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Biomedical subjects

M P Glauser

Publications and source records attributed to M P Glauser.

At least 19 recordsLinked to original sources
PubMed1992

[Fever of unknown origin in a cohort of HIV-positive patients].

The purpose of this study was to determine the prevalence of fever of unknown origin (FUO) in a cohort of HIV positive patients and to describe their evolution and the final diagnosis. The clinical records of 412 patients followed from January 1987 to December 1990 at our HIV outpatient clinic were reviewed: in 151 patients 255 episodes of fever had been observed of which 22 (in 21 patients) met the criteria for FUO. 19 patients (90%) presented with a CDC/WHO stage IV HIV infection and the mean CD4+ lymphocyte count was 0.160 G/l. The etiology was ultimately determined in 13/22 episodes (3 Pneumocystis carinii pneumonia, 3 invasive infections due to atypical mycobacteria, 2 bacterial pneumonia, 1 Cytomegalovirus colitis, 1 Isospora belli enteritis, 1 visceral leishmania, 1 candida septicemia and 1 lymphoma). In 6/22 episodes, the fever subsided after zidovudine was started and was therefore attributed to HIV itself. In 3/22 episodes no etiology was found. In conclusion, this series shows that FUO is usually seen in advanced HIV infection and that it often represents an early sign of opportunistic infection. This observation underlines the importance of follow-up, since it finally served to detect the etiology of FUO in 86% of cases. Trial treatment with zidovudine can be useful where no pathology has been discovered despite 3 weeks' follow-up and appropriate investigations.

AIDS-Related Opportunistic Infections↗
PubMed1992

Control of lipopolysaccharide (LPS) binding and LPS-induced tumor necrosis factor secretion in human peripheral blood monocytes.

We used flow cytometry to determine how LPS-binding protein (LBP) effects the binding of fluorescein-labeled LPS to human monocytes via receptor-dependent mechanisms. The addition of human, rabbit, mouse, or FCS strikingly increased the binding of LPS to monocytes compared with controls incubated in serum-free medium. This binding was totally prevented by preincubation of monocytes with MY4, an anti-CD14 mAb, or by enzymatic removal of CD14 from monocytes. Depletion of LBP from rabbit serum with anti-LBP antibodies also produced a similar suppression. Solutions of albumin did not support the enhanced binding observed in serum but the addition of purified rabbit LBP to albumin solutions resulted in binding similar to that observed in serum-containing medium. When type-specific anti-LPS mAb was added to human serum, LPS binding to monocytes occurred but was only partly inhibited by anti-CD14 mAb, suggesting that receptors other than CD14 (presumably Fc or complement receptors) were involved. Serum increased by 100- to 1000-fold the sensitivity of monocytes to the triggering by LPS resulting in TNF secretion. TNF secretion was inhibited by anti-CD14 mAb up to 100 ng/ml of LPS and by anti-LPS mAb up to 1 to 10 ng/ml. The inhibition of TNF secretion by anti-LPS mAb appeared to be the result of directing LPS to monocyte receptors other than CD14. In contrast, in medium containing normal as well as acute serum and in the absence of anti-LPS antibodies, the binding of LPS to monocytes and the triggering of TNF secretion appeared to be mediated mainly by interactions between CD14 and LBP-LPS complexes.

Acute-Phase Proteins↗
PubMed1992

Cytokine production after intravenous or peritoneal gram-negative bacterial challenge in mice. Comparative protective efficacy of antibodies to tumor necrosis factor-alpha and to lipopolysaccharide.

The production of TNF-alpha, IL-1, and IL-6 was measured in mice after bolus i.v. Escherichia coli O111 LPS injections and during bacteremia induced either by bolus i.v. or by i.p. challenges of live E. coli O111. High but transient TNF-alpha peaks were observed after bolus i.v. LPS or bacterial challenges. In contrast, the levels during lethal peritonitis increased progressively to values 50- to 100-fold lower than the peak values observed after i.v. injections, and remained sustained until death. Whereas after i.v. challenge with 1000 LD50 of LPS, anti-TNF-alpha antibody fully protected mice from death and reduced serum IL-1 and IL-6 levels, anti-TNF-alpha antibody did not improve the survival of mice nor reduced serum IL-1 and IL-6 levels after i.p. bacterial challenge. In contrast to anti-TNF-alpha antibodies, anti-LPS antibodies were protective in the peritonitis model. Protection was accompanied by a striking reduction of bacterial numbers and of TNF-alpha, IL-1, and IL-6 levels in the serum, but the levels of these cytokines were only marginally affected in the peritoneal lavage fluid. This latter observation demonstrates that the local peritoneal cytokines did not diffuse readily into the circulation, thus suggesting that at least part of the circulating cytokines are produced systemically. In conclusion, the striking differences between cytokine profiles as well as the divergent efficacy of anti-TNF-alpha antibody after i.v. bolus and after i.p. challenges suggest that TNF-alpha may not be as important in the pathogenesis of lethal peritonitis than after lethal acute bacteremia.

Animals↗
PubMed1992

Once-a-week azithromycin in AIDS patients: tolerability, kinetics, and effects on zidovudine disposition.

Toxoplasmic encephalitis is one of the leading causes of morbidity in patients with AIDS. Lifelong treatment is needed to prevent relapses, and primary prevention is desirable in high-risk patients, but the available drugs are often poorly tolerated. Azithromycin (AZM) has been considered a drug candidate because of its efficacy in the animal model and its kinetic properties, which would allow intermittent administration. The tolerability and kinetics of AZM and its effect on the disposition of zidovudine (ZVD) were therefore evaluated in a preliminary open study in nine human immunodeficiency virus-infected patients. AZM was administered once weekly for 5 weeks 2 h before the usual morning ZVD dose. The day before and on the first and fifth AZM dosings, blood samples were drawn every 30 min during 5 h for determination of the concentrations of ZVD and its glucuronide metabolite. Blood samples were drawn for AZM measurement over 72 and 360 h on the first and fifth AZM administrations, respectively, as well as before and 3 h after dosing on the second, third, and fourth AZM dosings. After the first and fifth administrations, maximum AZM concentrations in serum were 0.6 +/- 0.1 and 0.8 +/- 0.2 microM (mean +/- standard error of the mean), respectively; times to peak concentration in serum were 3.7 +/- 0.2 and 2.9 +/- 0.4 h, respectively; areas under the plasma concentration-time curves were 9.2 +/- 1.6 and 9.3 +/- 2.0 micrograms.h/ml, respectively; and half-lives were 61.0 +/- 5.4 and 63.8 +/- 6.7 h, respectively. On days -1, 1, and 29, ZVD kinetic parameters were as follows: maximum concentrations in serum, 3.1+/- 0.6, 4.3 +/- 0.6, and 4.2 +/- 0.9 microM, respectively; times to maximum concentrations in serum, 1.1 +/- 0.4, 0.8 +/- 0.2, and 1.2 +/- 0.3 h, respectively: areas under the plasma concentration-time curves, 5.3 +/- 0.9, 5.9 +/- 0.6, and 5.7 +/- 0.8 microgram . h/ml, respectively; and half-lives, 1.3 +/- 0.08, 1.4 +/- 0.04, and 1.3 +/- 0.04 h, respectively. Except for transient mild abdominal cramps that occurred at 2 to 3 h postdose (6 of 45 exposures) and nausea (4 of 45 exposures), neither subjective nor objective side effects were observed. The kinetics of AZM were similar after the first and repeated administrations, and the disposition of ZVD was not altered by this treatment. The efficacy of AZM in preventing cerebral toxoplasmosis can therefore be safely tested in human immunodeficiency virus-infected patients concomitantly treated with zidovudine.

Acquired Immunodeficiency Syndrome↗
PubMed1992

Teicoplanin versus vancomycin for prophylaxis of experimental Enterococcus faecalis endocarditis in rats.

Teicoplanin was compared with vancomycin for the prophylaxis of experimental Enterococcus faecalis endocarditis in rats. Single intravenous doses of teicoplanin (7 mg/kg of body weight) or vancomycin (15 mg/kg) were given 30 min before bacterial challenge. Two strains of E. faecalis (309 and 1209) isolated from patients with endocarditis were tested. Bacterial inocula ranged from 10(4) (i.e., the inoculum infecting 90% of the control rats [ID90]) to 10(7) CFU/ml. The MICs and MBCs of teicoplanin and vancomycin were, respectively, 0.25 to greater than 128 mg/liter and 2 to greater than 128 mg/liter for strain 309 and 0.5 to greater than 128 mg/liter and 0.5 to greater than 128 mg/liter for strain 1209. Vancomycin prevented endocarditis only in 60% (strain 309) and in 87% (strain 1209) of rats challenged with the smallest bacterial-inoculum size (ID90), whereas teicoplanin prevented endocarditis in 100% of rats challenged with the same inoculum (strain 309; P = 0.05), in 87% of rats challenged with 10 times the ID90 (strain 309; P = 0.02), and in 95% of rats challenged with 100 times the ID90 (strain 1209; P = 0.0003). The combination of teicoplanin plus gentamicin (4 mg/kg) extended the protection to inocula 100 times the ID90 (strain 309; 96% of sterile animals) and 1,000 times the ID90 (strain 1209; 100% of sterile animals). Prevention of endocarditis was likely to be due to a prolonged inhibition of bacterial growth by sustained levels of teicoplanin in serum and not to bacterial killing. Indeed, teicoplanin did not exhibit any bactericidal activity either in vitro (time-kill curves) or in vivo (serum bactericidal activity). Teicoplanin proved to be superior to vancomycin in the prophylaxis of experimental E. faecalis endocarditis in rats.

Animals↗
PubMed1992

Trimethoprim, alone or in combination with sulphamethoxazole, decreases the renal excretion of zidovudine and its glucuronide.

Trimethoprim and trimethoprim-sulphamethoxazole (co-trimoxazole) are often prescribed in HIV patients treated with zidovudine. The pharmacokinetics of zidovudine, after a dose of 3 mg kg-1 by constant rate intravenous infusion over 1 h were evaluated in nine HIV patients in an open, randomized, three-phase crossover study, without and with trimethoprim (150 mg) and trimethoprim-sulphamethoxazole (160 and 800 mg). The metabolic clearance of zidovudine was not significantly influenced by trimethoprim-sulphamethoxazole and trimethoprim. However, the renal clearance of zidovudine was decreased by 58 and 48%, respectively, and that of its glucuronide by 27 and 20% (P < 0.05). The fraction of the dose excreted as the parent compound fell by 47 and 39% and the metabolic ratio by 48 and 43% (P < 0.05). This kinetic drug interaction, apparently due solely to trimethoprim, may only be clinically important when hepatic glucuronidation is also impaired by liver disease or inhibited by other drugs.

Adult↗
PubMed1991

Alterations of host defenses: the key to the multifaceted spectrum of infections in immunocompromised patients.

Patients with cancer are subject to bacterial infections because of a variety of specific defects. Patients may suffer increased susceptibility to infection by virtue of the invasiveness and obstructiveness of their basic malignancy as well as because of malignant processes directly involved in the hematopoietic and lymphoid systems. Also, the potent therapeutic modalities useful in treating malignant disease carry with them an associated suppression of bone marrow and lymphoid functions which can also result in increased bacterial infection. Physicians caring for patients with cancer must be aware of the potential preventive measures, such as careful handwashing, use of laminar air flow units, partial gut decontamination, and possible use of vaccines and antibodies to minimize infection in their patients.

Antibody Formation↗
PubMed1991

High circulating levels of interleukin-6 in patients with septic shock: evolution during sepsis, prognostic value, and interplay with other cytokines. The Swiss-Dutch J5 Immunoglobulin Study Group.

PURPOSE AND PATIENTS: We measured the serum concentrations of interleukin-6 (IL-6) in 70 patients with established septic shock caused predominantly by gram-negative bacteria. The aims of the study were to determine whether and for how long IL-6 was detectable in the circulation of these patients, to assess whether IL-6 levels were associated with patients' outcomes, and, finally, to examine the interplay between IL-6, tumor necrosis factor (TNF), interleukin-1 beta (IL-1 beta), and interferon-gamma (IFN-gamma). RESULTS: IL-6 was detected in 64% of the patients at study entry but in only 18% on Day 1 and 2% on Day 10. Serum levels of IL-6 were higher (median: 3.5 ng/mL, range: less than 0.1 to 305 ng/mL) in patients dying of fulminant septic shock than in those surviving (median: 0.5 ng/mL, range: less than 0.1 to 135 ng/mL; p = 0.003) or in those with a transient reversal of shock but who ultimately died of a relapse of shock (median: less than 0.1 ng/mL, range: less than 0.1 to 12.5 ng/mL; p = 0.005). However, no cutoff values of IL-6 confidently predicted the outcome of an individual patient. The serum concentrations of IL-6 measured at study entry correlated with the duration of survival (r = -0.51, p = 0.004) and with the levels of TNF-alpha (r = 0.53; p less than 0.0001) but not with the levels of either IL-1 beta (r = 0.01, p = 0.90) or IFN-gamma (r = 0.06, p = 0.60). CONCLUSIONS: These results indicate that circulating levels of IL-6 are detectable in a majority of patients with gram-negative septic shock. Concentrations of IL-6 peaked near the onset of shock and rapidly decreased to undetectable levels within approximately 24 hours in most patients. Levels of IL-6 measured at study entry correlated with levels of TNF and with patients' outcomes. Yet, IL-6 does not appear to be a clinically useful laboratory test for predicting the outcome of an individual patient.

Adolescent↗
PubMed1991

Beta-lactam resistance mechanisms of methicillin-resistant Staphylococcus aureus.

In vitro and in vivo activity of amoxicillin and penicillin G alone or combined with a penicillinase inhibitor (clavulanate) were tested against five isogenic pairs of methicillin-resistant Staphylococcus aureus (MRSA) producing or not producing penicillinase. Loss of the penicillinase plasmid caused an eight times or greater reduction in the MICs of amoxicillin and penicillin G (from greater than or equal to 64 to 8 micrograms/ml), but not of the penicillinase-resistant drugs methicillin and cloxacillin (greater than or equal to 64 micrograms/ml). This difference in antibacterial effectiveness correlated with a more than 10 times greater penicillin-binding protein 2a affinity of amoxicillin and penicillin G than of methicillin and a greater than or equal to 90% successful amoxicillin treatment of experimental endocarditis due to penicillinase-negative MRSA compared with cloxacillin, which was totally ineffective (P less than .001). Amoxicillin was also effective against penicillinase-producing parent MRSA, provided it was combined with clavulanate. Penicillinase-sensitive beta-lactam antibiotics plus penicillinase inhibitors might offer a rational alternative treatment for MRSA infections.

Animals↗
PubMed1991

Antibodies to core lipopolysaccharide determinants: absence of cross-reactivity with heterologous lipopolysaccharides.

Using monoclonal antibodies directed against defined epitopes of endotoxin core, this study demonstrated that the presentation of lipopolysaccharide (LPS) to antibodies is critical for measuring the specific binding of antibodies to LPS structures. False cross-reactive reactions apparently were observed when free core LPS or lipid A were used as antigens in ELISA, whereas coating with complexes of high-density lipoproteins with core LPS increased both the sensitivity and the specificity of the test compared with coating with free core LPS, so that nonspecific binding of antibodies was largely avoided. Using this technique, it was not possible to find broadly cross-reactive core LPS antibodies after immunization of rabbits and humans with rough mutants of gram-negative bacteria. These observations underscore the need for careful evaluation of the potential for cross-reactivity of antisera and of monoclonal antibodies directed against endotoxin core.

Animals↗
PubMed1991

Antibodies to lipopolysaccharides after immunization of humans with the rough mutant Escherichia coli J5.

To investigate whether immunization with Escherichia coli J5 boiled cells induces antibodies directed at deep core structures, antibodies against J5 lipopolysaccharide (LPS), Re LPS, and lipid A were measured in the serum of 70 volunteers before and 2 weeks after immunization. To improve the sensitivity and the specificity of ELISA, complexes of core LPS with high-density lipoproteins were used instead of free core LPS as antigens. A median three-fold increase in antibodies directed against J5 LPS was observed, but no significant increase in the antibodies against Re LPS or lipid A was found. Since J5 antiserum did not react with several smooth LPS or with Re LPS and lipid A, cross-reactivity could not be demonstrated. Thus, immunization of volunteers with E. coli J5 produced a modest specific antibody response against J5 LPS. The mechanism of protection previously observed with J5 antiserum remains unclear.

Antibodies, Bacterial↗
PubMed1991

In-vitro activity of temafloxacin for gram-positive pathogens.

The antimicrobial activity of temafloxacin against aerobic Gram-positive cocci was compared to that of ciprofloxacin, ofloxacin, fleroxacin and pefloxacin using the broth microdilution technique. Temafloxacin was more active than the other four fluoroquinolones, particularly for viridans streptococci and Streptococcus pneumoniae. The MIC90 of temafloxacin was at least four-fold lower than that of ciprofloxacin and ofloxacin for viridans streptococci and penicillin-susceptible pneumococci. The MIC50s and MIC90s of temafloxacin were equal to or lower than those of the other fluoroquinolones for methicillin-susceptible Staphylococcus aureus (MSSA), methicillin-resistant S. aureus (MRSA), and methicillin-susceptible and methicillin-resistant coagulase-negative staphylococci. Temafloxacin was more active against all the other Gram-positive aerobes (except Enterococcus faecalis) tested than the other fluoroquinolones.

Anti-Infective Agents↗
PubMed1991

Anti-lipopolysaccharide and anti-tumor necrosis factor/cachectin antibodies for the treatment of gram-negative bacteremia and septic shock.

Endotoxin is composed of lipid A, the toxic moiety, of the core region, a conserved structure among Gram-negative bacteria, and of the O-side chains, a highly variable part responsible for the antigenic specificity. The concept of cross-protection afforded by antiserum raised against the core region of endotoxin is supported by the following data: experimentally antiserum protected against infections caused by a wide range of Gram-negative bacteria or endotoxins; in patients with Gram-negative bacteremia, survival was associated with high levels of anti-core antibodies, and mortality was reduced by the prophylactic or therapeutic use of immune serum or plasma. However, the proof that protection is afforded by cross-protective anti-core antibodies is still lacking. Furthermore, many experimental studies and clinical studies trials have shown controversial results. Ongoing experimental studies and recently completed clinical trials, using either polyclonal or monoclonal anti-core antibodies should help clarify the issues both of the clinical efficacy and of the mechanism of protection. Tumor necrosis factor/cachectin has been unequivocally shown, both in experimental animal models and in humans to be a pivotal mediator of the clinical and humoral manifestations of shock induced by endotoxin or by whole Gram-negative bacteria. In humans, TNF was been transiently detected in the blood of volunteers challenged with endotoxin, in a small proportion of patients with Gram-negative sepsis, but in the vast majority of patients with established septic shock. However, in patients the magnitude and the evolution of the blood concentration of TNF differed from that observed in animal models or in human volunteers after an acute challenge with either Gram-negative bacteria or endotoxin, probably reflecting differences in infectious stimuli. In children with meningococemia and in adults with Gram-negative septic shock, TNF was associated with the patient's outcome. Anti-TNF monoclonal antibodies are presently undergoing clinical investigation in patients with septic shock. However, one should keep in mind that TNF serves both beneficial and detrimental functions depending upon its concentration in body fluids.

Antibodies, Monoclonal↗