110,000. A third very useful serologic procedure is the exoantigen test for identification of putative cultures of C. immitis.

Nikkomycins X and Z, competitive inhibitors of fungal chitin synthase, were evaluated as therapeutic agents in vitro and in mouse models of coccidioidomycosis, histoplasmosis, and blastomycosis. In vitro, the nikkomycins were found to be most effective against the highly chitinous, dimorphic fungi Coccidioides immitis and Blastomyces dermatitidis, were less effective against yeasts, and were virtually without effect on the filamentous fungus Aspergillus fumigatus. Additionally, by transmission electron microscopy, nikkomycin Z was highly disruptive to the cell wall and internal structure of the spherule-endospore phase of C. immitis in vitro. In vivo, nikkomycin Z was more effective than nikkomycin X, was also found to be superior on a milligram per milligram basis to the majority of azoles tested in the models of coccidioidomycosis and blastomycosis, and was moderately effective in histoplasmosis. A study of the pharmacokinetics in mice showed that nikkomycin Z was rapidly eliminated after intravenous infusion but that absorption after oral administration was sufficiently slow to allow inhibitory levels to persist for more than 2 h. Results of limited toxicology tests suggest that nikkomycin Z was well tolerated at the dosages employed.Several antifungal compounds in use today affect the integrity of the fungal cytoplasmic membrane or the synthesis of its constituent ergosterol. Although some of these drugs have demonstrable efficacies and have been widely utilized for treatment of human patients and animals, there is a clear need for drugs with greater fungicidal activities. Because the cell walls of most medically important fungi contain chitin, a polymer not encountered in mammals, compounds which interfere with the synthesis or degradation of this polymer could be useful in therapy of mycoses (3). The polyoxins, which are specific inhibitors of fungal chitin synthase due to their similarity in structure to UDP-N-acetylglucosamine (reviewed in references 4 and 13), the substrate of chitin synthase, had previously been used in vitro against Candida spp. (1, 22, 31) and dimorphic fungi with some success (6,17). A related group of compounds is the nikkomycins, which are structurally similar to the polyoxins and are also inhibitors of chitin synthase (3, 7). We employed nikkomycins X and Z (NX and NZ, respectively) in vitro against selected medically important fungi representing true yeast, dimorphic, and filamentous groups. Because of the high level of activity of these agents against the dimorphic pathogenic fungi, we subsequently evaluated them in mouse models of coccidioidomycosis, blastomycosis, and histoplasmosis, and the results are reported herein. In addition, data are provided on the pharmacokinetics and safety of these compounds.

The superior sensitivity and specificity associated with the use of molecular assays has greatly improved the field of infectious disease diagnostics by providing clinicians with results that are both accurate and rapidly obtained. Herein, we review molecularly based infectious disease diagnostic tests that are Food and Drug Administration approved or cleared and commercially available in the United States as of December 31, 2010. We describe specific assays and their performance, as stated in the Food and Drug Administration's Summary of Safety and Effectiveness Data or the Office of In Vitro Diagnostic Device Evaluation and Safety's decision summaries, product inserts, or peer-reviewed literature. We summarize indications for testing, limitations, and challenges related to implementation in a clinical laboratory setting for a wide variety of common pathogens. The information presented in this review will be particularly useful for laboratories that plan to implement or expand their molecular offerings in the near term.

The performance of a disk diffusion test using broth from positive blood cultures as inoculum (direct disk diffusion [dDD]) was evaluated for a collection of 20 challenge isolates of ,, and Isolates seeded into human blood were inoculated into Bactec Plus Aerobic/F, VersaTREK Redox 1, and BacT/Alert FA Plus bottles and incubated in the respective automated blood culture systems. Disk diffusion results were compared to reference disk diffusion results. Categorical agreement (CA) values for dDD, after removal of random errors due to natural MIC variation, were 87.8%, 88.4%, and 92.2% for the BacT/Alert, Bactec, and VersaTREK systems, respectively. No very major errors (VME) were observed, and major error (ME) rates were 3.0%, 2.3%, and 1.7%, respectively. Incubation of the dDD test samples for 6 h compared to incubation for 16 to 18 h resulted in 19.9% of tests having too light of growth to allow reading of zones of inhibition. Among the evaluable dDD tests, CA values were 58.9%, 76.6%, and 73.2% for the isolates seeded into the BacT/Alert, Bactec, and VersaTREK systems, respectively. VME rates for isolates seeded into these systems were 2.2%, 1.8%, and 3.0%, respectively, and ME rates were 25.4%, 6.1%, and 2.8%, respectively, at the 6-h reading. The best performance of dDD was found for blood cultures with bacterial concentrations in the range of 7.6 × 10 to 5.0 × 10 CFU/ml; CA values ranged from 94.7 to 96.2% for these concentrations after 18 h of incubation and from 76.9 to 84.1% after 6 h of incubation. These preliminary data demonstrate the potential accuracy of dDD testing by the clinical laboratory.

This is the first report in the United States of bloodstream infection due to S. epidermidis with decreased susceptibility to vancomycin. Contact precautions likely played a role in preventing nosocomial transmission of this strain, and disk-diffusion methods may be inadequate to detect CNS with decreased susceptibility to vancomycin.

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