Jan M. Prins

Once versus thrice daily gentamicin in patients with serious infections

Aminoglycosides are usually given in two or three divided doses. A once-daily regimen might be more effective and less toxic. We have conducted a randomised trial in consecutive patients with serious infections for whom an aminoglycoside seemed warranted. Exclusion criteria were neutropenia or severely impaired renal function. 123 patients were enrolled. For efficacy analysis only those patients were considered in whom treatment with the aminoglycoside was not stopped within 72 h (n = 67); toxicity was analysed on patients receiving aminoglycosides for more than 48 h and not using other nephrotoxic medication (n = 85). Gentamicin 4 mg/kg every day (OD) or gentamicin 1.33 mg/kg three times daily (MD) (with dose-reduction in case of renal dysfunction) were given intravenously. In almost all patients intravenous amoxycillin 1 g every 6 h was also started. Baseline characteristics were comparable in both arms. A good clinical response was observed in 32/35 (91%) of the OD and in 25/32 (78%) in the MD group (difference 13%, 95% confidence interval -6.4% to +26.9%). 2 patients in each group died with uncontrolled infection. An insufficient bacteriological response (persistent positive cultures, resistance, or superinfection) was observed in 2 patients with OD and 3 patients with MD. In patients treated for more than 48 h duration of therapy and mean doses were 7.0 days (1590 mg) and 7.4 days (1672 mg) in OD and MD respectively. Mean first serum trough/peak levels were 0.6/10.2 mg/L and 1.4/5.2 mg/L. Nephrotoxicity (a rise in serum creatinine of 45 mumol/L or more) developed in 2/40 (5%) in OD and 11/45 (24%) in MD (p = 0.016). Risk factors for nephrotoxicity were duration of therapy and baseline creatinine clearance rate. High-tone audiometry was performed when possible; no significant differences were found in hearing loss (3/12 and 3/11) or prodromal signs of ototoxicity (5/12 and 4/11). A once-daily dosing regimen of gentamicin is at least as effective as and is less nephrotoxic than more frequent dosing.

Immuno-activation with anti-CD3 and recombinant human IL-2 in HIV-1-infected patients on potent antiretroviral therapy

BACKGROUND A stable reservoir of latently infected, resting CD4 T cells has been demonstrated in HIV-1-infected patients despite prolonged antiretroviral treatment. This is a major barrier for the eradication of HIV by antiretroviral agents alone. Activation of these cells in the presence of antiretroviral therapy might be a strategy to increase the turnover rate of this reservoir. METHODS Three HIV-1-positive patients on potent antiretroviral therapy, in whom plasma viremia had been suppressed to below 5 copies/ml for at least 26 weeks, were treated with a combination of OKT3 (days 1-5) and recombinant human IL-2 (days 2 6). RESULTS The side-effects were fever, headache, nausea, diarrhea, and in one of the patients transient renal failure and seizures. The regimen resulted in profound T cell activation. In one patient plasma HIV-1 RNA transiently increased with a peak at 1500 copies/ml. In the other two patients plasma HIV-1 RNA levels remained below the detection limit, but HIV-1 RNA levels in the lymph nodes increased two- to threefold. All patients developed antibodies against OKT3. CONCLUSION OKT3/IL-2 resulted in T cell activation and proliferation, and could stimulate HIV replication in patients having achieved prolonged suppression of plasma viremia. OKT3/IL-2 therapy was toxic and rapidly induced antibodies against OKT3.

Surgical Excision versus Antibiotic Treatment for Nontuberculous Mycobacterial Cervicofacial Lymphadenitis in Children: A Multicenter, Randomized, Controlled Trial

BACKGROUND The optimal treatment of nontuberculosis mycobacterial cervical lymphadenitis in children has not been established. Until recently, surgical excision was the standard treatment, but the number of reports of successful antibiotic treatment is increasing, which questions whether surgery is the preferred treatment. In this randomized, multicenter trial, we compared surgical excision with antibiotic treatment. METHODS One hundred children with microbiologically proven nontuberculous mycobacterial cervicofacial lymphadenitis were randomly assigned to undergo surgical excision of the involved lymph nodes or to receive antibiotic therapy with clarithromycin and rifabutin for at least 12 weeks. The primary end point was cure, defined as regression of the lymph node enlargement by at least 75%, with cure of the fistula and total skin closure without local recurrence or de novo lesions after 6 months, as assessed by clinical and ultrasound evaluation. Secondary end points included complications of surgery and adverse effects of antibiotic therapy. RESULTS Intention-to-treat analysis revealed that surgical excision was more effective than antibiotic therapy (cure rates, 96% and 66%, respectively; 95% confidence interval for the difference, 16%-44%). Treatment failures were explained neither by noncompliance nor by baseline or acquired in vitro resistance to clarithromycin or rifabutin. Surgical complications were seen in 14 (28%) of 50 patients; staphylococcal wound infection occurred in 6 patients, and a permanent grade 2 facial marginal branch dysfunction occurred in 1 patient. The vast majority of patients who were allocated to antibiotic therapy reported adverse effects (39 [78%] of 50 patients), including 4 patients who had to discontinue treatment. CONCLUSIONS Surgical excision is more effective than antibiotic treatment for children with nontuberculous mycobacterial cervicofacial lymphadenitis.

Antibiotic treatment strategies for community-acquired pneumonia in adults.

BACKGROUND The choice of empirical antibiotic treatment for patients with clinically suspected community-acquired pneumonia (CAP) who are admitted to non-intensive care unit (ICU) hospital wards is complicated by the limited availability of evidence. We compared strategies of empirical treatment (allowing deviations for medical reasons) with beta-lactam monotherapy, beta-lactam-macrolide combination therapy, or fluoroquinolone monotherapy. METHODS In a cluster-randomized, crossover trial with strategies rotated in 4-month periods, we tested the noninferiority of the beta-lactam strategy to the beta-lactam-macrolide and fluoroquinolone strategies with respect to 90-day mortality, in an intention-to-treat analysis, using a noninferiority margin of 3 percentage points and a two-sided 90% confidence interval. RESULTS A total of 656 patients were included during the beta-lactam strategy periods, 739 during the beta-lactam-macrolide strategy periods, and 888 during the fluoroquinolone strategy periods, with rates of adherence to the strategy of 93.0%, 88.0%, and 92.7%, respectively. The median age of the patients was 70 years. The crude 90-day mortality was 9.0% (59 patients), 11.1% (82 patients), and 8.8% (78 patients), respectively, during these strategy periods. In the intention-to-treat analysis, the risk of death was higher by 1.9 percentage points (90% confidence interval [CI], -0.6 to 4.4) with the beta-lactam-macrolide strategy than with the beta-lactam strategy and lower by 0.6 percentage points (90% CI, -2.8 to 1.9) with the fluoroquinolone strategy than with the beta-lactam strategy. These results indicated noninferiority of the beta-lactam strategy. The median length of hospital stay was 6 days for all strategies, and the median time to starting oral treatment was 3 days (interquartile range, 0 to 4) with the fluoroquinolone strategy and 4 days (interquartile range, 3 to 5) with the other strategies. CONCLUSIONS Among patients with clinically suspected CAP admitted to non-ICU wards, a strategy of preferred empirical treatment with beta-lactam monotherapy was noninferior to strategies with a beta-lactam-macrolide combination or fluoroquinolone monotherapy with regard to 90-day mortality. (Funded by the Netherlands Organization for Health Research and Development; CAP-START ClinicalTrials.gov number, NCT01660204.).

OKT3 and IL-2 treatment for purging of the latent HIV-1 reservoir in vivo results in selective long-lasting CD4+ T cell depletion.

Activation of resting T cells has been proposed to purge the reservoir of HIV-1-infected resting CD4+ T cells. We therefore treated three HIV-1-infected patients on antiretroviral therapy with OKT3, a CD3 monoclonal antibody, and recombinant human IL-2. Here we report the profound and partially long-lasting host responses induced by the OKT3 and IL-2 treatment. OKT3/IL-2 induced a strong but transient release of plasma cytokines and chemokines. The percentage CD4+ and CD8+ cells in the blood expressing the activation marker CD38 transiently increased to almost 100%, and in lymph nodes we “observed” a 10-fold increase in the number of dividing Ki67+ cells and increased numbers of apoptotic cells. Following OKT3/IL-2 treatment, a long-lasting depletion of CD4+ cells in the peripheral blood and lymph nodes occurred, suggesting the physical deletion of these cells. Increases in CD4+T cell numbers during the two year followup period were due mainly to increased memory cell numbers. CD8+ cells were also depleted in the blood, but less severely in lymph nodes, and returned to baseline levels within several weeks.

Real-Time PCR Assay Using Fine-Needle Aspirates and Tissue Biopsy Specimens for Rapid Diagnosis of Mycobacterial Lymphadenitis in Children

ABSTRACT A real-time PCR assay was developed to diagnose and identify the causative agents of suspected mycobacterial lymphadenitis. Primers and probes for the real-time PCR were designed on the basis of the internal transcribed spacer sequence, enabling the recognition of the genus Mycobacterium and the species Mycobacterium avium and M. tuberculosis. The detection limit for the assay was established at 1,100 CFU/ml of pus, and the specificity tests showed no false-positive reaction with other mycobacterial species and other pathogens causing lymphadenitis. From 67 children with suspected mycobacterial lymphadenitis based on a positive mycobacterial skin test, 102 samples (58 fine-needle aspirates [FNA] and 44 tissue specimens) were obtained. The real-time PCR assay detected a mycobacterial infection in 48 patients (71.6%), whereas auramine staining and culturing were positive for 31 (46.3%) and 28 (41.8%) of the patients. The addition of the real-time PCR assay to conventional diagnostic tests resulted in the recognition of 13 more patients with mycobacterial disease. These results indicate that the real-time PCR is more sensitive than conventional staining and culturing techniques (P = 0.006). The M. avium-specific real-time PCR was positive for 38 patients, and the M. tuberculosis-specific real-time PCR was positive for 1 patient. Analysis of 27 patients from whom FNA and tissue biopsy specimens were collected revealed significantly more positive real-time PCR results for FNA than for tissue biopsy specimens (P = 0.003). Samples from an age-matched control group of 50 patients with PCR-proven cat scratch disease were all found to be negative by the real-time PCR. We conclude that this real-time PCR assay with a sensitivity of 72% for patients with lymphadenitis and a specificity of 100% for the detection of atypical mycobacteria can provide excellent support for clinical decision making in children with lymphadenitis.

Elevated Plasma Concentrations of Interferon (IFN)-γ and the IFN-γ—Inducing Cytokines Interleukin (IL)-18, IL-12, and IL-15 in Severe Melioidosis

Interferon (IFN)-gamma plays an important role in the pathogenesis of sepsis. Production of IFN-gamma is stimulated by synergistic effects of interleukin (IL)-18, IL-12, and IL-15. To investigate the regulation of IFN-gamma production during severe gram-negative infection, the plasma concentrations of IFN-gamma, IL-18, IL-12, and IL-15 were measured in 83 patients with suspected melioidosis. The diagnosis was confirmed in 62 patients, 31 of whom had blood cultures positive for Burkholderia pseudomallei, of whom 12 died. Compared with healthy controls, patients had elevated levels of IFN-gamma, IL-18, IL-12p40, and IL-15 on admission, with significantly higher levels in blood culture-positive patients, and these levels remained elevated during the 72-h study period. In whole blood stimulated with heat-killed B. pseudomallei, anti-IL-12 had a stronger inhibitory effect than anti-IL-18 and anti-IL-15 on IFN-gamma production. This effect of anti-IL-12 was further enhanced by anti-IL-18. These data suggest that during gram-negative sepsis, IFN-gamma production is controlled at least in part by endogenous IL-18, IL-12, and IL-15.

Effectiveness of early switch from intravenous to oral antibiotics in severe community acquired pneumonia: multicentre randomised trial

Objectives To compare the effectiveness of an early switch to oral antibiotics with the standard 7 day course of intravenous antibiotics in severe community acquired pneumonia. Design Multicentre randomised controlled trial. Setting Five teaching hospitals and 2 university medical centres in the Netherlands. Participants 302 patients in non-intensive care wards with severe community acquired pneumonia. 265 patients fulfilled the study requirements. Intervention Three days of treatment with intravenous antibiotics followed, when clinically stable, by oral antibiotics or by 7 days of intravenous antibiotics. Main outcome measures Clinical cure and length of hospital stay. Results 302 patients were randomised (mean age 69.5 (standard deviation 14.0), mean pneumonia severity score 112.7 (26.0)). 37 patients were excluded from analysis because of early dropout before day 3, leaving 265 patients for intention to treat analysis. Mortality at day 28 was 4% in the intervention group and 6% in the control group (mean difference 2%, 95% confidence interval −3% to 8%). Clinical cure was 83% in the intervention group and 85% in the control group (2%, −7% to 10%). Duration of intravenous treatment and length of hospital stay were reduced in the intervention group, with mean differences of 3.4 days (3.6 (1.5) v 7.0 (2.0) days; 2.8 to 3.9) and 1.9 days (9.6 (5.0) v 11.5 (4.9) days; 0.6 to 3.2), respectively. Conclusions Early switch from intravenous to oral antibiotics in patients with severe community acquired pneumonia is safe and decreases length of hospital stay by 2 days. Trial registration Clinical Trials NCT00273676.

The Preventive Antibiotics in Stroke Study (PASS): a pragmatic randomised open-label masked endpoint clinical trial

BACKGROUND In adults with acute stroke, infections occur commonly and are associated with an unfavourable functional outcome. In the Preventive Antibiotics in Stroke Study (PASS) we aimed to establish whether or not preventive antimicrobial therapy with a third-generation cephalosporin, ceftriaxone, improves functional outcome in patients with acute stroke. METHODS In this multicentre, randomised, open-label trial with masked endpoint assessment, patients with acute stroke were randomly assigned to intravenous ceftriaxone at a dose of 2 g, given every 24 h intravenously for 4 days, in addition to stroke unit care, or standard stroke unit care without preventive antimicrobial therapy; assignments were made within 24 h after symptom onset. The primary endpoint was functional outcome at 3 months, defined according to the modified Rankin Scale and analysed by intention to treat. The primary analysis was by ordinal regression of the primary outcome. Secondary outcomes included death, infection rates, antimicrobial use, and length of hospital stay. Participants and caregivers were aware of treatment allocation but assessors of outcome were masked to group assignment. This trial is registered with controlled-trials.com, number ISRCTN66140176. FINDINGS Between July 6, 2010, and March 23, 2014, a total of 2550 patients from 30 sites in the Netherlands, including academic and non-academic medical centres, were randomly assigned to the two treatment groups: 1275 patients to ceftriaxone and 1275 patients to standard treatment (control group). 12 patients (seven in the ceftriaxone group and five in the control group) withdrew consent immediately after randomisation, leaving 2538 patients available for the intention-to-treat-analysis (1268 in the ceftriaxone group and 1270 in the control group). 2514 (99%) of 2538 patients (1257 in each group) completed 3-month follow-up. Preventive ceftriaxone did not affect the distribution of functional outcome scores on the modified Rankin Scale at 3 months (adjusted common odds ratio 0·95 [95% CI 0·82-1·09], p=0·46). Preventive ceftriaxone did not result in an increased occurrence of adverse events. Overgrowth infection with Clostridium difficile occurred in two patients (<1%) in the ceftriaxone group and none in the control group. INTERPRETATION Preventive ceftriaxone does not improve functional outcome at 3 months in adults with acute stroke. The results of our trial do not support the use of preventive antibiotics in adults with acute stroke. FUNDING Netherlands Organization for Health Research and Development, Netherlands Heart Foundation, and the European Research Council.

Cranberries vs antibiotics to prevent urinary tract infections: a randomized double-blind noninferiority trial in premenopausal women

BACKGROUND The increasing prevalence of uropathogens resistant to antimicrobial agents has stimulated interest in cranberries to prevent recurrent urinary tract infections (UTIs). METHODS In a double-blind, double-dummy noninferiority trial, 221 premenopausal women with recurrent UTIs were randomized to 12-month prophylaxis use of trimethoprim-sulfamethoxazole (TMP-SMX), 480 mg once daily, or cranberry capsules, 500 mg twice daily. Primary end points were the mean number of symptomatic UTIs over 12 months, the proportion of patients with at least 1 symptomatic UTI, the median time to first UTI, and development of antibiotic resistance in indigenous Escherichia coli. RESULTS After 12 months, the mean number of patients with at least 1 symptomatic UTI was higher in the cranberry than in the TMP-SMX group (4.0 vs 1.8; P = .02), and the proportion of patients with at least 1 symptomatic UTI was higher in the cranberry than in the TMP-SMX group (78.2% vs 71.1%). Median time to the first symptomatic UTI was 4 months for the cranberry and 8 months for the TMP-SMX group. After 1 month, in the cranberry group, 23.7% of fecal and 28.1% of asymptomatic bacteriuria E coli isolates were TMP-SMX resistant, whereas in the TMP-SMX group, 86.3% of fecal and 90.5% of asymptomatic bacteriuria E coli isolates were TMP-SMX resistant. Similarly, we found increased resistance rates for trimethoprim, amoxicillin, and ciprofloxacin in these E coli isolates after 1 month in the TMP-SMX group. After discontinuation of TMP-SMX, resistance reached baseline levels after 3 months. Antibiotic resistance did not increase in the cranberry group. Cranberries and TMP-SMX were equally well tolerated. CONCLUSION In premenopausal women, TMP-SMX, 480 mg once daily, is more effective than cranberry capsules, 500 mg twice daily, to prevent recurrent UTIs, at the expense of emerging antibiotic resistance. TRIAL REGISTRATION isrctn.org Identifier: ISRCTN50717094.