Comparative toxicity and concentrations of intravitreal amphotericin B formulations in a rabbit model

PURPOSE: To determine the toxicity of various doses of intravitreal amphotericin B deoxycholate, amphotericin B lipid complex (ABLC), and liposomal amphotericin B (L-AmB). METHODS: Fifty-two rabbits were divided into two treatment groups (groups A and B). Thirteen treatments were administered intravitreally to the 104 rabbit eyes. Treatments included a control plus 10, 20, 30, and 50 micro g amphotericin B deoxycholate, ABLC, and L-AmB. Eye examinations were performed before injection and on day 11 for group A and on day 18 for group B. At death, on days 13 and 21 in groups A and B, respectively, vitreous humor was aspirated and concentrations of amphotericin B were determined by high performance liquid chromatography (HPLC), followed by enucleation for histologic studies. RESULTS: Significantly more eyes treated with ABLC showed development of vitreal opacities than developed in eyes treated with amphotericin B deoxycholate or L-AmB (P < 0.05). Vitreal band formation was significantly higher in ABLC-treated eyes than in those treated with L-AmB, (P = 0.039). Vitreal inflammation was greater in eyes treated with L-AmB (75%), amphotericin B deoxycholate (78%), and ABLC (91%) than with the control (50%; P = 0.08). Retinal ganglion cell loss was greater in eyes treated with amphotericin B deoxycholate (81%), L-AmB (91%), and ABLC (97%) than with the control (38%; P = 0.003). Amphotericin B concentrations were measurable for all doses of the three formulations. CONCLUSIONS: Based on histologic data, increasing doses of all three agents appear to be associated with increasing toxicity, however based on ophthalmologic data, L-AmB appears to be less toxic than either amphotericin B deoxycholate or ABLC.     

Intravenous azithromycin

OBJECTIVE: To review the pharmacology, microbiology, chemistry, pharmacokinetics, efficacy, safety, tolerability, dosage, administration, and economic issues of intravenous azithromycin. DATA SOURCES: A MEDLINE search from 1978 to May 1998 of the English-language literature and an extensive review of journals and meeting abstracts was conducted. Due to the lack of published literature concerning the efficacy, safety, and pharmacokinetics of the intravenous formulation of azithromycin, the manufacturer was also contacted and requested to supply information concerning intravenous azithromycin. DATA EXTRACTION: In vitro and preclinical studies were included, as well as data from Phase II and III clinical trials. Efficacy, pharmacokinetic, safety, and tolerability data were also supplemented with information from the manufacturer, due to the lack of published reports. DATA SYNTHESIS: Azithromycin, an azalide subclass of the macrolide antibiotics, is now available as an intravenous formulation. The intravenous form is approved for the treatment of community-acquired pneumonia caused by Chlamydia pneumoniae, Haemophilus influenzae. Legionella pneumophila, Moraxella catarrhalis, Mycoplasma pneumoniae, Staphylococcus aureus (methicillin-sensitive), and Streptococcus pneumoniae, and for the treatment of pelvic inflammatory disease caused by Chlamydia trachomatis, Neisseria gonorrhoeae, and Mycoplasma hominis in situations in which intravenous therapy is required. Its spectrum of activity, unique pharmacokinetics, and high and sustained tissue penetration allow for once-daily dosing with monotherapy in many cases. Clinical and bacteriologic response rates as well as the adverse event profile have been similar to or better than comparative agents. CONCLUSIONS: Azithromycin offers advantages over other agents due to its unique pharmacokinetics, high and sustained tissue penetration, and spectrum of activity. This allows for monotherapy and once-daily intravenous dosing for mild-to-moderate community-acquired pneumonia or pelvic inflammatory disease in many instances. Future research should focus on total duration of antibiotic therapy and the need, or lack thereof, for extensive oral antibiotic follow-up.     

Cunninghamella bertholletiae infection in a bone marrow transplant patient: amphotericin lung penetration, MIC determinations, and review of the literature.

Infections caused by Cunninghamella bertholletiae, an opportunistic fungal organism, have an extremely high mortality rate. A fatal case of C. bertholletiae fungal pneumonia occurred in a man who had received an allogeneic bone marrow transplant. Aggressive debridement and high-dose liposomal amphotericin B failed to eradicate the infection. Right lung tissue samples obtained during lobectomy were assayed for amphotericin B concentrations by high-performance liquid chromatography, and minimum inhibitory concentration (MIC) determinations of amphotericin B against C. bertholletiae were determined by the macrobroth dilution method. The MIC for the isolate of C. bertholletiae was 4 microg/ml. Amphotericin B lung concentrations averaged 9.5 microg/ml (range 3.7-13.8 microg/ml), with a corresponding serum trough concentration of 0.9 microg/ml. To our knowledge, this is the first reported case of amphotericin B concentrations measured at the site of infection in a patient with a pulmonary Cunninghamella infection, together with a corresponding MIC of the organism. The patient's death, which occurred despite aggressive debridement and high amphotericin B lung concentrations, highlights the need for novel strategies to treat infections caused by invasive molds such as C. bertholletiae.     

Bactericidal Activity and Postantibiotic Effect of Levofloxacin against Anaerobes

The bactericidal activity and postantibiotic effect (PAE) of levofloxacin against nine anaerobes were determined. Levofloxacin at concentrations of the MIC and twice the MIC was bactericidal at 24 h to five of nine and nine of nine strains, respectively. The PAE of levofloxacin following a 2-h exposure ranged from 0.06 to 2.88 h.     

Quantitative changes in morphological parameters in the developing visual cortex of the marmoset monkey

Several quantitative morphological parameters were measured during postnatal development in area 17 of the marmoset monkey (Callithrix jacchus). In a series of 14 animals, at ages from birth to adulthood, we studied changes in the thickness, surface area and volume of area 17, as well as the neuronal and glial numerical densities, and total numbers. We found evidence for a rapid increase in thickness, area and volume, culminating between 6 weeks and 6 months postnatally, and then decreasing. The adult values are close to those observed in one-month-old animals. The overshoot in thickness and volume is greatest in layers II, III, IVa and IVc. The neuronal density shows a trend which is opposite to that of volume, and therefore the total number of neurons is constant postnatally, ca. 38 million neurons in area 17 of one hemisphere. The number of glial cells approximately doubles during the first postnatal month and remains stable afterwards, so that in the adult, there is one glial cell for two neurons. Morphological development of area 17 in this New World monkey is similar to that reported in Old World monkeys, as are the adult values for neuronal and glial densities.     

Symptomatic nephrolithiasis in prolonged survivors of Duchenne muscular dystrophy

In this study, we describe the association between Duchenne muscular dystrophy (DMD) and symptomatic nephrolithiasis. The DMD patients were matched to non-ambulatory control patients with non-DMD neurological diagnoses via retrospective chart review. All patients with DMD and symptomatic nephrolithiasis were over 20 years old. We found that six of the 29 at-risk DMD patients had nephrolithiasis (20.7%) while only one of the 68 control patients had nephrolithiasis (1.5%) (p<0.0001). Controlling for duration of immobilization with stratified analysis, the risk ratio for nephrolithiasis among DMD patients compared with controls was 9.94. Using rate-based estimates of renal stone development per 10,000 patient-years, the ratio of stone development among DMD patients compared with controls was 18.5. On logistic regression analysis, the corrected odds ratio for nephrolithiasis comparing DMD patients to controls was 14.26. We conclude that, in our study group, DMD was an independent risk factor for symptomatic nephrolithiasis.     

Comparison of the T2Dx instrument with T2Candida assay and automated blood culture in the detection of Candida species using seeded blood samples

As a delay in the diagnosis and treatment of candidemia is associated with increased mortality and healthcare costs, a more rapid method of detection is urgently needed. The T2Candida assay is a new rapid diagnostic test, which uses T2 magnetic resonance technology to identify Candida spp. directly from whole blood in approximately 3 hours. In this study, the performance of the BACTEC 9050 using Aerobic Plus/F blood culture bottles was compared to that of the T2Candida assay run on the T2Dx Instrument for detection of Candida albicans, Candida tropicalis, Candida parapsilosis, Candida glabrata, and Candida krusei, in seeded blood samples at concentrations between 3.1 and 11 CFU/mL. The BACTEC 9050 detected Candida growth in 100% of bottles (n = 20 replicates) within 5 days for all species (63.23 ± 30.27 hours), with the exception of Candida glabrata (0%). The T2Candida assay had a 100% detection rate for each species (n = 13–20 replicates) within 3 hours including C. glabrata. The sensitivity and specificity of the T2Candida assay were 1 and 0.978, respectively.