Prospective Evaluation of a Model-Based Dosing Regimen for Amikacin in Preterm and Term Neonates in Clinical Practice.

Based on a previously derived population pharmacokinetic model, a novel neonatal amikacin dosing regimen was developed. The aim of the current study was to prospectively evaluate this dosing regimen. First, early (before and after second dose) therapeutic drug monitoring (TDM) observations were evaluated for achieving target trough (<3 mg/liter) and peak (>24 mg/liter) levels. Second, all observed TDM concentrations were compared with model-predicted concentrations, whereby the results of a normalized prediction distribution error (NPDE) were considered. Subsequently, Monte Carlo simulations were performed. Finally, remaining causes limiting amikacin predictability (i.e., prescription errors and disease characteristics of outliers) were explored. In 579 neonates (median birth body weight, 2,285 [range, 420 to 4,850] g; postnatal age 2 days [range, 1 to 30 days]; gestational age, 34 weeks [range, 24 to 41 weeks]), 90.5% of the observed early peak levels reached 24 mg/liter, and 60.2% of the trough levels were <3 mg/liter (93.4% ≤5 mg/liter). Observations were accurately predicted by the model without bias, which was confirmed by the NPDE. Monte Carlo simulations showed that peak concentrations of >24 mg/liter were reached at steady state in almost all patients. Trough values of <3 mg/liter at steady state were documented in 78% to 100% and 45% to 96% of simulated cases with and without ibuprofen coadministration, respectively; suboptimal trough levels were found in patients with postnatal age <14 days and current weight of >2,000 g. Prospective evaluation of a model-based neonatal amikacin dosing regimen resulted in optimized peak and trough concentrations in almost all patients. Slightly adapted dosing for patient subgroups with suboptimal trough levels was proposed. This model-based approach improves neonatal dosing individualization.

Population pharmacokinetic modelling of total and unbound cefazolin plasma concentrations as a guide for dosing in preterm and term neonates.

OBJECTIVES: Cefazolin is frequently administered for antimicrobial prophylaxis and treatment of infections. In neonates, pharmacokinetic observations are limited and dosing regimens variable. The aim of this study was to describe the pharmacokinetics of cefazolin in neonates based on total and unbound concentrations to optimize cefazolin dosing. METHODS: Thirty-six neonates [median birth body weight 2720 (range 540-4200) g, current body weight (cBW) 2755 (830-4200) g and postnatal age (PNA) 9 (1-30) days] receiving intravenous cefazolin (50 mg/kg/8 h) were included. Based on 119 total and unbound plasma concentrations, a population pharmacokinetic analysis with a covariate analysis was performed. Monte Carlo simulations were performed aiming for unbound concentrations above an MIC of 8 mg/L (>60% of the time) in all patients. RESULTS: A one-compartment pharmacokinetic model was developed in which total and unbound concentrations were linked by maximum protein binding (Bmax) of 136 mg/L and a dissociation constant (KD) for cefazolin protein binding of 46.5 mg/L. cBW was identified as covariate for volume of distribution (V), bBW and PNA for clearance and albumin plasma concentration for Bmax, explaining 50%, 58% and 41% of inter-individual variability in V, clearance and Bmax, respectively. Based on Monte Carlo simulations, a body weight- and PNA-adapted dosing regimen that resulted in similar exposure across different weight and age groups was proposed. CONCLUSIONS: A neonatal pharmacokinetic model taking into account total and unbound cefazolin concentrations with saturable plasma protein binding was identified. As cBW and PNA were the most important covariates, these may be used for individualized dosing in neonates.

Intralenticular opacification of hydrophilic acrylic intraocular lenses.

PURPOSE: To find out the incidence of intraocular lens (IOL) optic opacification in a suspect IOL. METHODS: Retrospective review of patients' notes 3-4 years postimplant. RESULTS: In all, 56 IOLs showed signs of opacification, resulting in reduced vision out of 181 lenses traced. CONCLUSION: Certain hydrophilic acrylic IOLs like the model in question (SC60B-0UV) show opacification of the IOL, which may impair the vision of pseudophakic patients. However, not all lenses of this variety exhibit this cloudiness. Factors affecting this phenomenon are not yet completely clear but may include changes in the UV absorbant material incorporated in the lens substance itself. We report a series of patients who had received this lens and experienced loss of vision due to opacification of the IOL. In a follow-up ranging from 1 to 4 years postoperatively, a higher incidence of postoperative opacification of this lens emerges, after comparison with existing literature. IOL exchange in such patients is the only option. However, this mode of treatment should not be offered lightly as results may be guarded at best even in the face of a technically satisfactory procedure.

The spectrum of herpes simplex virus disease of the anterior segment in the 1990s.

We have sampled our clinic population in order to ascertain the proportion with herpetic eye disease of the anterior segment. The age, gender predominance, and incidence of bilateral disease amongst such patients has not changed over the past 20 years. The predominant disease type was stromal keratitis, with significant morbidity and visual handicap. Herpetic eye disease of the anterior segment utilizes only 1% of out-patient clinic resources overall, but 17% of specialist external disease clinic time. There was a statistically significant correlation between total length of follow-up and reduced visual acuity. It would seem that the prevalence of herpetic eye disease of the anterior segment appears to have halved since comparable reports were published. In addition, the prognosis of the disease, in terms of the prevalence of visual impairment, has worsened.

Phototherapeutic keratectomy in recurrent corneal erosions refractory to other forms of treatment.

BACKGROUND: Recurrent corneal erosions can occur as a sequel of trauma, of dystrophies or spontaneously. Therapeutic options include topical lubricating and desiccating agents, therapeutic contact lenses, anterior stromal puncture and, most recently, phototherapeutic keratectomy. At present there are no studies available assessing the value of these different therapeutic options. METHODS: Fifteen eyes of 12 patients underwent therapeutic excimer photoablation after failure of other forms of treatment (lubricating agents in all cases, therapeutic contact lenses in 8, anterior stromal puncture in 2). Ablation depth was 5 microns, except in patients with stromal dystrophy or myopia (6 eyes), who had a deeper ablation. RESULTS: After a first photokeratectomy 9 eyes remained asymptomatic (mean follow-up 12.8 months), 2 eyes had persistent symptoms and 4 had recurrent corneal erosions after 1-24 months. The chance of success after one treatment was 60% after 12 months as calculated by the Kaplan-Meier method. CONCLUSIONS: The method of photoablation as applied in this study has a similar chance of success to other surgical methods such as anterior surgical stromal puncture. Patients included in this study, however, were highly selected and were refractory to other forms of treatment.

Clinical audit of malaria diagnosis in urban primary curative care clinics, Zimbabwe.

Clinical audit was performed on the accuracy of malaria diagnosis by nursing staff within Harare City Health Department using diagnosis by doctors as the reference standard. This was found to be about 10 pc based on symptoms. The criteria for diagnosis of malaria as in ZEDAP manuals and in-house training were not being utilised. Pyrexia was not present in 40 pc of the patients. Serious illnesses were occasionally dismissed as malaria and not treated appropriately or reviewed. The most common misdiagnosis was of acute respiratory tract infections which also have clear guidelines for diagnosis. More appropriate training methods need to be developed to improve the diagnostic capacity of nursing staff who are frontline providers of primary health care. This study shows the importance of performing an audit for process evaluation, compared to set standards and to be used for improving the quality of services.

PIP: Malaria remains a serious public health problem in many areas of Zimbabwe, especially during the wet season from February to May. Findings are reported from a clinical audit conducted between July 1989 and January 1990 on the accuracy of malaria diagnosis by nursing staff in the Harare City Health Department using diagnosis by six clinic doctors as the reference standard. The study was scheduled for the dry season to minimize the number of malaria cases presenting, with questionnaires completed on 92 subjects from 11 clinics. The investigation found approximately 10% of the diagnoses to be based upon symptoms, the criteria for diagnosing malaria as outlined in Zimbabwe Essential Drugs Action Program manuals and in-house training were not being followed, pyrexia was not present in 40% of patients, serious illnesses were occasionally dismissed as malaria and not treated appropriately or reviewed, and the most common misdiagnosis was of acute respiratory tract infections which also have clear guidelines for diagnosis. Better training methods need to be developed to improve the diagnostic capacity of nursing staff, the frontline providers of primary health care.

Topical heparin in the treatment of ligneous conjunctivitis.

BACKGROUND: Ligneous conjunctivitis is a rare acute or subacute membranous conjunctivitis of unknown etiology for which no generally accepted form of treatment is available. METHODS: Between 1972 and 1993, 17 patients with ligneous conjunctivitis were treated with excision biopsy, meticulous hemostasis, and immediate, intensive topical treatment with heparin, steroids, and, in 12 patients, alpha-chymotrypsin until all signs of conjunctival inflammation had subsided. RESULTS: On histologic examination, the lesions consisted of subepithelial deposits of fibrin in all patients. Eight patients had no recurrence (mean follow-up, 33.1 months) and in four patients the conjunctivitis was controlled after one repeat excision and topical treatment (mean follow-up, 40.3 months). One patient had three recurrences before responding to treatment (follow-up, 24 months). In four patients, treatment was unsuccessful, although lesion-free intervals were longer than usually seen in this condition (mean, 7.8 months). CONCLUSION: These results suggest that intensive and early use of topical heparin may improve therapy results in ligneous conjunctivitis.

Penetrating keratoplasty in the West Bank and Gaza.

Four hundred and sixteen penetrating keratoplasties performed at St John Ophthalmic Hospital, Jerusalem, between January 1988 and July 1992 were reviewed retrospectively. The leading indications were keratoconus, microbial keratitis, trachomatous corneal scarring and herpes simplex keratitis. After a mean follow-up of 12.4 months (> 1-48 months) 79.8% of the grafts remained clear. The results in terms of graft clarity and visual improvement varied among the different diagnostic groups. No relationship was found between donor age, cadaver time or storage time and graft survival. This series demonstrates the viability of penetrating keratoplasty in this area of low economic development but highlights the need for strict patient selection to ensure optimal use of scarce donor material.

Childhood blindness in the West Bank and Gaza Strip: prevalence, aetiology and hereditary factors.

A study of all the schools for the blind in the West Bank and Gaza Strip was undertaken during 1991-2. Two hundred and five children had a complete ophthalmic examination. This represented 94% of all children aged 5-15 years attending schools for the blind. According to WHO categories of visual loss, 63% were blind and 21% had severe visual impairment. The main causes of blindness and severe visual loss were retinal (52%), optic atrophy (12%), glaucoma (9%) and cataract (7%). Common retinal diseases included degenerative myopia, Leber's congenital amaurosis, cone dystrophy and retinitis pigmentosa. Depending on the locality, 44-85% of these children were the product of a consanguineous marriage and a positive family history was present in 57%. The minimum prevalence of childhood blindness was estimated to be 0.32/1000 children. A reduction in the prevalence of blindness requires a reduction in consanguineous marriages, genetic counselling for affected families and public health measures to ensure early referral for management of cataract and glaucoma.

Delleman syndrome: a case report and review.

A case of oculocerebrocutaneous syndrome is presented, to our knowledge the first to be reported in West Bank and Gaza. The child was of consanguinous parents. The clinical features of orbital cyst, periorbital cutaneous malformations, and cerebral malformations are described, together with a brief review of previous reports. The need for neurological follow-up of these cases is emphasised.