Clinical management of meningococcal disease. Laboratory confirmation is important.
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Clinical Laboratory Techniques↗
Biomedical subjects
M J Gill
Publications and source records attributed to M J Gill.
A randomized, double-blind trial of valaciclovir prophylaxis for cytomegalovirus disease in patients with advanced human immunodeficiency virus infection. AIDS Clinical Trials Group Protocol 204/Glaxo Wellcome 123-014 International CMV Prophylaxis Study Group.
Cytomegalovirus (CMV) disease is a common complication of advanced human immunodeficiency virus (HIV) infection. Administration of oral valaciclovir, a valine ester of acyclovir, achieves sufficient plasma acyclovir levels to inhibit many clinical isolates. Acyclovir has been associated with enhanced survival in AIDS but not with CMV disease prevention. CMV-seropositive patients (1227) with CD4 cell counts <100/mm3 were enrolled in a randomized, double-blind trial. Valaciclovir, 8 g/day, was compared with acyclovir, 3.2 or 0.8 g/day, for CMV prevention; all three arms were compared for survival. The confirmed CMV disease rate was 11.7% among valaciclovir recipients and 17.5% in the pooled acyclovir arms, a 33% reduction in risk. Time to confirmed CMV disease was significantly longer for the valaciclovir group (P = .03). A trend toward earlier mortality for valaciclovir recipients was seen (P = .06). Toxicity and earlier medication discontinuation were more common in this group. Valaciclovir significantly reduces the risk of CMV disease. Further exploration of a better-tolerated dose is warranted.
AIDS-Related Opportunistic Infections↗
Does in vitro susceptibility to rifabutin and ethambutol predict the response to treatment of Mycobacterium avium complex bacteremia with rifabutin, ethambutol, and clarithromycin? Canadian HIV Trials Network Protocol 010 Study Group.
The in vitro susceptibilities of baseline Mycobacterium avium complex (MAC) blood isolates from 86 patients with AIDS who were treated with clarithromycin, ethambutol, and rifabutin were determined to examine whether these results predict bacteriologic response to treatment. No patient received prior prophylaxis with clarithromycin or azithromycin. Minimum inhibitory concentrations (MICs) of clarithromycin for all isolates were < or = 2 micrograms/mL. The median MIC of rifabutin was between 0.25 and 0.5 microgram/mL, and all isolates were susceptible to < or = 2 micrograms of rifabutin/mL. The median MIC of ethambutol was 4 micrograms/mL, and the MIC90 was 8 micrograms/mL. There was no correlation between ethambutol susceptibility and subsequent bacteriologic clearance. At all time points through week 12, bacteriologic clearance occurred more frequently in patients with isolates for which MICs of rifabutin were lower, but this difference was statistically significant only at week 2. Susceptibility testing for baseline MAC isolates from AIDS patients not previously treated with clarithromycin or azithromycin does not appear to be useful in guiding therapy.
AIDS-Related Opportunistic Infections↗
Gonococcal resistance to beta-lactams and tetracycline involves mutation in loop 3 of the porin encoded at the penB locus.
penB is a chromosomal mutation that confers resistance to beta-lactams and tetracyclines and reduced susceptibility to quinolones in Neisseria gonorrhoeae. It is linked to the porin gene (por) and requires the increased expression of an efflux pump due to mtr. Transformation of a susceptible gonococcus (strain H1) with chromosomal DNA from strain FA140 (penA mtr penB; porin serovar IB1) and conjugal transfer of a beta-lactamase-expressing plasmid was used to produce isogenic strains for determination of equilibrium periplasmic penicillin concentrations by the method of Zimmermann and Rosselet (W. Zimmermann and A. Rosselet, Antimicrob. Agents Chemother. 12:368-372, 1977). In transformants with the Mtr and PenB phenotypes, equilibrium concentrations of penicillin were reduced. DNA sequence analysis of por from isogenic penB and penB+ transformants revealed 14 sequence differences; nine of these differences resulted in amino acid changes. Three amino acid changes were found in the putative gonococcal equivalent of the pore-constricting loop 3 of Escherichia coli OmpF. Two of these changes (Gly-101-Ala-102-->Asp-Asp) result in an increased negative charge at this position in por loop 3. PCR products comprising the complete por gene from strain FA140 were transformed into strain H1-2 (penA mtr; porin serovar IB-3), with the resulting transformants having the antibiotic susceptibility phenotype associated with penB. penB-like mutations were found in loop 3 of clinical isolates of gonococci with chromosomally mediated resistance to penicillin. We conclude that penB is a mutation in loop 3 of por that reduces porin permeability to hydrophilic antibiotics and plays an important role in the development of chromosomally mediated resistance to penicillin and tetracycline in gonococci.
Anti-Bacterial Agents↗
Prevalence of a putative efflux mechanism among fluoroquinolone-resistant clinical isolates of Streptococcus pneumoniae.
Twenty-three norfloxacin-selected first-step mutants of Streptococcus pneumoniae showed low-level fluoroquinolone resistance. Their susceptibility to norfloxacin in the presence or absence of reserpine and known efflux pump substrates was determined by an agar dilution method. Five mutants showed four- to eightfold increases in their susceptibility to norfloxacin in the presence of reserpine and four- to eightfold decreases in their susceptibility to acriflavine and ethidium bromide. This phenotype is suggestive of an efflux mechanism of resistance. A representative of these mutants, 1N27, accumulated significantly less ethidium bromide than the parent strain; reserpine abolished these differences. No changes in the quinolone resistance-determining regions of parC, parE, gyrA, or gyrB were found in this mutant. By our validated agar dilution method, the efflux phenotype was sought in clinical isolates of S. pneumoniae. Of 1,037 clinical isolates examined from the United Kingdom, 273 showed reduced susceptibility to norfloxacin or ciprofloxacin. Of these, 45.4% showed the efflux phenotype. Our findings suggest that an efflux mechanism may be a frequent cause of clinically significant fluoroquinolone resistance in pneumococci.
Anti-Infective Agents↗
Gene transfer, gentamicin resistance and enterococci.
Enterococci are versatile pathogens by virtue of their ability to exhibit low-level intrinsic resistance to clinically useful antibiotics and their tolerance to adverse environmental conditions. In the last 20 years these pathogens have become progressively more difficult to treat because of their aptitude for acquiring antibiotic-resistance genes. Of increasing concern is the rapid dissemination of the AAC6'-APH2" bi-functional aminoglycoside modifying enzyme. This enzyme confers high-level resistance to gentamicin and all other related aminoglycosides with the exception of streptomycin. The gene conferring this phenotype has been associated with both narrow and broad host range plasmids, and has recently been found on conjugative transposons. The nature of these conjugative elements raises the possibility of the resistance gene spreading to other pathogenic bacteria.
Anti-Bacterial Agents↗
Confidence and accuracy in person perception: do we know what we think we know about our relationship partners?
A cross-sectional study of dating partners and a longitudinal study of college roommates revealed that the confidence and accuracy of their impressions were often dissociated. For example, relationship length and degree of involvement tended to increase the confidence of people's impressions, but neither variable consistently increased the accuracy of their impressions of their partners' sexual histories, activity preferences, and so on. A third study showed that relationship length and involvement increased the richness of impressions, and richness fostered confidence. The authors conclude that although confidence-accuracy dissociations are surely problematic in some instances, their apparent pervasiveness raises the possibility that confidence may sometimes contribute to relationship quality even when it is unrelated to accuracy.
Adolescent↗
Transmission of human immunodeficiency virus through blood transfusion: the use of lookback and traceback approaches to optimize recipient identification in a regional population.
BACKGROUND: The purpose of this study was to define the epidemiologic features of the transmission of human immunodeficiency virus (HIV) by blood transfusion in a region of Canada between 1980 and 1985 and the results of intensive recipient-identification practices. STUDY DESIGN AND METHODS: Lookback (notification of all recipients of blood from an HIV-infected donor) and traceback (identification of the HIV-infected source donor, after an HIV-infected recipient of blood cites transfusion as a risk for infection) programs were established linking (with patient consent) a transfusion service and an HIV clinic to identify HIV-infected donors and the recipients of their blood. RESULTS: Twenty-two cases of documented HIV infection and 26 cases of presumed infection were found in local blood recipients. Twenty-eight recipients have died of causes unrelated to HIV. Twelve recipients have developed AIDS. Six of the seven living recipients have yet to develop an AIDS condition. These 48 infections have been linked to 11 donors who have subsequently tested positive for HIV infection. Six donors were found on subsequent blood donation. Five donors were found by traceback. CONCLUSION: Forty-eight recipients of blood from donors who subsequently tested positive for HIV were identified in a low-prevalence area. Active lookback and traceback programs linking a transfusion service and an HIV clinic were successful in identifying infected recipients.
Acquired Immunodeficiency Syndrome↗
Topical undecylenic acid for herpes simplex labialis: a multicenter, placebo-controlled trial.
A multicenter, patient-initiated, double-blind, placebo-controlled trial of 15% undecylenic acid cream was conducted with 573 patients with recurrent herpes labialis. Treatment was applied 5 or 6 times daily until crusting and then thrice daily until healing. Patients were assessed daily until 48 h after crusting and then every other day until healing. Undecylenic acid significantly reduced the incidence and duration of viral shedding and the duration and severity of itching but did not increase abortive episodes or reduce times to healing, crusting, or progression of lesion size. When treatment was initiated during the prodrome, the time to crusting was reduced (P = .02) and the area under the symptom-time curve for pain and tenderness was reduced, approaching statistical significance (P = .06). Active treatment was well tolerated but caused dysgeusia and local irritation. Undecylenic acid 15% cream reduces viral shedding in recurrent herpes labialis, but clinical benefits are minimal and largely restricted to patients initiating therapy during the prodrome.
Administration, Topical↗
The effect of reserpine, an inhibitor of multi-drug efflux pumps, on the in-vitro susceptibilities of fluoroquinolone-resistant strains of Streptococcus pneumoniae to norfloxacin.
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Anti-Infective Agents↗
Quantification of human immunodeficiency virus type 1 RNA from dried plasma spots collected on filter paper.
To assess dried plasma spots (DPSs) as a source of material for virus quantification, human immunodeficiency virus type 1 (HIV-1) RNA levels were quantified in matched DPS and liquid plasma samples from 73 infected patients, including 5 neonates and 4 adult patients with acute HIV-1 infection. Quantifications were performed by commercially available assays (NASBA [nucleic acid sequence-based amplification] or Amplicor, or both). There was a strong correlation between HIV-1 RNA levels in plasma and DPSs. More importantly, there was no decline in HIV-1 RNA levels in DPSs stored for as long as 2 weeks at 20 degrees C. Similarly, storage of DPSs for 3 days at 37 degrees C resulted in no decrease in viral RNA levels. For patients with primary infection, the DPS method allowed for the measurement of RNA levels in plasma during the initial spike in the level of viremia and in the subsequent period of suppressed viral replication. DPS quantification was equally informative in the neonatal setting, with all five newborns showing HIV-1 RNA loads of greater than 4.991 log10 copies/ml. We conclude that the viral RNA levels in DPSs are equivalent to those measured in fresh-frozen plasma. The ease and economy of DPS sampling, the minute volumes required, and the unexpected stability of dried RNA suggest that the use of DPSs will be particularly valuable for small-volume neonatal samples and large, population-based studies in which cold storage and transportation present special problems, as is often the case in developing countries. The ability to measure viral changes during primary infection suggests that the method will be useful for assessing vaccine efficacy in large field trials.
Acquired Immunodeficiency Syndrome↗
Phenotypic variations and switches in HIV isolated from the blood and the gastrointestinal tissues of patients with HIV-1 infection. HIV/GI Research Study Group.
The objective of this study was to determine the initial and subsequent phenotypes of HIV-1 isolated from the blood, duodenal, and colonic biopsies of 51 HIV-1 positive patients followed prospectively over 2 years. Blood and tissues were cocultured with stimulated peripheral blood monocytes, and HIV was analyzed for phenotypic expression of syncytia-induction (SI). A total of 45/51 patients had HIV-1 isolated from the blood and 35/51 had HIV isolated from gastrointestinal tract. In 12/45 patients SI-HIV-1 was isolated from the blood. In 6/12 patients the blood phenotype reverted to the NSI phenotype. SI phenotypes were also isolated from the colon and duodenum of 8/35 patients and reversion from SI to NSI virus phenotype was again observed in gut tissue of 3/8 patients. These results show that gastrointestinal tissues can harbor SI HIV phenotype. Discordant phenotypes can be found in tissue and blood of late-stage patients. Reversion of phenotypic SI expression to NSI may occur in patients receiving monotherapy as antiretroviral treatment. These results suggest that gastrointestinal tissues may act as a separate and distinct site involved in HIV replication and its associated pathogenesis.
Biopsy↗
A comparison of two regimens for the treatment of Mycobacterium avium complex bacteremia in AIDS: rifabutin, ethambutol, and clarithromycin versus rifampin, ethambutol, clofazimine, and ciprofloxacin. Canadian HIV Trials Network Protocol 010 Study Group.
BACKGROUND: Bacteremia with the Mycobacterium avium complex is common in patients with the acquired immunodeficiency syndrome (AIDS), but the most effective treatment for this infection remains unclear. METHODS: We randomly assigned 229 patients with AIDS and M. avium complex bacteremia to receive either rifampin (600 mg daily), ethambutol (approximately 15 mg per kilogram of body weight daily), clofazimine (100 mg daily), and ciprofloxacin (750 mg twice daily) (the four-drug group) or rifabutin (600 mg daily), ethambutol (as above), and clarithromycin (1000 mg twice daily) (the three-drug group). In the three-drug group the dose of rifabutin was reduced by half after 125 patients were randomized, because 24 of 63 patients had uveitis. RESULTS: Among 187 patients who could be evaluated, blood cultures became negative more often in the three-drug group than in the four-drug group (69 percent vs. 29 percent, P<0.001). Among patients treated for at least four weeks, the bacteremia resolved more frequently in the three-drug group (78 percent vs. 40 percent, P<0.001). In the three-drug group, bacteremia resolved more often with the 600-mg dose of rifabutin than with the 300-mg dose (P=0.025), but the latter regimen was more effective than the four-drug regimen (P<0.05). The median survival was 8.6 months in the three-drug group and 5.2 months in the four-drug group (P = 0.001). The median Karnofsky performance score was higher in the three-drug group than in the four-drug group from week 2 to week 16 (P<0.05). Mild uveitis developed in 3 of the 53 patients receiving the 300-mg dose of rifabutin, an incidence about one quarter that observed with the 600-mg dose (P<0.001). CONCLUSIONS: In patients with AIDS and M. avium complex bacteremia, treatment with the three-drug regimen of rifabutin, ethambutol, and clarithromycin leads to resolution of the bacteremia more frequently and more rapidly than treatment with rifampin, ethambutol, clofazimine, and ciprofloxacin, and survival rates are better.
AIDS-Related Opportunistic Infections↗
Zidovudine absorption and small intestinal function in HIV seropositive patients.
Zidovudine absorption was evaluated in HIV seropositive patients with (n = 15) and without diarrhoea (n = 20) in a standardised prospective pharmacokinetic study using single oral 200 mg doses. Zidovudine was rapidly absorbed with large peak variation (Cmax: 1.10 +/- 0.43 mg/L). There were no significant associations between pharmacokinetic parameters and presence of diarrhoea, CD4 counts, red blood cell folate concentrations, stool cultures/leucocytes or the lactulose/mannitol absorption test. Mean diarrhoea AUC (mg/L.h) was 1.13 +/- 0.30 and 1.07 +/- 0.36 in non-diarrhoeal patients. Antidiarrhoeals increased AUC and Cmax values in a small, non statistically significant subset of diarrhoea patients. Although zidovudine absorption varies significantly, our data do not support dosage individualisation based on any of the above parameters.
Administration, Oral↗
Functional characterization of a sialyltransferase-deficient mutant of Neisseria gonorrhoeae.
Previous studies indicate that sialylation of lipopolysaccharide (LPS) by host CMP-N-acetylneuraminic acid (CMP-NANA) catalyzed by bacterial sialyltransferase rendered gonococci resistant to killing by phagocytes, to entry into epithelial cell lines, to killing by immune serum and complement, and to absorption of complement component C3. These results have been confirmed by comparing a sialyltransferase-deficient mutant (strain JB1) with its parent (strain F62) in appropriate tests. In contrast to F62, JB1 was very susceptible to killing by human polymorphonuclear phagocytes in opsonophagocytosis tests and incubation with CMP-NANA did not decrease the level of killing. The inherent resistance of F62 in these tests was probably due to LPS sialylation by CMP-NANA and lactate present in the phagocytes. A JB1 variant expressing the invasion-associated Opa protein was as able to enter Chang human conjunctiva epithelial cells as an Opa-positive variant of F62, suggesting that the sialyltransferase is not required for Opa-mediated entry. After incubation with CMP-NANA, the number of F62 variant gonococci entering cells but not that of JB1 variant gonococci was drastically reduced. Both JB1 and F62 were killed by incubation with rabbit antibody to gonococcal major outer membrane protein, protein I, and human complement, but only F62 was rendered resistant to the killing by incubation with CMP-NANA. Finally, both JB1 and F62 absorbed similar amounts of complement component C3 and the binding was decreased by incubation with CMP-NANA only for the wild type, F62.
Animals↗
Roberta Hyalos: a case of hidden psychosis.
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Adult↗
HIV-associated non-Hodgkin's lymphoma of the gastrointestinal tract.
OBJECTIVE: To determine the number of HIV-associated non-Hodgkin's lymphoma (NHL) of the gastrointestinal tract (GI) in a population of HIV-infected patients from a distinct geographic region (southern Alberta, Canada), from 1983 to 1995. The type and location of NHL within the GI tract as well it's affect on survival was examined. Patients with GI HIV-associated NHL were compared to patients with extraintestinal HIV-associated NHL. METHODS: The Southern Alberta HIV Clinic in Calgary (SAC) serves all of southern Alberta which has an estimated population of one million. SAC provided primary care for 1086 patients from January 1983 to August 1995. Data were obtained by reviewing the clinic's data base and patient's charts. RESULTS: Over a 12-yr period, 13 cases of NHL of the GI tract and 26 cases of extraintestinal NHL were diagnosed in the 1086 HIV-infected patients. HIV-associated GI NHL occurred in individuals of similar age, sex, HIV risk factors, incidence of preceding AIDS-defining illnesses and CD4 count compared to those with extraintestinal NHL. The most common presentations of GI NHL were; abdominal pain (77%), abdominal tenderness (77%), weight loss (77%), and GI bleeding (38%). The most common sites of GI involvement were the large bowel (46%), ileum (39%), and stomach (23%). Those with GI NHL survived longer (1.96 +/- 0.50 yr vs 0.95 +/- 0.20 yr, p < 0.05) and were more likely to respond to therapy (72.7% vs 33.3%, p < 0.03) than those with extraintestinal NHL. CONCLUSIONS: This study suggests that; 1) the GI tract is common site of involvement in HIV-associated NHL, 2) HIV-associated GI NHL occurs in similar individuals as HIV-associated extraintestinal NHL, 3) those with HIV-associated GI NHL survive longer and are more likely to respond therapy than those with extraintestinal HIV-associated NHL.
Adult↗
Use of antibiotics to select auxotrophic mutants of Neisseria meningitidis.
Antibiotic selection of auxotrophs has been a powerful tool in the elucidation of bacterial metabolic pathways, but it has been difficult to adapt this method to Neisseria spp. We describe a procedure by which a population of mutagenized N. meningitidis is enriched for mutants with specific growth phenotypes. These experiments used a simple defined medium (modified from that described in J Bacteriol 1962; 83: 470-4) in which meningococci grow well on a variety of carbon sources. Nitrosoguanidine-treated meningococci were incubated with an antibiotic (cefotaxime, streptomycin or nalidixic acid) in a defined medium that was nonpermissive for the desired phenotype. The survivors were grown for several generations in a permissive defined medium to reduce the proportion of mutants with phenotypes other than that desired, then subjected to a second antibiotic treatment in nonpermissive medium. Survivors of the second antibiotic treatment were plated, and colonies were screened to identify auxotrophs. This procedure has allowed the isolation of meningococcal mutants with amino acid or vitamin requirements or with altered utilization of carbon sources.
Anti-Bacterial Agents↗