Management of Ganciclovir Resistant Cytomegalovirus Retinitis in a Solid Organ Transplant Recipient: A Review of Current Evidence and Treatment Approaches.

Purpose: Cytomegalovirus retinitis (CMVR) is a serious and potentially sight-threatening infection in immunocompromised individuals. Strategies for the management of drug-resistant CMVR are described. Methods: A case of severe bilateral CMVR in a single lung transplant patient, with UL97 mutation conferring ganciclovir-resistance, is presented. Treatment with standard antiviral agent and adjuvant leflunomide, immunosuppression modifications (calcineurin inhibitors and corticosteroid), intravitreal antiviral therapy and novel use of CMV-immunoglobulin is described. A literature review to support drug-resistant CMVR management is presented. Results: Severe and progressive CMV retinitis was refractory to intravitreal foscarnet and systemic leflunomide. Drug-toxicity restricted systemic antiviral therapy options. The use of combined leflunomide and CMV-immunoglobulins, in the absence of viremia, has not been previously reported. Loss of ganciclovir-resistance was eventually observed permitting successful treatment with systemic and intravitreal ganciclovir. Conclusions: Drug-resistant CMVR is a complex clinical challenge. Multiple systemic and local treatment strategies may be necessary but toxicity, resistance, and co-morbidities may severely restrict available options.

Isolation of Aspergillus species from the airway of lung transplant recipients is associated with excess mortality.

BACKGROUND: Aspergillus spp. are the leading cause of invasive fungal infection in lung transplant recipients. We investigated the relationship between the isolation of Aspergillus spp. from the respiratory tract of lung transplant recipients and their risk of mortality. METHODS: A retrospective, observational cohort study of all patients who received lung allografts between January 1999 and May 2011 at a single UK centre was performed. The time from transplantation to death was analysed using Cox regression models. Isolation of Aspergillus spp. from the respiratory tract was included as a covariate in the Cox regression model. RESULTS: Two hundred-thirteen patients were included. The median follow-up time was 5 years during which 102 patients (47.9%) died. Aspergillus was isolated from 74 (34.7%) patients. Twenty patients (27%) had Aspergillus isolated in the first 60 days post-transplant. Forty-one patients (55.4%) in the Aspergillus group and 61 patients (43.9%) in the non-Aspergillus group died during follow-up. A hazard ratio of 2.2 (95% CI 1.5-3.3; P < 0.001) for death following a positive Aspergillus sample was observed. CONCLUSION: Isolation of Aspergillus spp. from patients following lung transplantation is associated with a significant increase in mortality. Novel preventative strategies are required to minimise the impact of Aspergillus in lung transplant recipients.

Comparison of methods of assessment of renal function in cystic fibrosis (CF) patients.

Renal failure is increasingly being recognised in CF patients, usually as a consequence of long-term nephrotoxic therapy. There is a need for a simple method of assessment of renal function in this patient group. We compared measured creatinine clearance from validated timed urine collections (the generally accepted practical test of glomerular filtration) with 10 formulae used to estimate creatinine clearance in a group of 74 CF adult patients and 29 matched normal controls. Compared to direct measurement, formulae gave a range of values (95% CI for mean bias -13 to +27.9 ml/min). Even those with the best correlation (r=0.7) gave wide error ranges (limits of agreement: -42.3 to 45.9 ml/min). The most commonly used formulae (Cockroft-Gault [CGF] and abbreviated Modification of Diet in Renal Disease [aMDRD]) were not superior to most other formulae tested. Both CGF and aMDRD-derived estimates compared less favourably in CF patients than controls (mean bias: 9.7 vs 3.4 ml/min (p<0.05) and 4.9 vs 1.4 (p<0.05) respectively; 78% vs 95% (p<0.01) and 77% vs 97% (p<0.01) of estimates within 33% of measurement respectively). In particular, both CGF and aMDRD grossly overestimated renal function (mean bias 18.3 and 15.8 ml/min respectively, p<0.001) in CF patients with reduced creatinine clearance (<80 ml/min). CGF, aMDRD and other formulae cannot be used to reliably assess renal function in CF patients, since they will fail to detect those with renal impairment. Some form of carefully supervised direct measurement is still required.

Renal impairment in cystic fibrosis patients due to repeated intravenous aminoglycoside use.

Although there are reports of cases of acute renal failure occurring in cystic fibrosis (CF) patients, usually in association with the use of nephrotoxic antibiotic therapy, there have been no studies of renal function in this patient group. We hypothesized that long-term use of intravenous (IV) nephrotoxic antibiotics (aminoglycosides and colistin sulphomethate) may contribute to renal disease in CF patients. In a prospective study, we assessed creatinine clearance as an index of renal function with two techniques (24-hr urine collections and the Cockroft-Gault formula) in a group of 80 stable adult CF outpatients chronically infected with Pseudomonas aeruginosa but with no history of preceding renal disease. Using a multiple linear regression model, we evaluated their renal function in terms of their lifetime IV use of aminoglycosides and colistin. Between 31% (Cockroft-Gault formula method) and 42% (24-hr urine collection method) of patients had a creatinine clearance below normal range. Using either method, there was a strong correlation between aminoglycoside use and diminishing renal function (r=- 0.32, P=0.0055), which was potentiated by the coadministration of colistin (r=- 0.42, P <0.0002). However, there was no correlation with colistin when used in combination with other antibiotics alone (r=0.18, P=NS). Repeated IV aminoglycoside use in CF is associated with long-term renal damage. Although this effect is potentiated by colistin, colistin on its own in moderate doses does not appear to be nephrotoxic. IV aminoglycosides should be used cautiously in CF patients, with regular monitoring of renal function.

Increased morbidity associated with chronic infection by an epidemic Pseudomonas aeruginosa strain in CF patients.

BACKGROUND: Chronic pulmonary infection with transmissible Pseudomonas aeruginosa strains in individuals with cystic fibrosis (CF) has been reported, raising issues of cross infection and patient segregation. The first such strain to be described (the Liverpool epidemic strain, LES) is now widespread in many UK CF centres. However, whether such infection carries a worse prognosis is unknown. To address this, the clinical course of a group of CF patients chronically infected by LES was compared with that in patients harbouring unique strains. METHODS: Using P aeruginosa strain genotyping, two cohorts of CF patients attending the Liverpool CF service were identified who were LES positive or negative in 1998 and remained so until 2002. From these, two groups of 12 patients were matched in 1998 for age, spirometric parameters, and nutritional state and their clinical course was followed for 5 years. Patients chronically infected with Burkholderia cepacia were excluded. RESULTS: Patients chronically infected with LES had a greater annual loss of lung function than those not chronically infected by LES (mean difference between groups -4.4% (95% CI -8.1 to -0.9; p<0.02)), and by 2002 their percentage predicted forced expiratory volume in 1 second (FEV1) was worse (mean 65.0% v 82.6%, p<0.03). Their nutritional state also deteriorated over the study period (mean difference between groups in body mass index -0.7 (95% CI -1.2 to -0.2; p<0.01)), such that by 2002 they were malnourished compared with LES negative patients (mean BMI 19.4 v 22.7, p<0.02). CONCLUSIONS: Chronic infection with the Liverpool epidemic P aeruginosa strain in CF patients confers a worse prognosis than infection with unique strains alone, confirming the need for patient segregation. Since this strain is common in many CF units, strain identification in all CF centres is essential. This can only be carried out using genomic typing methods.

Sensitization of the mesoaccumbens dopamine response to nicotine.

This article reviews the evidence that pretreatment with nicotine causes a regionally selective sensitization of its stimulatory effects on a pathway, the mesoaccumbens dopamine (DA) system, which has been implicated in the locomotor stimulant response to nicotine and its ability to reinforce self-administration. The sensitization evoked by daily injections of nicotine is associated with a regionally selective downregulation of the control of mesoaccumbens DA neurons by inhibitory autoreceptors and depends upon co-stimulation of NMDA glutamatergic receptors. It is suggested that the sensitization is related to enhanced burst firing of mesoaccumbens neurons, which results in an enhancement of DA release into the extracellular space between the cells where it acts upon putative extrasynaptic dopamine receptors. The studies with NMDA receptor antagonists revealed a dissociation between the expression of sensitized mesoaccumbens DA and locomotor responses to nicotine. It is proposed, therefore, that the sensitized mesoaccumbens DA responses to nicotine may be implicated in psychopharmacological responses to drug concerned more closely with nicotine dependence.