CD4+ count-guided interruption of antiretroviral treatment.

BACKGROUND: Despite declines in morbidity and mortality with the use of combination antiretroviral therapy, its effectiveness is limited by adverse events, problems with adherence, and resistance of the human immunodeficiency virus (HIV). METHODS: We randomly assigned persons infected with HIV who had a CD4+ cell count of more than 350 per cubic millimeter to the continuous use of antiretroviral therapy (the viral suppression group) or the episodic use of antiretroviral therapy (the drug conservation group). Episodic use involved the deferral of therapy until the CD4+ count decreased to less than 250 per cubic millimeter and then the use of therapy until the CD4+ count increased to more than 350 per cubic millimeter. The primary end point was the development of an opportunistic disease or death from any cause. An important secondary end point was major cardiovascular, renal, or hepatic disease. RESULTS: A total of 5472 participants (2720 assigned to drug conservation and 2752 to viral suppression) were followed for an average of 16 months before the protocol was modified for the drug conservation group. At baseline, the median and nadir CD4+ counts were 597 per cubic millimeter and 250 per cubic millimeter, respectively, and 71.7% of participants had plasma HIV RNA levels of 400 copies or less per milliliter. Opportunistic disease or death from any cause occurred in 120 participants (3.3 events per 100 person-years) in the drug conservation group and 47 participants (1.3 per 100 person-years) in the viral suppression group (hazard ratio for the drug conservation group vs. the viral suppression group, 2.6; 95% confidence interval [CI], 1.9 to 3.7; P<0.001). Hazard ratios for death from any cause and for major cardiovascular, renal, and hepatic disease were 1.8 (95% CI, 1.2 to 2.9; P=0.007) and 1.7 (95% CI, 1.1 to 2.5; P=0.009), respectively. Adjustment for the latest CD4+ count and HIV RNA level (as time-updated covariates) reduced the hazard ratio for the primary end point from 2.6 to 1.5 (95% CI, 1.0 to 2.1). CONCLUSIONS: Episodic antiretroviral therapy guided by the CD4+ count, as used in our study, significantly increased the risk of opportunistic disease or death from any cause, as compared with continuous antiretroviral therapy, largely as a consequence of lowering the CD4+ cell count and increasing the viral load. Episodic antiretroviral therapy does not reduce the risk of adverse events that have been associated with antiretroviral therapy. (ClinicalTrials.gov number, NCT00027352 [ClinicalTrials.gov].).

Specific antibody promotes opsonization and PMN-mediated killing of phagocytosis-resistant Enterococcus faecium.

Many clinical isolates of Enterococcus faecium are resistant to neutrophil (PMN)-mediated phagocytosis and killing in the presence of normal human serum. We have now examined the ability of specific polyclonal rabbit antibodies to promote opsonization and killing of phagocytosis-resistant E. faecium. Immune rabbit serum generated against formalin-killed E. faecium TX0016, a phagocytosis-resistant strain, markedly promoted binding of TX0016 organisms to PMNs and PMN-mediated killing. These effects were dramatically reduced by (a) adsorption of immune serum with E. faecium TX0016, but not by adsorption with a strain of E. faecium susceptible to phagocytosis, and (b) incubation of immune serum with carbohydrate purified from TX0016, but not by incubation with a surface protein extract from TX0016. IgG purified from immune serum was unable by itself to promote bacterial binding to PMNs. However, specific IgG was able to promote binding to PMNs and PMN-mediated killing in the presence of normal human serum as a complement source, as were F(ab')(2) and Fab fragments produced from it, and the alternative pathway of complement was sufficient to promote IgG- and F(ab')(2)-mediated opsonization. PMN complement receptor type 3, but not complement receptor type 1, was involved in bacterial binding to PMNs induced by the combination of F(ab')(2) fragments and normal human serum. These results suggest that opsonization by antibodies potentially directed against bacterial carbohydrate, in conjunction with complement activation, has an important role in the host defense against phagocytosis-resistant E. faecium.

Travellers' diarrhoea.

Although TD is usually a mild and self-limited illness, 30-50% of travellers from industrialized to less developed countries are affected. Enterotoxigenic E. coli (ETEC) remain the most frequent cause, being identified in 40-70% of cases. TD frequently occurs within the first 2 weeks of arrival in the foreign country. The clinical manifestation is variable, but watery diarrhoea is the most common clinical presentation. Chronic diarrhoea or remitting symptoms after empirical therapy in the returning traveller are indications for a stool culture and a careful search for stool parasites. Since the major precaution against TD is to avoid exposure to the infectious agents, careful selection of food and beverage is crucial. Bismuth subsalicylate has been proven to be safe and effective in the treatment and prophylaxis of TD. The tablet form has removed the inconvenience of previously required luggage space. Doxycycline, trimethoprim/sulphamethoxazole, trimethoprim and the quinolones have been shown to be effective for prevention of diarrhoea. However, side-effects, superinfection, development of antibiotic resistance and easy-to-treat illness may limit the use of these antimicrobial agents to those travellers with concomitant serious medical conditions that would be adversely affected by diarrhoea, or travellers with unaffordable temporary incapacity. A new oral-killed whole-cell and B-subunit cholera toxin vaccine was demonstrated to induce protection against severe ETEC-associated diarrhoea. This is a promising field under investigation. Finally, fluid replacement is the most important aspect of treatment. Patients with moderate to severe TD can be treated with one of the above-mentioned antimicrobial agents for 3-5 days. Selection of the antimicrobial agent is based on the pattern of resistance and the enteric organism prevalent in the geographical area. While TMP-SMX remains active against the strains prevalent in Mexico during summertime, the quinolones represent the choice for the therapy of diarrhoea acquired in the high-risk areas of South America, Africa and Asia.

High-level resistance to aminoglycosides: comparison of community and nosocomial fecal isolates of enterococci.

Fecal carriage of enterococci highly resistant to streptomycin, gentamicin, and kanamycin was examined in 64 healthy volunteers with no exposure to hospitals and in 53 hospitalized individuals. High-level resistance to streptomycin and gentamicin was found in fecal specimens from 3% and 0, respectively, of the healthy volunteers and in fecal specimens from 41% and 15%, respectively, of the hospitalized individuals. We found that high-level resistance to kanamycin was also more common among hospitalized individuals than among healthy volunteers (36% vs. 17%). The frequent occurrence of high-level resistance to kanamycin in fecal isolates confirms that amikacin is a poor choice when attempting to achieve synergistic therapy for enterococcal infections, in particular for those infections that are nosocomially acquired.

Roles of antibodies and complement in phagocytic killing of enterococci.

The contributions of complement and antibodies to polymorphonuclear leukocyte (PMN)-mediated killing of enterococci were investigated with pooled normal human serum (PNHS) or immune human sera (IHS) from patients with serious enterococcal infections. Each IHS containing antienterococcal antibodies demonstrated by enzyme-linked immunosorbent assay and Western blotting (immunoblotting) was examined with the enterococcus strain isolated from the same patient. PNHS promoted PMN-mediated killing of enterococci similar to that for IHS. PMN-mediated killing was consistently abrogated after preopsonization with heat-inactivated PNHS, but some heat-inactivated IHS supported neutrophil bactericidal activity. Inhibition of the classical pathway of complement by chelation of either PNHS or IHS with Mg-EGTA [Mg-ethylene glycol-bis(beta-aminoethyl ether)-N,N,N',N'-tetraacetic acid] did not alter PMN-mediated killing, suggesting that activation of the alternative pathway of complement is sufficient to promote killing of enterococci by PMNs. PMN-mediated killing assays were also performed with normal rabbit serum and immune rabbit serum against enterococci. Preopsonization with heat-inactivated immune rabbit serum resulted in PMN-mediated killing of enterococci, which was ablated after adsorption of the serum with the same isolate used for immunization. The influence of different phenotypic enterococcal traits on neutrophil-mediated killing was also investigated. Similar kinetics of killing were observed for derivatives of Enterococcus faecalis strains regardless of resistance to antimicrobial agents or production of beta-lactamase, hemolysin, gelatinase, or surface proteins involved in the aggregative response to pheromones. In summary, PMN-mediated killing of enterococci appears to depend primarily on complement activation by either the classical or the alternative pathway. Human antienterococcal antibodies generated during infection variably promoted neutrophil bactericidal activity, while antibody raised in a rabbit supported PMN-mediated killing of the organism examined. Finally, the different phenotypic properties of E. faecalis examined did not influence the neutrophil-mediated killing of these organisms.

Nocardiosis in renal transplant recipients undergoing immunosuppression with cyclosporine.

Nine cases of nocardiosis were diagnosed among 1,255 renal transplant recipients given cyclosporine (CsA)-prednisone for immunosuppression between August 1980 and March 1992 (incidence, 0.7%). Of these nine patients presenting with nocardiosis 32-1,806 days after transplantation, eight had pulmonary involvement, two had skin manifestations (one with localized disease), and one had a cerebral abscess and a pleural effusion. All cases required aggressive diagnostic procedures. Nocardia asteroides was isolated in seven cases and Nocardia brasiliensis in two. All but one case was cured. Included among the cures were all of four cases treated with amoxicillin/clavulanic acid. Therapy with CsA-prednisone was continued throughout the infection in eight cases. Analysis of a group of 154 historical controls who received azathioprine (AZA)-prednisone for immunosuppression after renal transplantation (performed before 1980 at the same center) revealed four cases of nocardiosis (incidence, 2.6%). Thus nocardiosis is apparently less common among renal transplant recipients given CsA-prednisone than among those given AZA-prednisone. The clinical presentation of nocardiosis in renal transplant recipients is variable, with pulmonary involvement predominating. Diagnosis requires an aggressive approach. Chemotherapy is successful in most cases, including those treated with amoxicillin/clavulanic acid when the isolate is susceptible.

Validity of the Household and Leisure Time Activities questionnaire (HLTA) in a multiethnic HIV-positive population.

As individuals with HIV/AIDS continue to have longer life expectancies, it is vital that other health outcomes, such as functional status, be considered. The purpose of this study was to explore the psychometric properties of a new functional status measure, the Household and Leisure Time Activities (HLTA) questionnaire, in a multiethnic low-income HIV/AIDS population. The HLTA is an 11-item questionnaire consisting of two scales designed to assess an individual's ability to perform routine home activities (household functioning scale) and to participate in leisure time activities (leisure-time functioning scale). The HLTA was administered, in the form of self-report questionnaires, to 385 consecutive patients seen at a comprehensive HIV/AIDS care facility serving low-income residents of Houston, Texas. Various psychometric procedures were then performed to assess properties, including reliability, construct validity, and concurrent validity. Reliability, assessed by Cronbach's alpha, was good for both scales (0.92, household functioning; and 0.94, leisure-time functioning). Validity was supported by findings from the confirmatory factor analysis and findings from the concurrent validity analyses. Overall, the results indicated that the HLTA has satisfactory psychometric properties and is appropriate for use with multicultural low-income HIV/AIDS patients.

Resistance of Enterococcus faecium to neutrophil-mediated phagocytosis.

During a previous study of the opsonic requirements for neutrophil (polymorphonuclear leukocyte [PMN])-mediated killing of enterococci, we identified two strains of Enterococcus faecium (TX0015 and TX0016) that were resistant to PMN-mediated killing. To better define the mechanism of this resistance, we examined phagocytosis with a fluorescence assay and found that TX0016 was completely resistant to phagocytosis by PMNs; this finding was confirmed by electron microscopy. Examination of multiple strains of enterococci revealed that all 20 strains of Enterococcus faecalis tested were readily phagocytosed (mean, 18 intracellular organisms per PMN; range, 7 to 28). In contrast, only 13 (50%) of 26 strains of E. faecium tested were susceptible to phagocytosis (> or = 7 organisms per PMN); the other 13 strains showed < or = 3 organisms per PMN. Enterococcus casseliflavus ATCC 25788 and one strain of Enterococcus hirae were also resistant to phagocytosis, while two strains of Enterococcus durans, Enterococcus mundtii ATCC 43186, and one strain each of Enterococcus raffinosus and Enterococcus solitarius were readily phagocytosed. Exposure of E. faecium TX0016 to sodium periodate, but not to the protease trypsin or pronase or to phospholipase C, eliminated resistance to phagocytosis. Sialic acid, a common periodate-sensitive structure used by microorganisms to resist opsonization, could not be demonstrated in E. faecium TX0016 by the thiobarbituric acid method, nor was phagocytosis of TX0016 altered by neuraminidase treatment. This study suggests that there is a difference in susceptibility to phagocytosis by PMNs between different species of enterococci and that a carbohydrate-containing moiety which is not sialic acid may be involved in the resistance of E. faecium TX0016 to phagocytosis.

Serological investigation of enterococcal infections using western blot.

To assess the usefulness of Western blot in the diagnosis of enterococcal infections, a pilot study was conducted with a newly developed Western blot using sera from patients with confirmed enterococcal infections. Sera from 17 of 19 patients with enterococcal endocarditis reacted strongly to enterococcal antigens on the Western blot, and most produced specific bands at molecular weights 98 kDa and 54 kDa. Sera from patients with bacteremic cholangitis and pyelonephritis reacted frequently as well, but the pattern of bands was different from that observed with endocarditis. Eighty-five percent of 26 sera tested from patients with bacteremia and associated deep-seated infections (endocarditis, cholangitis, and pyelonephritis) were positive on Western blot, compared to 30% of sera from bacteremic patients with no clinically determined deep focus of infection (p < 0.001).