Evaluating the usefulness of the estimated glomerular filtration rate for determination of imipenem dosage in critically ill patients.

BACKGROUND: Antibiotic dosing in critically ill patients is complicated by variations in the pharmacokinetics of antibiotics in this group. The dosing of imipenem/cilastatin is usually determined by severity of illness and renal function. OBJECTIVES: To determine the correlation between estimated glomerular filtration rates (eGFRs) calculated with the Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) equation and imipenem trough levels in critically ill patients. METHODS: This prospective observational study was done in the surgical intensive care unit (ICU) at Steve Biko Academic Hospital, Pretoria, South Africa. Imipenem trough levels were measured by high-performance liquid chromatography and compared with eGFRs calculated with the CKD-EPI equation. Correlation was evaluated by the Pearson product-moment correlation coefficient. RESULTS: The study population consisted of 68 critically ill patients aged between 18 and 81 years; 43 (63%) were male, and the mean weight was 78 kg (range 40 - 140). On admission, 30 patients (44%) had sepsis, 16 (24%) were admitted for trauma, and 22 (32%) were admitted for miscellaneous surgical conditions. Acute Physiology and Chronic Health Evaluation II (APACHE II) scores ranged from 4 to 39 (mean 18). The 28-day mortality rate was 29%. The mean albumin level was 16 g/L (range 7 - 25), the mean creatinine level 142 µmol/L (range 33 - 840), and the mean eGFR 91 mL/min/1.73 m2 (range 6 - 180). Imipenem trough levels ranged between 3.6 and 92.2 mg/L (mean 11.5). The unadjusted Pearson product-moment correlation coefficient between eGFR and imipenem trough level was -0.04 (p=0.761). CONCLUSION: Considering the high mortality rate of sepsis in ICUs and the rapid global increase in antimicrobial resistance, it is crucial to dose antibiotics appropriately. Owing to the variability of antibiotic pharmacokinetics in critically ill patients, this task becomes almost impossible when relying on conventional dosing guidelines. This study found that eGFRs do not correlate with imipenem blood levels in critically ill patients and should not be used to determine the dose of imipenem/cilastatin. Instead, the dose should be individualised for patients through routine therapeutic drug monitoring.

Investigating the need for therapeutic drug monitoring of imipenem in critically ill patients: Are we getting it right?

BACKGROUND: The drug levels and clearances of imipenem in critically ill patients are not comprehensively described in current literature, yet it is vital that adequate levels be achieved for therapeutic success. OBJECTIVES: To determine the proportion of critically ill patients treated with imipenem/cilastatin with sub-therapeutic imipenem plasma levels, and to compare the clinical outcomes of those patients with therapeutic levels with those who had sub-therapeutic levels. METHODS: Trough imipenem plasma levels of 68 critically ill patients from a surgical intensive care unit were measured using a validated high-performance liquid chromatography method. Imipenem trough levels were compared with the minimum inhibitory concentration (MIC) of the causative bacterial agents, based on a target value of 100% time above MIC (¦T >MIC). RESULTS: The proportion of participants with sub-therapeutic imipenem levels was 22% (95% confidence interval (CI) 13% - 34%). The 14- and 28-day mortality rates in the sub-therapeutic group were 33% and 40%, respectively, compared with 19% (p=0.293) and 26% (p=0.346), respectively, in the therapeutic group. Sub-therapeutic imipenem plasma levels are associated with adjusted hazard ratio of 1.47 (95% CI 0.55 - 3.91). CONCLUSIONS: The lower proportion of critically ill patients with sub-therapeutic imipenem plasma levels in this study compared with previous studies may be attributed to the practice of higher dosages and the administration method of extended infusions of imipenem/cilastatin in our setting. The results demonstrate a trend of higher mortality in patients with sub-therapeutic imipenem levels, although the results were not statistically significant at this sample size.

Ciprofloxacin pharmacokinetic profiles in paediatric sepsis: how much ciprofloxacin is enough?

OBJECTIVE: To determine the pharmacokinetic profile of ciprofloxacin 20 mg/kg per day (10 mg/kg administered intravenously 12 hourly) in paediatric patients with severe sepsis. DESIGN: Open and prospective. SETTING: Tertiary referral multi-disciplinary ICU. PATIENTS: Twenty patients (two groups - group A: 3 months-1 year; group B 1-5 years). INTERVENTIONS: Timed blood samples were taken for pharmacokinetics after the first dose (D(0)), as well as day 2 (D(2)) and then between days 6-8. MEASUREMENTS AND RESULTS: Ciprofloxacin serum levels were measured by high performance liquid chromatography. Demographic and clinical data and all adverse events were noted. Standard pharmacokinetic variables were calculated by non-compartmental methods. Peak concentrations (C(max)) for group A were D(0) 6.1+/-1.2 mg/l, D(2) 9.0+/-1.8 mg/l and D(7) 5.8+/-1.3 mg/l and, for group B, 7.4+/-1.3 mg/l, 7.8+/-1.6 mg/l and 6.4+/-1.3 mg/l, respectively, for the study periods. Concentration 12 h after the start of infusion (C(min)) for all periods were 0.2 mg/l or less. Areas under the curve (AUC, 12 h) were group A: 15.6+/-1.3, 19.2+/-1.63 and 14.1+/-1.4 mg/h per l, and group B: 15.9+/-1.3, 18.0+/-1.7 and 13.2+/-1.26 mg/h per l. One patient presenting with seizures, initially controlled, had another convulsion and a further patient developed seizures whilst on ciprofloxacin. C(max) in these patients were higher than the average C(max). The convulsions of both patients were easily controlled. No other drug-related serious adverse events occurred. No arthropathy was noted. Three patients died of their underlying disease. CONCLUSIONS: There was no accumulation of drug even after 7 days of administration. Our C(max) and AUC were lower than that achieved in a similar adult pharmacokinetic study. To achieve end points of area under the inhibitory curve (AUIC) of 100-150 mg/h per l, 10 mg/kg ciprofloxacin eight hourly would be required for some resistant ICU organisms.

Pharmacokinetic profiles of high-dose intravenous ciprofloxacin in severe sepsis. The Baragwanath Ciprofloxacin Study Group.

The pharmacokinetics of 400 mg of ciprofloxacin given intravenously (i.v.) every 8 h (q8h) in severely septic adults was documented in a multidisciplinary, tertiary referral intensive care unit (ICU). Sixteen evaluable patients (three pharmacokinetic profiles) without renal dysfunction and with severe sepsis were studied. Ciprofloxacin at a dosage of 400 mg given i.v. q8h was administered over 1 h. Plasma samples for assay (high-pressure liquid chromatography) were taken at timed intervals (preinfusion, at the end of infusion, and at 1, 2, 3, 5, and 7 h postinfusion) for first-dose kinetics (day 0 [D0]), D2, and between D6 and D8. All pharmacokinetic variables were calculated by noncompartmental methods. Standard intensive care was provided. Peak ciprofloxacin concentrations were as follows: D0, 6. 01 +/- 1.93 mg/liter; D2, 6.68 +/- 2.01 mg/liter; and D6 to D8 6.45 +/- 1.54 mg/liter. Trough levels were as follows: D0, 0.6 +/- 0.5 mg/liter; D2, 0.7 +/- 0.4 mg/liter; and D6 to D8 0.6 +/- 0.4 mg/liter. The areas under the concentration curves (8 h) were as follows: D0, 13.3 +/- 3.8 mg . h/liter; D2, 16.8 +/- 5.4 mg . h/liter; and D6 to D8, 15.5 +/- 4.7 mg . h/liter. No drug-related serious adverse events occurred. For 17 of 18 patients enrolled in the study, the causative organisms were susceptible to ciprofloxacin. One patient developed renal failure (non-drug related) after the administration of three doses of ciprofloxacin. One patient was infected with ciprofloxacin-resistant organisms on enrollment. Nine of 16 evaluable patients had clinical cures, and 8 had bacteriological cures. One patient developed a ciprofloxacin-resistant superinfection. In two patients the clinical course was indeterminate. Two bacteriological failures occurred. We conclude that in critically ill adults ciprofloxacin at a dosage of 400 mg given i.v. q8h is safe. Its pharmacokinetic profile provides bactericidal activity against most organisms encountered in an ICU. Except for some initial accumulation on D2, no further accumulation occurred in patients without renal failure. Ciprofloxacin should be administered i.v. at a dosage of 400 mg q8h for severe sepsis.

Changes in vancomycin pharmacokinetics in critically ill infants.

We aimed to assess the pharmacokinetics of vancomycin in critically ill infants, and to evaluate the standard recommended dose of 10 mg/kg 6 hourly. All infants admitted to the Baragwanath Hospital ICU who had arterial lines in situ, and for whom vancomycin 10 mg/kg 6 hourly was prescribed for an infective insult and who had parental consent, were included in the study. Vancomycin was infused over 60 minutes. Serum samples were taken immediately before the dose and at 30, 60, 120 and 300 minutes after the end of the vancomycin infusion, on days 2 and 8 of therapy. Extrapolated peak concentration (Cmax), trough concentration (Cmin), apparent volume of distribution (Vd), elimination half-life (t1/2el) and clearance (CL) were determined for each patient. Day 2 values were compared with those of day 8. Day 2 serum concentrations were assayed on 20 patients and day 8 concentrations in 15. The mean vancomycin Vd on day 2 (0.81 l/kg) was significantly (P = 0.007) larger than that on day 8 (0.44 l/kg). The change in Vd resulted in a significant change in mean Cmax (29.1 vs 35.5 micrograms/ml) (P = 0.02) and mean t1/2el (5.3 vs 3.4h) (P = 0.01) over the treatment period. Critically ill infants displayed a large initial volume of distribution which probably resulted from aggressive fluid resuscitation. This also results in a large variation in other pharmacokinetic parameters, namely Cmax and t1/2el. Although the routine monitoring of vancomycin serum concentrations remain controversial, we feel that in view of these large pharmacokinetic variations, the critically ill infant is a specific group where monitoring of vancomycin serum levels is indicated.

Determining aspects of primary health care coverage in urban and rural areas of the Orange Free State.

The study was undertaken to determine the primary health coverage of blacks living in urban and rural areas of the Orange Free State. A multistage cluster sampling method was used to select 120 clusters in each of the urban and rural areas. The field work was conducted and completed in less than a week per region by nursing staff employed by health services rendering services in urban and rural areas. Interviews were conducted at 948 urban and 970 rural black households. Over 95% of the inhabitants had access to safe water, 50.9% of urban and 45.1% of rural children who had had an acute diarrhoeal attack appeared to have received adequate oral rehydration therapy, and 65.6% of children 12-23 months of age in urban areas and 38.1% in rural areas were considered fully immunised. The infant mortality rate was 45.3/1,000 in urban areas and 100.7 in rural areas. To reduce the infant mortality rates the World Health Organisation's programme for the control of diarrhoeal diseases has subsequently been introduced in the Orange Free State.

The use of sensitivity discs in the identification of Campylobacter species.

Filter paper discs were impregnated with a solution containing 20 mg of triphenyltetrazolium chloride per millilitre, and used in the typing of catalase-positive Campylobacter species. Also used were filter paper discs impregnated with cephalothin at 30 micrograms/ml, 60 micrograms/ml and 3 mg/ml and nalidixic acid at the same concentrations, as well as commercially available discs containing 30 micrograms of, respectively, cephalothin and nalidixic acid. Results obtained proved the technique to be reliable and easier to interpret than previously used methods, and laboratory prepared filter paper discs compared favourably with commercial discs.

The orbital muscle of Müller.

The orbital muscle consists of smooth muscle fibres interspersed with blood lacunae and is therefore both contractile and erectile. Contraction is under sympathetic control, whereas erection appears to be under parasympathetic (pterygopalatine) influence. Apart from its possible effect on the position of the eyeball in the orbit, the muscle seems to be mainly concerned with directing facial venous blood to or away from the cavernous sinus which acts as a heat exchanger for internal carotid blood.