Antimicrobial-induced endotoxaemia in patients with sepsis in the field of acute pyelonephritis.

BACKGROUND: In vitro results have shown that antimicrobial agents may induce the Gram-negative bacteria to release endotoxins (LPS), which in turn, could trigger the secretion of cytokines from monocytes. AIMS: To compare the effect of cefuroxime, netilmicin or ciprofloxacin on serum levels of LPS and tumour necrosis factor-alpha (TNFalpha). METHODS: Seventy-four patients with acute pyelonephritis caused by Gram-negative bacteria and signs of sepsis were randomly assigned to receive one of three intravenous regimens of cefuroxime, netilmicin or ciprofloxacin. Blood samples were collected before therapy and at specified time intervals for 96 hours after the initiation of treatment for the determination of serum levels of LPS and of TNFalpha. RESULTS: Patients treated with cefuroxime presented an early peak of LPS and of TNFalpha in serum two hours after the initiation of treatment compared to the other study groups. After that time interval, concentrations of LPS and TNFalpha were similar in all the study groups. Fever accompanied by endotoxaemia was still detected for 48 hours after the start of therapy in 36, 37.5 and 36% of patients treated with cefuroxime, netilmicin and ciprofloxacin respectively. The corresponding figures for these agents at 72 hours were 28, 12.5 and 24%, respective and 12, 4.2 and 4% at 96 hours (P value not significant). CONCLUSIONS: With the exception of an early peak in the serum levels of LPS and TNFalpha in patients treated with cefuroxime, no significant difference could be detected amongst the study groups as far as their effect on serum levels of LPS and TNFalpha were concerned. This suggests that these three antimicrobial agents may be administered safely at the early stages of sepsis.

Participants in HIV clinical trials in Europe.

In recent years an increasing number of antiretrovirals have become available. In order to define the optimal treatment regimens an increasing number of clinical trials are needed. Our objective was to study the profile of participants in HIV clinical trials in Europe and learn from their experience and views. Between August 1996 and September 1997, self-administered anonymous questionnaires were distributed to people with HIV infection at inpatient and outpatient clinics in 11 European countries. One thousand three hundred and sixty-six people completed the questionnaire (50% response rate). Four hundred and twenty (31%) of the respondents reported that they had previously participated in at least one HIV clinical trial. The percentage of people who had taken part in a clinical trial varied widely between the different centres, from 12% in Athens to 61% in Antwerp and Brussels. A significantly higher participation rate was observed in the northern and central part of Europe compared with the south (respectively 40% vs 18%) and also among people with a higher income. Most people (92%) stated that they were 'well' or 'very well' informed prior to enrolment in the trial. However, 4% reported that they had not given written approval and 22% felt that they were pushed into participating. Only 21% stated that they were informed about the outcome of the study on its completion. The most important reason for non-participation (37% of the non-participants) was because a clinical trial had never been proposed. In conclusion, a majority of people with HIV infection in European HIV treatment reference centres were willing to participate in clinical trials. HIV clinical trials in Europe should adhere more strictly to universal ethical standards.

Primary care involvement in human immune deficiency virus infection-a pan-European view. The Eurosupport Study Group.

OBJECTIVE: The aim of this study was to compare the primary care experiences of human immunodeficiency virus (HIV)-positive individuals across Europe. METHODS: An anonymous self-administered questionnaire study was carried out between August 1996 and August 1997. A total of 15 HIV/AIDS treatment centres and 14 HIV support organizations in 11 European countries participated in the distribution of questionnaires. Overall, 1366 completed questionnaires were included in the analysis from a total of 2751 distributed (50% response rate). The majority of respondents were homosexual men (53.6%), and 54.2% had AIDS or symptomatic HIV disease. The main outcome measures were use of GP services in the preceding 6 months, GP involvement in HIV care provision, satisfaction with current service provision and reasons for non-involvement of the primary care services. RESULTS: Most patients (64.8%) had visited their GP at least once in the preceding 6 months, but 53.9% of respondents reported that their GP was not involved in their HIV care. Of these patients, 53.4% would like their GP to be involved. Patients from central European countries were more likely to have seen their GP than their counterparts from northern and southern countries (P < 0.005), and were less worried that the GP would not have enough knowledge about HIV (P = 0.002) or would not be sympathetic (P = 0.052). CONCLUSIONS: There are clear differences in GP utilization by HIV-positive individuals across Europe, reflecting in part local service provision but primarily patients' attitudes and beliefs. Strategies to promote the involvement of primary health care services need to address patients' core beliefs, if these are to be changed.

CD28 costimulation and CD28 expression in T lymphocyte subsets in HIV-1 infection with and without progression to AIDS.

In a prospective study of 152 HIV-1 patients (with and without progression to AIDS) we examined CD28 MoAb costimulation and CD3 MoAb response using whole blood culture at baseline and up to either the time of AIDS diagnosis or the end of the observation period. CD28 antigen expression on both CD4+ and CD8+ T lymphocytes was also studied in both groups of patients. In patients who progressed to AIDS, CD28 MoAb costimulation was found to be decreased. Univariate time-dependent analysis showed that decreases in (i) absolute numbers of either CD4+, CD4+CD28+, CD8+CD28+ T cells, (ii) CD28 MoAb costimulation, and (iii) CD3 MoAb response, and an increase in CD8+CD28- %, are significant predictors for progression to AIDS. In addition, multivariate time-dependent analysis demonstrated that a decrease in CD28 MoAb costimulation (but not a decrease in CD3 MoAb response) was predictive for progression to AIDS, as were decreases in the percentage of CD4+ T cells and the absolute number of CD4+CD28+ T cells. Thus, CD28 MoAb costimulation can be considered a useful assay for monitoring HIV-1 infection. Furthermore, apart from the early increase in the percentage of CD8+CD28- T cells and an increase in the percentage of CD28- on CD8+ T cells in both groups of patients at baseline compared with normal controls, a negative correlation was found to exist between the percentages of CD4+ or CD4+CD28+ T cells and the percentage of CD8+CD28- T cells; this suggests that these cells are probably mutually regulated.

Cost-minimisation analysis of sequential treatment with ofloxacin or ciprofloxacin in hospitalised patients.

This study evaluated the cost of sequential treatment with once-daily ofloxacin or twice-daily ciprofloxacin in 474 hospitalised patients in different countries. The patients were treated intravenously for at least 3 days, then orally for 7 to 10 days or for 3 days beyond the disappearance of infection-related symptoms. The overall clinical cure rate (86.8% with ofloxacin and 89.6% with ciprofloxacin) and the overall bacteriological response rate (89.9 and 89.0%, respectively) were similar, and a cost-minimisation analysis was conducted. The acquisition costs for ofloxacin and ciprofloxacin in Greece, Israel, Slovenia and Turkey were used and converted to Deutschmarks (DM), and the costs of administration were analysed for each hospital. The different cost categories for oral and intravenous (IV) treatment (e.g. antimicrobial acquisition, drug monitoring, drug delivery costs) were used to identify any differences. The total costs per patient varied between the countries involved, but were higher for ciprofloxacin (ofloxacin: DM239 to DM724; ciprofloxacin: DM540 to DM976). In a sensitivity analysis using identical daily acquisition costs for the 2 fluoroquinolones, the total cost of treatment was higher for ciprofloxacin, as a result of the lower cost of administration of ofloxacin in the once-daily regimen. Continuing IV therapy would be approximately 50% more expensive than switching to oral administration; however, whenever possible, both drugs can be switched from IV to oral treatment.

A randomised, multinational study with sequential therapy comparing ciprofloxacin twice daily and ofloxacin once daily.

In a multinational, open, randomised, controlled clinical study, 474 hospitalised patients with moderate or severe infections were treated with sequential regimens of ofloxacin or ciprofloxacin. Ofloxacin 400 mg once daily or ciprofloxacin 200 mg twice daily were given intravenously for at least 3 days followed by oral treatment with ofloxacin 400 mg once daily or ciprofloxacin 500 mg twice daily. Overall cure rates of 86.8% (85.7%) in the ofloxacin group and 89.6 (89.5%) in the ciprofloxacin group were achieved in the intention-to-treat analysis (per protocol analysis). The overall bacteriological response rate (ofloxacin 89.5%, ciprofloxacin 89.0%) was comparable to the clinical cure rate. Both drugs were well tolerated and adverse events were rarely observed. It is concluded that ofloxacin and ciprofloxacin can be used successfully in the treatment of hospitalised patients with aerobic gram-positive and gram-negative infections. Ofloxacin has the advantage of a once-daily regimen, compared to the twice-daily regimen with ciprofloxacin.

Factors associated with the development of Pneumocystis carinii pneumonia in 5,025 European patients with AIDS. AIDS in Europe Study Group.

This study examined the factors associated with the development of a first episode of Pneumocystis carinii pneumonia (PCP) in 5,025 patients with AIDS, including 1,976 patients with primary PCP at the time of AIDS diagnosis and 635 with primary PCP occurring subsequently. Compared with untreated patients, patients treated with zidovudine were at similar risk of developing PCP during the first year of therapy but were at greater risk after longer intervals of treatment. The following factors were associated with an increased risk of PCP (either at the time of AIDS diagnosis or thereafter): lack of primary PCP prophylaxis, male homosexuality/bisexuality, diagnosis of AIDS in northern Europe, and CD4 cell count below 200 x 10(6)/L at the time of AIDS diagnosis. Patients with severe weight loss had a 60% higher risk of developing PCP during follow-up than those without such weight loss. Thus, the occurrence of PCP depended on geographic location, mode of acquisition of human immunodeficiency virus and AIDS, degree of immunodeficiency, and use of various treatment regimens.

Downregulation of CD28 surface antigen on CD4+ and CD8+ T lymphocytes during HIV-1 infection.

A progressive significant decrease of CD28 surface antigen expression on CD4+ (mean, 90, 86, 79, 68% in stages I, II, III, and IV, respectively, versus 96% in normals), as well as on CD8+ T lymphocytes (mean, 38, 32, 31, and 29% in stages I, II, III, and IV, respectively, versus 47% in normals) was observed during HIV-1 infection. The increase of cytotoxic/suppressor T cells, in both percentage and absolute numbers, that was observed in almost all HIV-1 patients, was associated with an increase of the CD8+ cells lacking the CD28 surface antigen. The loss of CD28 antigen expression was parallel to the increase of CD38, human leukocyte antigen (HLA)-DR, and CD45RO antigen expression on T lymphocytes throughout the disease. Furthermore, a positive significant correlation within the CD4+ but not the CD8+ subset was observed between the percentage of cells lacking the CD28 antigen and the percentage of cells expressing the HLA-DR and CD38 antigens, a finding suggesting that the loss of CD28 antigen expression on CD4+ lymphocytes may be associated with T-lymphocyte activation. Patients treated with zidovudine showed no significant differences in the percentages of either CD4+CD28+ or CD8+CD28+ T-cell subsets when compared to untreated patients. These phenotypic changes may be associated with the functional defects of T lymphocytes in HIV-1 infected individuals.

Asymptomatic bacteriuria of pregnancy: do obstetricians bother?

In view of the potentially serious consequences of asymptomatic bacteriuria of pregnancy (ASB), we surveyed the attitudes of Greek obstetricians towards this entity. A total of 108 obstetricians practicing in the area of Athens completed a questionnaire concerning ASB. Only 73 of the 108 stated that they screen their clients for ASB (51 of them when pyuria is present and only 22 in all pregnant women). Of special interest is the finding that a larger percentage of younger obstetricians (practicing for up to 9 years) habitually screen their patients, compared to older ones (83% vs 60%). Concerning treatment of ASB, only 45 out of 73 doctors screening for ASB give any treatment when ASB is present. Most obstetricians (87%) prefer a beta-lactam antibiotic. In almost all cases 7-10 days are considered the appropriate duration of treatment. Better education of obstetricians, especially the older ones, concerning detection and management of ASB is needed.

International comparative study of cefepime and ceftazidime in the treatment of serious bacterial infections.

In this randomized multicentre study, we compared the safety and efficacy of cefepime, 2.0 g bd i.v., with that of ceftazidime, 2.0 g tid i.v., as initial treatment of adult patients with serious infections of bacterial aetiology. Three hundred and forty-eight patients were entered into the study, 173 received cefepime and 175 ceftazidime. The treatment groups were comparable with respect to demographic characteristics, including the types of infection (cefepime/ceftazidime: urinary tract, 55/72; lower respiratory tract, 83/74; skin and soft tissue, 23/14; septicaemia, 81/81; and others, 15/5). Gram-positive bacteria were identified as pathogens on 86 occasions (cefepime/ceftazidime: 48/41), including 20 Staphylococcus aureus isolates (13/7) and 27 Streptococcus pneumoniae isolates (14/13). Gram-negative bacilli were isolated on 261 occasions (126/135), and included 219 Enterobacteriaceae (cefepime/ceftazidime: 108/111) and 34 strains of Pseudomonas aeruginosa (14/20). An intention-to-treat analysis revealed satisfactory clinical response rates of 80% and 79% for the cefepime and ceftazidime groups, respectively, and bacteriological eradication rates of 85% and 88% for the cefepime and ceftazidime groups, respectively. Of patients with microbiologically documented infections, 86% (84 of 98) treated with cefepime and 87% (94 of 108) treated with ceftazidime responded satisfactorily. Thirty-two patients (19%) treated with cefepime and 26 (15%) treated with ceftazidime died. Thirty-six patients in the cefepime group and 23 in the ceftazidime group experienced adverse events; therapy was discontinued prematurely in four and two patients in the cefepime and ceftazidime groups, respectively. Of the patients experiencing adverse events, 22 (13%) treated with cefepime developed intolerance at the injection site, compared with 11 (6%) treated with ceftazidime (P = 0.045). In conclusion, twice-daily cefepime (2 g bd) is at least as effective as ceftazidime (2 g tid), as initial empirical therapy for serious bacterial infections in non-neutropenic patients.

A double-blind study of once-daily temafloxacin in the treatment of bacterial lower respiratory tract infections.

The safety and efficacy of a seven to 14 day course of temafloxacin 600 mg once daily were compared to ciprofloxacin 500 mg bd in adult patients with bacterial infections of the lower respiratory tract in a multicentre, double-blind, randomized clinical trial. Patients were enrolled if they had symptoms and signs of infection consistent with acute exacerbation of chronic bronchitis or uncomplicated pneumonia, confirmed by X-ray. Clinical and bacteriological evaluations were performed within 48 h before enrollment, during treatment (study day 2 to 5), 1-3 days post-treatment, and 5-9 days post-treatment. Interim results are reported. Temafloxacin produced a similar clinical success to ciprofloxacin, 98% (114 of 116) and 97% (117 of 121) of patients respectively; all treated patients with pneumococcal infection except one who received ciprofloxacin were clinical successes. Temafloxacin resulted in earlier bacteriological response, especially apparent after the second and third day of therapy and among smokers and the elderly (greater than or equal to 65 years old). Five to nine days after stopping treatment 98% of pretreatment pathogens were eradicated: 124/126 and 132/135 in the temafloxacin and ciprofloxacin groups respectively. Adverse reactions occurred among 8.6% (12 of 140) of temafloxacin treated patients compared to 5.8% (8 of 138) of ciprofloxacin treated patients. All adverse events reported were of mild to moderate severity and no patients withdrew from the study prematurely due to these events. The preliminary results from this study suggest that once daily temafloxacin gives high rates of clinical and bacteriological success, similar to twice daily ciprofloxacin, in the management of bacterial infections in the lower respiratory tract.

Acute prostatitis: which antibiotic to use first.

Six antimicrobial agents were administered to 48 patients (divided in 6 groups) who underwent prostatectomy. Half of the patients received the antibiotic in a single dose one hour before the operation and the rest in divided doses 24 hours before the operation. The concentration levels in serum and in prostatic tissue were measured for each of the antibiotics and for each mode of administration. The obtained ratios of prostatic tissue to serum concentrations and the relative antimicrobial activity to local pathogens of each agent indicate that the agent of choice for prostatic disease is netilmicin followed by aztreonam, cefuroxime and the ticarcillin-clavulanic acid combination.

Comparison of three different regimens in the treatment of acute brucellosis: a multicenter multinational study.

The present study was undertaken to evaluate efficacy, safety and patient acceptability of three antibiotic regimens for the treatment of acute brucellosis. Six different centres were involved: three in France, one in Greece and two in Spain. The regimens were: oral rifampicin 900 mg/day plus oral doxycycline 200 mg/day for 45 days (A), oral doxycycline 200 mg/day for 45 days plus im streptomycin 1 g/day for 21 days (regimen B) [corrected] and the WHO regimen (C) combining oral tetracycline 2 g/day for 21 days plus im streptomycin, 1 g/day, for 14 days. Regimens A and B were randomly allocated in all centres, while regimen C was allocated only in two centres. All patients were suffering from acute brucellosis clinically and biologically proven. 143 patients were allocated for treatment and analysed. Their mean age was 41 years (range 13-70), 49 were female and 94 male, and their mean weight was 64 kg (range 35-98). Among these patients, 14% had localized disease (nine orchitis, eight osteo-articular involvement and one pleural effusion), but there was no statistical difference between the three regimens in regard to this localized disease. Forty-five per cent of the patients had positive blood cultures. The cure rate with regimen A was 95%, 96% with regimen B and 59% with regimen C. Thus regimen A presented the same efficacy rate as regimen B, but regimen C cannot be regarded as the treatment of choice for acute brucellosis.

Fleroxacin in single dose oral therapy of uncomplicated lower urinary tract infection.

A randomized comparative study was performed in twenty women with acute uncomplicated lower urinary tract infection (UTI). They received a single oral dose of either fleroxacin 600 mg or amoxycillin 3 g. Pathogens were Escherichia coli (17), Proteus mirabilis (2) and Staphylococcus aureus (1). A complete clinical and microbiological cure was observed in all patients of both groups. One patient in the fleroxacin group had gastric irritation. A single oral dose of fleroxacin may be suitable for the treatment of lower UTI even when it is due to organisms resistant to amoxycillin and other traditional oral antimicrobials.

Staphylococcal infections in hospital: the Greek experience.

Resistance rates of various species to many antimicrobials are very high in Greece. Mean resistance rates of Staphylococcus aureus isolated in 12 Athens hospitals in the second half of 1986 were 80% for penicillin, 32% for methicillin, 22% for gentamicin, 27% for erythromycin, 17% for lincomycin and 16% for co-trimoxazole. In a prospective study in the General Hospital of Athens from May to July 1987, 40 coagulase-positive staphylococcal strains were isolated from various materials from inpatients. Of these 78% were resistant to penicillin, 50% to methicillin at 37 degrees C, 62% to methicillin at 30 degrees C, 38% to erythromycin, 32% to tobramycin, 15% to clindamycin, 15% to fusidic acid, 9% to amikacin, 5% to netilmicin and 0% to vancomycin. Ten of these strains (seven methicillin-resistant) were responsible for severe infections and three of the affected patients died (two nosocomial pneumonias, one infected burn, all due to methicillin-resistant strains). Another 11 strains (eight methicillin-resistant) were responsible for mild infections. From 41 coagulase-negative staphylococci isolated from inpatients, seven (five methicillin-resistant) were held responsible for mild infections. Of the 20 patients with infections due to methicillin-resistant strains, nine had previously received a beta- lactam antibiotic. Staphylococci are not responsible, however, for a large proportion of infections in our hospital at the moment. High resistance rates in Greece are due to overuse of antibiotics, a phenomenon attributed to a consumer's society behaviour of doctors and patients.