K.Paul Bouter

Once-daily dosing regimen for aminoglycoside plus β-Lactam combination therapy of serious bacterial infections: Comparative trial with netilmicin plus ceftriaxone☆

PURPOSE Once-daily dosing of aminoglycosides has been suggested to improve their efficacy and reduce their toxicity. To test the clinical validity of this suggestion, we conducted a prospective, randomized trial comparing a conventional multiple-daily-dosing regimen of netilmicin with once-daily administration of the same total daily dose of this aminoglycoside. PATIENTS AND METHODS We enrolled 141 predominantly elderly patients with severe bacterial infections. All patients received once-daily doses of 2 g ceftriaxone, in addition to netilmicin. RESULTS Patients randomized to either of the two dosing strategies were comparable regarding age, APACHE II score, concomitant diseases, infection site, and rate of culture-proven bacteremia. Netilmicin treatment did not differ significantly in mean daily dose per kg body weight and days of therapy between the two treatment arms. Compared to patients receiving conventional doses, patients treated with a once-daily dose had higher serum peak netilmicin levels and lower trough levels. Outcome of infection and mortality were not influenced by dosing strategy. Although the overall incidence of nephrotoxicity was similar in both groups (16%), the occurrence of nephrotoxicity in patients treated with once-daily doses of netilmicin was significantly shifted to those given prolonged treatment, i.e., beyond 9 days. Auditory toxicity was documented in one patient treated with conventional doses and two patients treated with once-daily doses. CONCLUSION Once-daily dosing of an aminoglycoside plus a long-acting cephalosporin in these patients constituted cost-effective and safe treatment for severe bacterial infections. Netilmicin-induced toxicity may be reduced by using once-daily dosing regimens and limiting the duration of treatment.

Preprocedural serum levels of acute-phase reactants and prognosis after percutaneous coronary intervention.

OBJECTIVE In this study we evaluate the value of baseline concentrations of acute-phase reactants on prognosis after percutaneous coronary intervention (PCI). METHODS Blood samples were drawn immediately before PCI to measure baseline concentrations of C-reactive protein (CRP), interleukin-6 (IL-6), lipoprotein(a) (Lp(a)), and fibrinogen. Follow-up data were collected at 8 months. Repeat PCI, CABG, myocardial infarction, and death were recorded as major adverse clinical events (MACE). Furthermore the recurrence of angina pectoris was noted. RESULTS The study included 600 consecutive patients after a successful PCI. Sixty-four percent of the patients were stented. The mean age was 61.6 years and 68.9% were male. CRP levels were significantly higher in patients who were to have repeat angina as compared with those who were not (P=0.0322). IL-6 levels were not correlated with angina or MACE. Lp(a) and fibrinogen concentrations were both significantly related to MACE (P=0.0337 and P=0.0253, respectively). CONCLUSION Our study clearly supports the role of inflammation in restenosis after PCI as measured in statistically higher levels of Lp(a) and fibrinogen in patients with MACE and CRP in patients with repeat angina.

EFFECT OF EPIDEMIC INFLUENZA ON KETOACIDOSIS, PNEUMONIA AND DEATH IN DIABETES MELLITUS : A HOSPITAL REGISTER SURVEY OF 1976-1979 IN THE NETHERLANDS

The influence of epidemic influenza on hospitalizations because of influenza, pneumonia and diabetic acidosis in patients with diabetes mellitus was investigated. Data on the weekly incidence of influenza-like illness were obtained from the Continuous Morbidity Registration and the cumulative data on hospitalizations in short-stay hospitals were obtained from the National Medical Registration. Patients with duodenal ulcer were used as a control population. Epidemic elevations of influenza infections were observed in 1976 and 1978. The estimated relative risk for hospitalization because of influenza infection was 1.1 and 1.0 for the two non-epidemic years 1977 and 1979, respectively. For the epidemic years 1976 and 1978 this risk was calculated to be 5.7 and 6.2, respectively. An increased relative risk was also noted for pneumonia; being 25.6 for both epidemic years. The estimated relative risk of dying during hospitalization rose from 30.9 in 1977 to 91.8 in 1978. The number of hospitalizations for ketoacidosis was 50% higher in 1978 than in the other three years. During the epidemic years, 25.7% of patients hospitalized for pneumonia died, while this percentage was 14.6% in the non-epidemic years (P less than 0.05). Differences in mortality due to diabetic acidosis were similar: 25.4% in epidemic and 14.7% in non-epidemic years (P less than 0.01). During the 1978 epidemic, one out of every 1300 patients with diabetes mellitus was hospitalized because of pneumonia. It is estimated that 1 of every 260 patients with IDDM was hospitalized for diabetic acidosis. It is concluded that patients with diabetes mellitus have indeed a very high influenza-associated morbidity.

Tissue Concentrations after a Single-Dose, Orally Administered Ofloxacin in Patients with Diabetic Foot Infections

We studied the penetration of orally administered ofloxacin at the site of diabetes-related foot infections in patients with a planned debridement of the lesion. A total of nine patients received 800 mg of oral ofloxacin 120 to 150 minutes before surgery. During surgery, vital margin tissue and a serum sample were obtained. Serum and tissue concentrations of ofloxacin were measured. From seven patients sufficient amounts of tissue were obtained. Mean serum concentration was 7.0 ± 3.5 mg/liter; mean tissue concentrations was 11.5 ± 8.4 mg/kg. Mean serum and tissue concentrations exceed the minimal inhibitory concentration90 (MIC90) of commonly involved pathogens. This indicates that orally administered ofloxacin can be an effective treatment for infected diabetic foot lesions.

Patients with diabetes mellitus and atherosclerosis; a role for cytomegalovirus?

Diabetic patients are known to have an impaired immune response to viral antigens and a high incidence of atherosclerosis. This study was initiated to evaluate the association between cytomegalovirus infection and atherosclerosis in patients with diabetes mellitus. Patients with diabetes mellitus type 1 and 2 (> 5 years) with (group A) and without (group B) clinical signs of atherosclerosis were included. Cytomegalovirus cultures were obtained, serum was screened for CMV-antibodies and CMV-IgG and CMV-IgM titers were determined. Cytomegalovirus antibodies were detected more often in diabetic patients with atherosclerosis compared to patients without atherosclerosis (70.7 vs. 45.2%, P = 0.018. In female patients the prevalence of CMV-antibodies was 89.5 vs. 40.0% (P = 0.0037). CMV IgG titers were twice as high in group A compared to group B. Cytomegalovirus was cultured from four urine samples and two throat swabs in group B and in one urine and one throat swab in group A. The prevalence of cytomegalovirus antibodies was higher in diabetic patients with atherosclerosis compared to diabetic patients without atherosclerosis. This difference was most striking in the female population. CMV-IgG titers were twice as high in the atherosclerosis group. These data suggest that cytomegalovirus may play a role in the development of clinical atherosclerosis in patients with diabetes mellitus.

Treatment of diabetic foot infection: an open randomised comparison of imipenem/cilastatin and piperacillin/clindamycin combination therapy

OBJECTIVE To compare the clinical outcome and bacteriological response in diabetic patients with a foot infection treated with imipenem/cilastatin or a combination of piperacillin/clindamycin. METHODS Patients hospitalised for diabetic foot lesions Wagner Stages II, III or IV were randomly assigned to receive either imipenem/cilastatin 500 mg QID or piperacillin 3000 mg QID in combination with clindamycin 600 mg TID. Cultures were obtained and clinical observations were made. RESULTS Forty-six patients (mean age 71.4 +/- 9.8 years) entered the study, 22 received imipenem/cilastatin (IC) and 24 received piperacillin/clindamycin (PCL) combination therapy. In the IC group 22.2% was considered to be clinically cured, 76.2% improved. In the PCL group this was 25.0% and 50.0%, respectively. In the IC treatment group 45.0% of baseline pathogens was eradicated compared to 70.0% in the PCL group. Adverse events were more often reported in PCL treated patients (50.0% vs. 19.0% P < 0.05). CONCLUSIONS Impipenem/cilastatin and piperacillin/clindamycin combination therapy were equally effective in the treatment of patients with diabetic foot lesions. The imipenem/cilastatin regimen caused less side effects.

Acute-phase response of human hepatocytes after infection with Chlamydia pneumoniae and cytomegalovirus.

Background There is increasing evidence that chronic inflammation plays a pivotal role in the development of atherosclerosis. Whether inflammation is the cause or consequence of vascular damage is unclear. Also, the source of inflammation is unknown, but may well be infection by Cytomegalovirus (CMV) or Chlamydia pneumoniae (C. pneumoniae). Infection of the liver by CMV or C. pneumoniae may induce a general inflammatory reaction contributing to accelerated atherogenesis.

Endothelin blockers and renal protection: a new strategy to prevent end-organ damage in cardiovascular disease?

Time for primary review 27 days. The endothelin (ET) family comprises three 21-amino acid peptides: ET-1, ET-2 and ET-3. Endothelin-1 has been identified as the major cardiovascular isopeptide. Release of the active peptide ET-1 requires cleavage of a Trp21–Val22 bond in the carboxyterminal of the precursor molecule, big ET-1 [1]. This reaction is catalyzed by a membrane bound metalloprotease, endothelin converting enzyme (ECE-1) [1, 2]. An intracellularly located ECE (ECE-2) has been identified as well [3]. Endothelin release is increased transcriptionally when the endothelium is exposed to vasoconstrictor peptides, inflammatory cytokines and physical factors (e.g. angiotensin II, thrombin, TGF-β). Although the human kidney contains mRNA for all three isoforms of endothelin (ET), ET-1 appears to be the only peptide expressed at the protein level [4]. Expression of ET-1, its precursor, big ET-1, and the ECE in the non-diseased kidney is largely confined to the glomerular and vascular endothelium [4, 5]. However, when proteinuria is present, there is tubular expression of ET-1 as well [6]. ET-1 released by the renal vasculature or nephron segments mainly acts on cells in the immediate vicinity in an autocrine/paracrine fashion. ET-1 mediates its biological effects by interacting with two receptors, the ETA and ETB receptors, which have been cloned and well characterized. The ETA receptor is preferentially expressed in vascular smooth muscle cells and mediates the potent constrictor actions of ET-1 [7]. The ETB receptor is primarily expressed in endothelial cells and binds all three ET isoforms. When this receptor is activated, nitric oxide and prostacyclin are released, possibly as a feedback loop to the constrictor actions of ET-1. This is exemplified by recent observations where both administration of a selective ETB antagonist in animals as well as specific knock-out … * Corresponding author. Tel: +31-30-250-7329; Fax: +31-30-254-3492; E-mail: t.rabelink@digd.azu.nl