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Objectives: To evaluate the spermicidal efficacy of non-hormonal vaginal gel in vitro and in a post-coital test, and to evaluate its contraceptive efficacy in Canadian women of childbearing age., Methods: We conducted single-centre trial to assess spermicidal and contraceptive efficacy of vaginal gel. Participants were healthy, sexually active women aged 18-49 years and their regular male sexual partners (30 couples). Measured outcomes included effect of vaginal gel on sperm motility in vitro, its effect on sperm in a post-coital test, and its effect on pregnancy prevention over 3 months., Results: For in vitro spermicidal effect, 98% and 67% of sperm were immotile in the presence of the gel with sodium lauryl sulfate (gel-SLS) and gel alone, respectively. For the post-coital test, 99% and 93% of sperm were immotile in the presence of gel-SLS and gel alone, respectively. In the second part of trial, a total of 410 instances of vaginal intercourse in 95 menstrual cycles were protected (during 3-month period of gel-SLS use before each sexual intercourse with probability of 24 conceptions prevented according to Wilcox's table). Four women became pregnant during the study period; 2 during unprotected vaginal intercourse around the time of ovulation, and 2 attributed to user failure., Conclusion: Based on our results, the vaginal gel demonstrated important spermicidal and contraceptive effect. A larger phase III contraceptive efficacy trial is warranted. The vaginal gel may represent a non-hormonal spermicide/contraceptive option for women., (Copyright © 2021 The Society of Obstetricians and Gynaecologists of Canada/La Société des obstétriciens et gynécologues du Canada. Published by Elsevier Inc. All rights reserved.)

Objective: Conventional vaginal applicators with a single apical hole do not distribute vaginal formulations homogenously and do not cover the entire vaginal and cervical mucosa. To overcome this problem and offer women further protection against vaginal infections, we designed a unique vaginal applicator with multiple apical and lateral holes. We have previously shown that the new applicator distributes an investigational vaginal gel homogenously over the entire vaginal and cervical mucosa. In this study, we investigated (using MRI) whether the new applicator works as well with marketed vaginal gels and creams., Methods: Eighteen women participated in the study and six vaginal gels and creams were tested. Each woman used a marketed vaginal product with its own commercial applicator (CA) once and with our universal vaginal applicator (UVA) once to deliver the same product. The applications were separated by a one-week period. Pelvic MRI was performed immediately after vaginal application to evaluate the product's distribution and mucosal coverage., Results: Immediately after application of the vaginal product, the UVA homogenously distributed the six products (3 gels and 3 creams) over the entire vaginal and cervical mucosa. On the other hand, the tested CA delivered four products (3 gels and 1 cream) mainly to the cervix and the upper vagina, but not to the mid and lower vagina; for the other two creams, the distribution was similar to that of UVA. Furthermore, the UVA received the highest acceptability score., Conclusion: The UVA can be used to deliver different vaginal gel and cream products homogenously throughout the vagina. This was the first time the UVA had been tested with marketed vaginal gels and creams. This applicator, giving uniform mucosal coverage and being highly acceptable, may help women to better protect themselves against sexually transmitted infections.

We sequenced the evolutionarily conserved genes 16S rRNA, atpD, tuf, and recA from Streptococcus pseudopneumoniae, Streptococcus pneumoniae, Streptococcus mitis, and Streptococcus oralis. Phylogenetic analysis revealed that recA provided good resolution between these species, including discrimination of the novel species S. pseudopneumoniae. By contrast, the more conserved 16S rRNA, tuf and atpD are not sufficiently discriminatory. Therefore, recA sequences were used to develop a real-time PCR assay with a locked nucleic acid-mediated TaqMan probe for the specific detection and identification of S. pseudopneumoniae. The PCR assay showed excellent specificity and a detection limit of <10 genome copies for the detection and identification of S. pseudopneumoniae strains, which makes it a promising tool for molecular identification and epidemiological studies. In conclusion, this article describes for the first time a PCR assay for the specific identification of S. pseudopneumoniae., (© 2011 The Authors. Clinical Microbiology and Infection © 2011 European Society of Clinical Microbiology and Infectious Diseases.)

There is an urgent need to develop vaginal microbicides to empower women to better control their own sexual life and to protect themselves against HIV and other sexually transmitted infections (STIs). Prevention of STIs with its 330 million cases a year would have a great global health impact. Because of their anatomy, women are up to 8 times more susceptible than men to STIs including HIV. Women who can't negotiate condom use with their male partners have no means of protecting themselves from these infections. In the last few years, especially after the recent failures of several microbicides in Phase III trials, there was increasing pressure from those favoring the use of a more targeted approach to introduce marketed antiretroviral drugs (ARVs) into microbicides. This Pre-Exposure Prophylaxis (PrEP) concept which targets only HIV using specific ARVs contrasts with the primary approach of broad spectrum microbicides which aimed at offering universal protection against several sexually transmitted pathogens. However, before using ARVs as PrEP for HIV prevention, there are still many important issues to consider. In this article, we compare both strategies, while reviewing the last 15 years of microbicide research and its future., (Copyright © 2011 International Society for Infectious Diseases. Published by Elsevier Ltd. All rights reserved.)

In 2007, nearly 7000 new cases of HIV infection occurred each day. There is a constant increase in the proportion of women newly infected with HIV in the global population; this increase is particularly high in some areas of the world such as sub-Saharan Africa. Microbicides are products that are being developed to empower women against HIV. First- and second-generation microbicides are broad-spectrum products that include surface active agents, vaginal defense enhancers, and blocking agents. Third-generation microbicides are HIV-specific and include replication and entry inhibitors formulated as gels or as vaginal rings. However, there is a concern that antiretroviral-based microbicides could lead to drug resistance if they are used by HIV-positive women who are unaware of their HIV status. To reach the highest number of women possible, microbicides should be available over-the-counter, which might not be the case with antiretroviral-based formulations. In contrast, non-antiretroviral-based microbicides will have the advantage of being initiated and controlled by women themselves and they will not jeopardize the use of life-saving drugs., (Copyright © 2010 International Society for Infectious Diseases. Published by Elsevier Ltd. All rights reserved.)

In recent years, we have witnessed many transitions in healthcare systems around the globe. For example, population expansion and ageing, and the human immunodeficiency virus (HIV)-AIDS epidemics, have exerted pressure to decentralize the practice of healthcare outside of traditional settings to bring care to those in need. Upstream of patient management, diagnosis is aimed at adequately orienting medical decisions, and considerable efforts have been made to make this process faster and more efficient. However, there are several diseases and medical conditions that may/will benefit from technologies and tests that can be performed closer to the patient, at the point of care or even in the home. In this review, and in light of the paradox that technology and assay developers and healthcare officials must take into consideration for advancing human health in developed and developing countries, we present an overview of rapid diagnosis of infectious diseases at the point of care and of technologies that may contribute to enhancement of the worldwide point-of-care testing market.

Background: Invisible Condom gel formulations being developed as microbicides to prevent the sexual transmission of HIV are advancing through the phases of clinical trials. The objectives of this study were to evaluate, after 8 weeks of vaginal application, the extended safety and acceptability of two Invisible Condom vaginal gel formulations: (i) the polymer alone and (ii) the polymer containing sodium lauryl sulfate (SLS) compared to placebo., Study Design: This study is a randomized, doubled-blind, placebo-controlled Phase II extended safety study in healthy sexually active women from Yaoundé, Cameroon. Women were randomized into three gel arms: (i) placebo, (ii) polymer alone and (iii) polymer/SLS. Women applied gel intravaginally twice daily for 8 weeks., Results: A total of 194 sexually active women applied placebo (n=41), polymer alone (n=76) and polymer/SLS (n=77). Invisible Condom gel formulations were well tolerated with no reported serious adverse events. The majority of reported adverse events were mild or moderate and mostly similar in all three arms, except for pelvic pain that was 10% higher in the polymer and polymer/SLS arms compared to placebo. Colposcopy showed neither genital ulceration nor mucosal lesions. Nugent score, H(2)O(2)-producing lactobacilli and vaginal pH were not affected by the study products. The gel formulations and applicator were generally acceptable and comfortable., Conclusion: This extended safety study showed that the Invisible Condom gel formulations and applicator were well tolerated and acceptable when applied intravaginally twice daily for 8 weeks. Thus, further phases of clinical development of Invisible Condom as a potential microbicide to prevent sexual transmission of HIV are warranted.

Background: The objectives of this clinical trial were to evaluate the safety, tolerance and acceptability of two gel formulations of the Invisible Condom: (i) the polymer alone and (ii) the polymer-containing sodium lauryl sulfate (SLS) compared to placebo when applied intravaginally with our unique applicator in sexually abstinent and active woman volunteers., Study Design: A randomized, doubled-blind, placebo-controlled study in healthy women from Yaoundé, Cameroon. Two hundred sixty women were randomized into three gel arms: (a) gel alone, (b) gel plus SLS and (c) placebo gel. Thirty-seven sexually abstinent women applied gel intravaginally once a day for 14 days, while 75, 74 and 74 sexually active women applied gel intravaginally once, twice or three times daily for 14 days, respectively., Results: Retention rate was high at 85% and 221 women applied the two products and the placebo for a total of 6005 times. Nugent score, H(2)O(2)-producing lactobacilli and vaginal pH were stable throughout the study and were not affected by the study products. Colposcopy showed neither genital ulceration nor mucosal lesions. No study product-related serious adverse events were reported. The majority of reported adverse events were mild or moderate and largely similar in all 3 arms. Satisfaction questionnaire showed that the gel formulations and applicator were generally comfortable and acceptable., Conclusion: The Invisible Condom formulations and applicator were found to be comfortable, well tolerated and acceptable when applied intravaginally once, twice or thrice daily for 14 days. Thus, expanded safety evaluation is warranted.

Objective: The objective of this study was to evaluate the vaginal distribution of a microbicidal gel (Invisible Condom) before, during and after simulated intercourse using an artificial phallus. The gel was delivered using either a new proprietary vaginal applicator (PVA), which has multiple lateral and apical holes, or a commercial applicator (CA), which has a single apical hole. The persistence of the gel was evaluated up to 24 h after its administration., Study Design: Nine women (five women using the PVA and four women using the CA) applied the vaginal gel once, and pelvic images were taken immediately after application. An artificial phallus was inserted and the women had 30 vaginal thrusts, then another set of images was taken while the phallus was still inside the vagina. On exit of the phallus, one more set of images was taken. Images were subsequently taken at 30 min, 2 h, 6 h and 24 h after gel application., Results: Immediately after gel application, the PVA distributed the gel throughout the vaginal/cervical mucosae, while the CA delivered the gel only to the cervical area. During simulated intercourse, the phallus further pushed the gel delivered with the CA into the fornix, whereas it spread the gel delivered with the PVA more evenly throughout the mucosal surface. After simulated intercourse, both applicators gave similar gel distributions between 30 min and 6 h after application. However, at 24 h, using the PVA, only 5% of the gel persisted in the vagina, compared to 40% of the gel using the CA., Discussion and Conclusion: Using the new PVA, the Invisible Condom covered the vaginal/cervical mucosae before and during simulated intercourse, offering immediate protection, whereas only the cervical mucosa was covered using the CA. Forty percent of the gel persisted mostly in the upper vaginal/cervical area at 24 h following its administration with the CA, while only 5% of the gel was left using the PVA. The new applicator, with its unique design, ensures an even and immediate coating lasting throughout the first 6 h and could prevent potential microbicide vaginal toxicity at 24 h.

Objectives: The study was conducted to evaluate the safety and acceptability of the Invisible Condom when applied once or twice daily for 14 days in healthy women and their male sexual partners., Study Design: Forty-one women and 23 men divided into three cohorts were enrolled. Cohort 1:14 sexually abstinent women applying gel twice daily for 14 days; Cohort 2:14 sexually active women with tubal ligation applying gel once daily for 14 days and their 14 sexual partners who did not use gel; Cohort 3:13 women on oral contraceptive applying gel once daily for 14 days and 9 of their sexual partners., Results: No serious adverse events (AEs) were reported. Colposcopy showed no genital ulceration nor epithelial lesions. No major changes in vaginal flora or vaginal pH were detected. None of the women had to stop product application because of AEs. The majority of AEs were mild. Common AEs were itching, dryness, burning sensation, erythema and discharge. Satisfaction questionnaire showed that the gel and applicator were acceptable., Conclusion: The Invisible Condom and applicator were safe, well tolerated and acceptable when applied intravaginally for 14 days. Thus, expanded safety and effectiveness evaluation is warranted.

A low-cost, disposable card for rapid polymerase chain reaction (PCR) was developed in this work. Commercially available, adhesive-coated aluminum foils and polypropylene films were laminated with structured polycarbonate films to form microreactors in a card format. Ice valves [1] were employed to seal the reaction chambers during thermal cycling and a Peltier-based thermal cycler was configured for rapid thermal cycling and ice valve actuation. Numerical modeling was conducted to optimize the design of the PCR reactor and investigate the thermal gradient in the reaction chamber in the direction of sample thickness. The PCR reactor was experimentally characterized by using thin foil thermocouples and validated by a successful amplification of 10 copy of E. coli tuf gene in 27 min.

These experiments were conducted in order to determine the influence of the time of day of drug administration on the pharmacokinetics of isepamicin. Six healthy volunteers were given 400mg isepamicin IM, on 2 separate occasions, either in the morning (8 AM) or in the evening (8 PM). Within-subject differences in the pharmacokinetic parameters between the morning and evening dosing regimens were evaluated. The plasma concentrations of isepamicin were not significantly different between the morning and evening trials, but significant time-dependent changes were found with a lower elimination rate constant and a longer elimination half-life in patients administered isepamicin at night. Our finding suggests that isepamicin may have the same clinical effects irrespective of whether dosing takes place in the morning or in the evening, but its clearance tends to be depressed when taken in the evening. Therefore, morning therapy is desirable because of possible interference from aminoglycoside toxicity., (Copyright © 1996 Japanese Society of Chemotherapy and the Japanese Association for Infectious Diseases. Published by Elsevier Ltd. All rights reserved.)

Amphotericin B is a potentially nephrotoxic agent used for the treatment of severe mycoses and numerous fungal infections. Temporal variation in the nephrotoxicity of amphotericin B was studied in rats maintained on a light-dark period of 14 hrs of light and 10 hrs of darkness (light on: 06h00). Subgroups of animals were treated with a single daily i.p. dose of either 5% dextrose or amphotericin B (10 mg/kg/day) given at either 07h00, 13h00, 19h00 or 01h00 for 4 and 10 days. On day 4, no significant difference was observed in any parameter studied. On day 10, the cellular regeneration ([3H]-thymidine incorporation into DNA of renal cortex)(p<0.01), BUN levels (p<0.05), serum creatinine (p<0.05), and accumulation of amphotericin B in the renal cortex (p<0.05) were significantly higher when animals were treated with similar subcellular localization of amphotericin B in the proximal tubular cells of the renal cortex. These results showed a temporal variation in the nephrotoxicity of amphotericin B (peak toxicity occurred at 07h00) which is different from that of other nephrotoxic antibiotics such as aminoglycosides.

Aminoglycosides are still widely used alone or in combination with a beta-lactam antibiotic for the treatment of severe Gram negative infection. Oto- and nephrotoxicity are the major side effects associated with the use of these drugs. Although several risk factors associated with aminoglycoside nephrotoxicity have been identified, only few therapeutic approaches were suggested to reduce the incidence of their toxicity in patients. The single daily injection is the only approach actually used to reduce the renal toxicity of aminoglycosides in patients. However, the relationship between the nephrotoxicity of aminoglycosides and the time of the day these drugs should be given has never been explored in patients. Data obtained in laboratory animals indicated that temporal variations can be detected in the renal toxicity of aminoglycosides: the nephrotoxicity was observed during the rest period of the animals while no toxicity was found at other times of the day. Other studies suggested also that food intake can modulate the temporal variations in the nephrotoxicity of aminoglycosides. A better knowledge of the risk factors associated with the renal toxicity of aminoglycosides, a reduction in the number of daily injections of aminoglycosides, administration of aminoglycosides at the time of the lowest toxicity of the drug in patients submitted to an appropriate diet are the most interesting approaches to reduce the incidence of the renal toxicity of these agents.

Daptomycin was previously shown to reduce gentamicin renal toxicity and this toxicity was not delayed by the concomitant injection of daptomycin (Thibault N., L. Grenier, M. Simard, M. G. Bergeron, and D. Beauchamp, Antimicrob. Agents Chemother., 38 1027-1035 (1994)). The protective effect of daptomycin against gentamicin toxicity was evaluated in 96 female Sprague-Dawley rats. Normal and nephrectomized rats were treated with saline (NaCl, 0.9%), gentamicin (30 mg/kg/12 hrs, i.p.), daptomycin (10 mg/kg/12 hrs, s.c.) or with a combination of daptomycin plus gentamicin during 4 and 10 days. On day 4, gentamicin and daptomycin cortical levels were higher in nephrectomized gentamicin-daptomycin-treated rats (p < 0.05) as compared to all other groups. The accumulation of gentamicin or daptomycin in nephrectomized gentamicin-daptomycin-treated or gentamicin-saline-treated rats was higher on day 4 (p < 0.01) than on day 10. Other parameters such as the sphingomyelinase activity in the renal cortex, the serum creatinine, and the histopathology showed significantly fewer changes in daptomycin-gentamicin-treated rats as compared to animals given gentamicin alone. On the other hand, the protection of daptomycin was less extensive in nephrectomized rats as compared to normal rats. Daptomycin and gentamicin were localized in the lysosomes of proximal tubular cells of animals treated with daptomycin and gentamicin given alone or in combination. These results suggest that daptomycin protects against gentamicin toxicity in nephrectomized rats but to a lesser extent than in normal rats.

The present study was undertaken to examine a possible effect of aprotinin, a 6.5-kDa polypeptide with an inhibitory effect on proteolysis, on aminoglycoside nephrotoxicity. Experimental animals (female Sprague-Dawley rats, 175-200 g body wt) were treated for 4 days with 40 mg/kg gentamicin given ip at 12-hr intervals. Aprotinin (40,000 kIU per animal) was infused i.v. over a period of 8 days, using subcutaneously implanted miniosmotic pumps. In protocol A, infusion pumps were placed 4 days before starting gentamicin treatment. In protocol B, pumps were implanted 15-18 hr prior to first gentamicin administration. In addition to rats exposed to both gentamicin and aprotinin (GAP), animals were treated with gentamicin ip+saline i.v. (G), saline ip+aprotinin i.v. (AP), or received only saline by both routes of administration (C). All rats were terminated 4 days after the end of gentamicin dosing. One hour before sacrifice, 200 microCi of [3H]thymidine was given ip to each animal in order to monitor cell turnover in renal tissue. The kidneys were analyzed with respect to (i) histopathological alterations and renal dysfunction, (ii) aminoglycoside tissue accumulation, and (iii) tubular regeneration (measurement of cell proliferation). In animals receiving aprotinin alone, histological examination of renal cortex on paraffin sections disclosed mild tubular injury with focal cell necrosis. In plastic-embedded tissue, proximal tubule epithelium was characterized by the presence of numerous inclusions densely stained with toluidine blue. At the ultrastructural level, these inclusions appeared filled with amorphous electron-dense material. In gentamicin-treated animals, cortical drug accumulation reached values higher than 0.3 mg/g renal tissue, but a significant 30-40% decrease of gentamicin accumulation was noted in GAP groups, compared to G groups. Histological examination of renal cortex (paraffin sections) revealed the development of acute tubular necrosis in both G and GAP groups. Tubular injury was accompanied by mild renal dysfunction, as shown by the level of serum creatinine which was increased almost 3-fold in the G group, compared to C and AP groups. Aprotinin infusion produced a further increase of serum creatinine, particularly in protocol A where it was 72% higher for the GAP group than for the G group. In both G and GAP groups, postnecrotic tubular regeneration was evidenced by determining the rate of DNA synthesis and the frequency of S-phase cells in renal cortex. Both methods gave consistent results and showed a 8- to 13-fold increase of cell proliferation in groups receiving gentamicin alone, compared to C groups.(ABSTRACT TRUNCATED AT 400 WORDS)

The circadian and the circannual variations of the nephrotoxicity of tobramycin were studied in female Sprague-Dawley rats. Animals were maintained on a light-dark period of 14/10 hrs (light on: 06h00 to 20h00). They were injected once daily for 4 and 10 days with saline or tobramycin at a dose of 40 mg/kg/day i.p. at either 08h00, 14h00, 20h00 and 02h00, in April 1991, July 91, October 91, January 92. In April 91, tobramycin injected at 14h00 during 10 days induced a significant increase of [3H]-thymidine incorporation into DNA of renal cortex as compared to other groups (p < 0.01): toxicity was highest at 14h00 and lowest at 02h00. No temporal change was observed in the renal cortical accumulation of tobramycin, and in serum creatinine after the 4 or 10 days of treatment. In experiments done in April, July and October 1991 and in January 1992, no circannual variation was found in tobramycin cortical levels but peaks of toxicity were observed at 02h00 in April and October 1991 and at 14h00 in July 1991 and January 1992. There was no linear correlation between the toxicity and the tobramycin accumulation in the renal cortex (r = 0.21). The data suggest that the circadian changes in tobramycin toxicity are due to temporal changes in the susceptibility of renal cells to tobramycin.

Aminoglycoside antibiotics play an integral role in antimicrobial chemotherapy. Unfortunately, these drugs are known to cause nephrotoxicity in man and experimental animals. In fact, the incidence of renal dysfunction during the course of clinical treatment with aminoglycoside antibiotics is approximately 10%. Over the past two decades the elucidation of the pathogenesis of aminoglycoside-induced nephrotoxicity has been the subject of numerous investigations. This review describes the recent theories postulated to play a role in the pathogenesis of antibiotic-induced renal damage. In particular, the importance of amino-glycoside levels in the renal cortex or at the membrane binding site is examined in detail. The relevance of antibiotic tissue levels is reflected in the ability of other drugs to modify nephrotoxicity through an alteration in renal aminoglycoside content. The role of factors including age and diet in drug-induced nephrotoxicity is described. In clinical practice, aminoglycoside antibiotics may often be with other agents. The influence of aminoglycoside interaction with other drugs including vancomycin, cephalosporins and cytotoxic drugs is examined in the light of reports that nephrotoxicity is potentiated in these situations. In addition, this review focuses on the role of infection (pyelonephritis and septicemia) and bacterial endotoxin as pathogenic factors involved in aminoglycoside nephrotoxicity. Both the direct influence of endotoxin and the indirect effects of vasoactive mediators and inflammatory processes will be discussed. A multiplicity of factors is involved in the pathogenesis of aminoglycoside-induced nephrotoxicity and these are further amplified in the presence of infection.

Multiple factors may increase the nephrotoxic potential of aminoglycosides. We studied gentamicin susceptibility of kidneys infected with E. coli. Several parameters of renal function, histological changes on light and electron microscopy, and drug levels in renal parenchyma were compared in pyelonephritic and normal rats treated with low doses (10 mg/kg/Q8 hr for 3 days), or high doses (60 mg/kg/day for 14 days), of gentamicin. A significant increase (P less than 0.01) in beta-galactosidase and protein excreted in urine over a period of 17 days associated with severe changes in diuresis and osmolality was noted in the infected treated rats (low doses) compared with normal, treated, infected or control animals. Histological modifications compatible with gentamicin nephrotoxicity were more persistent in the infected treated animals. A significant decrease in 14C inulin (P less than 0.01) and 3H-PAH clearance and secretion (P less than 0.02) was observed in the infected treated rats receiving high doses of antibiotics. Cellular necrosis and tubular desquamation also were more severe in this group. Gentamicin levels in the cortex and medulla of infected animals were significantly higher than in the normals (P less than 0.01) and might have been responsible for the increased toxicity noted in the pyelonephritic animals. Infected kidneys appeared to be more susceptible to the nephrotoxic potential of gentamicin.

Flucloxacillin, a recent addition to the group of isoxazolyl penicillins, was studied in vitro and in normal volunteers. The bactericidal activity of the drug against most strains of gram-positive bacteria including penicillin-resistant Staphylococcus aureus was similar to that of oxacillin and approximately fourfold greater than that of cloxacillin. Each of the three penicillins was administered orally to a group of ten volunteers for eight days in a dose of 500 mg four times a day. The mean concentrations of flucloxacillin in the serum were two- to sixfold higher than those of the other two agents on the first, fourth and eighth days of therapy. The percentage of flucloxacillin bound by serum protein was 94.6 per cent; for cloxacillin and oxacillin the values were 93.5 and 91.5 per cent, respectively. Using these data, the concentrations of free flucloxacillin in serum were found to be twice as high as those of cloxacillin and oxacillin. These findings suggest that, when administered orally, this new agent may offer some therapeutic advantage over oxacillin and cloxacillin.

Symptoms of uveitis developed in the left eye of a 61-year-old woman 2 weeks after bronchoscopy to investigate hemoptysis. The true diagnosis of metastatic endophthalmitis was unsuspected for 1 month. Both sputum and vitreous samples yielded Pseudomonas aeruginosa when cultured. Despite aggressive medical treatment, subtotal vitrectomy and intraocular injections of antibiotics, enucleation was eventually necessary. To our knowledge this is the first reported case of metastatic endophthalmitis following bronchoscopy. It is also the first report of the concentration of ceftazidime pentahydrate in the vitreous humour of an infected human eye.

A high-performance liquid chromatographic analysis of erythromycin and its esters in plasma, urine and saliva is presented. A diethyl ether extract of sample was chromatographed on a reversed-phase column and components of the column effluent were monitored by electrochemical detection at +0.9 V (vs. Ag/AgCl). The method sensitivity limit was 10 ng with inter-day coefficients of variation from 3.2 to 10.3%. In order to assess precisely the relative concentrations of erythromycin esters (ethylsuccinate or estolate) and their active by-product erythromycin base, it is necessary to adopt measures preventing their continuous hydrolysis in biological fluids and during sample preparation.

The importance of high intrarenal levels of gentamicin on the outcome of experimental pyelonephritis was studied in rats receiving either a short course (three days) of gentamicin (G) alone or combined with a longer course (14 days) of ampicillin (A), cephalothin (C), or trimethoprim (T), or two weeks of therapy with ampicillin, cephalothin, trimethoprim and gentamicin given alone. While ampicillin, cephalothin and trimethoprim were undetectable in the medulla within six hours of cessation of therapy, gentamicin was still detectable in levels six folds above the MIC up to six months after treatment had ceased. Six months after the end of treatment, the percentage of sterile left kidneys in animals treated with ampicillin (50%), cephalothin (15%), trimethoprim (20%) was lower than the percentage of animals receiving 14 days of gentamicin (100%), or the combinations AG:89%, CG:67% and TG:60%, P less than 0.01. Following three days of gentamicin, 50% of the left kidneys were sterilized. When compared to ampicillin, cephalothin or trimethoprim alone, combined therapies significantly reduced the number of CFU in the kidneys P less than 0.01. These combinations were almost as effective as two weeks of therapy with gentamicin. Short-term therapy (three days) with an aminoglycoside which concentrates in the renal parenchyma, combined with an antibiotic which will accumulate in other parts of the nephron, may result in "pharmacological synergy". This new approach to therapy of pyelonephritis may be promising.