Acquired renal arteriovenous fistula is a rare complication following a nephrectomy and its diagnosis may be made many years after the intervention. The closure of the fistula is advisable in most cases, since it represents a risk for heart failure and rupture of the vessel. There are an increasing number of publications describing different techniques of occlusion. The case of a 70-year-old woman with abdominal discomfort due to a large renal arteriovenous fistula, 45 years after nephrectomy, is presented and current literature is reviewed. Percutaneous embolization was performed by placing an occluding balloon through the draining vein followed by the release of nine coils through arterial access. One day after successful occlusion of the fistula, clinical symptoms disappeared.
Abstract. Introduction: Standardization of diagnostic and treatment concepts in diabetes-related foot infection (DFI) is challenging. In 2019, specific recommendations regarding diagnostic principles and antibiotic therapy (ABT) for DFI, including the one for osteomyelitis (DFO), were introduced in our institution. In this study, we assessed the adherence to these in-house guidelines 2 years after their implementation. Methods: Adult patients with DFI with and without DFO who underwent surgical intervention between 2019 and 2021 were included. Patients' charts were retrospectively reviewed. Accordance to recommendations regarding biopsy sampling, labeling, requesting microbiological and histopathological examinations, and treatment duration were assessed. Results: A total of 80 patients with 117 hospital episodes and 163 surgical interventions were included; 84.6 % required an amputation. Patients with HbA1c levels of <6.5 % more often required a revision during the same hospitalization than those with HbA1c levels of ≥6.5 % (29.4 % vs. 12.1 %, respectively, p=0.023). Specimens were obtained in 71.8 % of operations and sent for histological examination in 63.2 %. The mean duration of ABT was 9 (interquartile range (IQR) 5–15) d in macroscopically surgically cured episodes and 40.5 (IQR 15–42) d in cases with resection margins in non-healthy bone (p<0.0001). Treatment duration results were similar when using histological results: 13 (IQR 8–42) d for healthy bone vs. 29 (IQR 13–42) d for resection margins consistent with osteomyelitis (p=0.026). Conclusion: The adherence to recommendations in terms of biopsy sampling was good, moderate for histopathological analysis and poor for labeling the anatomic location. Adherence to recommendations for ABT duration was good, but further shortening of treatment duration for surgically cured cases is necessary.
Background Genotypic antiretroviral resistance testing (GRT) in HIV infection with drug resistant virus is recommended to optimize antiretroviral therapy, in particular in patients with virological failure. We estimated the clinical effect, cost and cost-effectiveness of using GRT as compared to expert opinion in patients with antiretroviral treatment failure. Methods We developed a mathematical model of HIV disease to describe disease progression in HIV-infected patients with treatment failure and compared the incremental impact of GRT versus expert opinion to guide antiretroviral therapy. The analysis was conducted from the health care (discount rate 4%) and societal (discount rate 2%) perspective. Outcome measures included life-expectancy, quality-adjusted life-expectancy, health care costs, productivity costs and cost-effectiveness in US Dollars per quality-adjusted life-year (QALY) gained. Clinical and economic data were extracted from the large Swiss HIV Cohort Study and clinical trials. Results Patients whose treatment was optimized with GRT versus expert opinion had an increase in discounted life-expectancy and quality-adjusted life-expectancy of three and two weeks, respectively. Health care costs with and without GRT were $US 421,000 and $US 419,000, leading to an incremental cost-effectiveness ratio of $US 35,000 per QALY gained. In the analysis from the societal perspective, GRT versus expert opinion led to an increase in discounted life-expectancy and quality-adjusted life-expectancy of three and four weeks, respectively. Health care costs with and without GRT were $US 551,000 and $US 549,000, respectively. When productivity changes were included in the analysis, GRT was cost-saving. Conclusions GRT for treatment optimization in HIV-infected patients with treatment failure is a cost-effective use of scarce health care resources and beneficial to the society at large.
Le suivi postopératoire des patients après l’implantation d’une prothèse articulaire constitue une mission multidisciplinaire de longue haleine. Il nécessite une bonne collaboration du médecin en charge du suivi avec un chirurgien orthopédiste et un infectiologue, afin qu’un patient avec suspicion d’infection périprothétique puisse être rapidement adressé au médecin compétent et traité, si l’infection est confirmée.
Many scientists and clinical pharmacologists have advocated for the right choice and combinations of repurposed drugs with which to treat patients in COVID-19,1, 2 based on sound knowledge of clinical pharmacology, physiology and clinical therapeutics. ASCEPT-BPS subsequently highlighted the importance of applying core pharmacology principles at all stages of research to help identify the right dose of repurposed therapies, the right patient and the right treatment protocol.3 One of the recommendations was that there should be a thorough assessment of safety end-points in all trials, including those due to drug-drug and drug-disease interactions to ensure that there is a complete profile of the hazards of the medicine in relation to the benefits at different stages of the disease. We wish to comment further on this important point in relation to the impact of inflammation on drug disposition and drug-drug interactions (DDIs). The systemic inflammatory response to SARS-CoV-2 results in the release of cytokines in symptomatic COVID-19 patients. Subsequently, intracellular signalling cascades are activated, leading to the downregulation of cytochrome P450 enzymes (CYP),4 particularly CYP3A4.5 These findings are in line with the reported strikingly elevated concentrations of the boosted CYP3A4 substrate lopinavir (LPV)6, 7 and are supported by clinical observations showing a correlation between elevated C-reactive protein (CRP) values and high plasma concentrations of LPV/r.7 Inflammatory cytokines also impact drug transporters such as P-glycoprotein (P-gp) and breast cancer resistance protein (BCRP)4 leading to increased absorption of substrate drugs. Several drugs repurposed for the treatment of COVID-19 undergo varying degrees of CYP3A4-mediated metabolism (i.e., lopinavir/ritonavir (LPV/r), atazanavir, chloroquine, hydroxychloroquine, dexamethasone, and ruxolitinib) consequently their exposure may be increased in COVID-19 patients with significant systemic inflammatory response. Elevated drug concentrations may increase the risk of adverse drug effects and accentuate the magnitude of DDIs with comedications whose metabolism is inhibited by LPV/r. The effect of inflammation on dexamethasone is more difficult to predict. Dexamethasone has been used at a dose of 6 mg once daily up to 10 days in the RECOVERY trial.8 Dexamethasone is known to be a weak (low dose) to moderate (high dose) inducer of CYP3A4. In the context of inflammation, dexamethasone exposure is expected to increase initially thereby increasing the inducing effect (i.e., going from a weak inducing effect as expected with a 6 mg dose to a moderate inducing effect due to the predicted initial twofold to threefold increase in dexamethasone exposure). The moderate inducing effect of dexamethasone together with the decrease in inhibitory cytokines is expected to reverse the initial inhibitory effect of inflammation on CYP3A4 leading to an overall inducing effect over the treatment course. Finally, data indicate that hydroxychloroquine plasma concentrations are not elevated in COVID-19 patients unlike LPV,7, 9 and this may reflect the involvement of multiple metabolic pathways. Since hydroxychloroquine accumulates highly in tissues, concentrations in plasma might not be appropriate to reflect the effect of inflammation. The observation that inflammation has a profound effect on LPV exposure (thereby increasing the potential for enhanced pharmacokinetic boosting) raises the question of whether this should be taken into account when prescribing other CYP3A4 drugs in COVID-19 patients, particularly for drugs with a narrow therapeutic index (NTI). Important examples are anticoagulants or antiplatelet agents which are often prescribed to COVID-19 patients due to the higher risk of thrombotic complications. Importantly, 12 patients were closely monitored when receiving direct oral anticoagulant treatment (DOAC) before and after acquiring COVID-19. The patients were maintained on the same dose of DOAC after starting LPV/r or darunavir/ritonavir, another strong CYP3A4 inhibitor. There was clear evidence that the DDIs between LPV/r or darunavir/ritonavir and various DOACs were more profound in the COVID-19 patients compared with the original DDI studies. For instance, rivaroxaban exposure increased by sevenfold to 31-fold in COVID-19 patients treated with LPV/r10 whereas this drug combination resulted in a 2.5-fold increase in rivaroxaban in healthy volunteers. Also, the exposure of dabigatran, a P-gp substrate, was increased by fourfold in COVID-19 patients10 whereas a modest DDI has been observed in HIV-patients receiving this combination. Altogether, these observations indicate that inflammation can substantially impact the exposure of CYP3A4 and also P-gp substrates. Inflammation likely amplifies the magnitude of DDIs by increasing both the exposure of the perpetrator (i.e., drug causing the DDI) and the victim drug (i.e., drug being impacted by the perpetrator). Importantly, given that ritonavir is a mechanism based inhibitor of CYP3A4, the disappearance of the inhibitory effect may take up to 5 days after stopping LPV/r.11 Inflammation can also impair the efficacy of a prodrug undergoing CYP activation. For instance, the ratio of clopidogrel's active metabolite to clopidogrel parent drug was shown to be 48-fold lower in critically ill patients compared with healthy volunteers, thereby confirming that inflammation downregulates CYP2C19 involved in clopidogrel activation.12 This is supported by the observed association between increased CRP levels and diminished platelet inhibition under clopidogrel treatment.13 There is emerging evidence of the impact of inflammation on drug metabolism in COVID-19 patients. However, we need further studies to better characterize the impact of inflammation on both the range of drugs affected and the magnitude of DDIs. Currently, it remains unclear whether the degree of inflammation is correlated with the exposure of susceptible CYP or P-gp substrates and, in turn, with the magnitude of DDI (in the case of inhibitors). The limited available data suggest that the magnitude of a DDI can be accentuated. Thus, we recommend that coadministration of NTI CYP3A4 and/or P-gp drugs should be avoided when possible in the presence of DDI perpetrators like LPV/r or atazanavir. Furthermore, we advise close monitoring and dosage adjustment of a NTI drug (Table 1), in the absence of a perpetrator given that inflammation, per se, inhibits metabolism. It should be emphasized that dosage adjustment of a NTI drug might not be required if anti-inflammatory drugs like dexamethasone, the interleukin inhibitors (i.e., anakinra, sarilumab, and tocilizumab) or the janus kinase inhibitors (i.e., baricitinib and ruxolitinib) are initiated in COVID-19 patients at an early stage of the inflammatory response. These drugs will normalize metabolism due to their inhibitory effect on inflammatory cytokines. Finally, we encourage the use of a specialist web resource such as www.covid19-druginteractions.org to check for DDI. Should we take into account inflammation when prescribing in COVID-19 patients? The emerging evidence is yes—at least with some drugs. But maybe this discussion has only just started and research opportunities await. C.M. was supported by the Adolf and Mary Mil foundation. D.J.B. has received educational grants from AbbVie, Novartis, Merck, Gilead and Sobi and lecture/consultancy fees from AbbVie, Gilead, Merck and ViiV. The other authors have nothing to disclose in relation to this paper. C.M. drafted the first version. M.B., P.S., and D.J.B. added parts of new texts. All authors reviewed subsequent versions and approved the final version.
