Summary Background In the era of highly effective direct‐acting antivirals (DAAs) for treatment of patients with chronic hepatitis C virus (HCV) infection, ribavirin (RBV) is still considered beneficial in certain patients. Aim To assess the association between RBV steady‐state plasma levels and sustained virological response (SVR). Methods Consecutive HCV‐infected patients treated with DAAs plus RBV from four Dutch academic medical centres were enrolled. RBV steady‐state plasma levels were prospectively measured at treatment week 8 using validated assays. Logistic regression analyses were performed to assess the influence of RBV steady‐state plasma level on SVR, and RBV therapeutic range was explored using area under the ROC curve analyses. Results A total of 183 patients were included, of whom 85% had one or more difficult‐to‐cure characteristics (ie treatment experienced, HCV genotype 3, cirrhosis). The majority was treated with a sofosbuvir‐based regimen and 163 (89%) patients achieved SVR. Median RBV dose was 12.9 (interquartile range 11.2‐14.7) mg/kg/d, and median RBV steady‐state plasma level was 2.66 (1.95‐3.60) mg/L. In multivariable analyses, higher RBV steady‐state plasma level (adjusted odds ratio 1.79 [95% CI 1.09‐2.93]) was an independent predictor of SVR. With regard to the optimal RBV therapeutic range, 2.28 mg/L was the optimal lower cut‐off for achieving SVR and 3.61 mg/L was the upper cut‐off for preventing significant anaemia (Haemoglobin < 10 g/dL). Conclusion In this cohort of mainly difficult‐to‐cure patients treated with DAAs plus RBV, higher RBV steady‐state plasma level was an independent predictor of SVR.
The development and use of and increasingly potent antibiotics did not have a progressive impact on the survival rate of patients with gram-negative sepsis. In this thesis we have studied the effects of several new antibiotics, generally used in the management of patients with sepsis, on the release of endotoxin from gram-negative bacteria in-vitro and in-vivo. ... Zie: Summary and conclusions
Initial antibiotic treatment of severe infections can lead to clinical deterioration due to sudden endotoxin release and concomitant exaggerated inflammatory response. Antibiotic-induced morphological changes may contribute to this phenomenon. High-dose ceftazidime, which inhibits penicillin-binding protein (PBP)-1 in Gram-negative bacteria, causes quick bacteriolysis and low endotoxin release. Low-dose ceftazidime leads to PBP-3 inhibition, which causes bacterial filament formation, associated with high endotoxin releases. PBP-2-specific antibiotics induce spheroplasts, again associated with low endotoxin release. We hypothesized that antibiotic type, concentration and regimen influence bacterial morphology, endotoxin levels and inflammatory response.Neutropenic mice with Escherichia coli or Pseudomonas aeruginosa sepsis were treated with ceftazidime or meropenem 10-320 mg/kg as an intravenous bolus or as continuous tail vein infusions of 0.1 mL/h. Four hours later, bacterial counts, morphology, plasma endotoxin, pro-inflammatory cytokines [tumour necrosis factor-alpha (TNF-alpha) and interleukin-6 (IL-6)] and antibiotic concentrations were measured.Continuous infusion of 80 mg/kg ceftazidime was the lowest dose preventing filaments in E. coli infections. Bolus treatment resulted in filament formation, irrespective of the dose. During continuous treatment, IL-6 and TNF-alpha concentrations were higher compared with bolus treatment and controls for both antibiotics and both strains. A clear relationship between cfu counts in muscle and circulating IL-6 was shown (r=- 0.579, P=0.007), suggesting that plasma IL-6 is a valuable indicator of bacterial killing at the infection site.Our findings show that not PBP affinity but the method of antibiotic administration is crucial during initial treatment of severe infections.
The number of chronic hepatitis C virus (HCV)-infected patients who have been lost to follow-up (LTFU) is high and threatens HCV elimination. Micro-elimination focusing on the LTFU population is a promising strategy for low-endemic countries like the Netherlands (HCV prevalence 0.16%). We therefore initiated a nationwide retrieval project in the Netherlands targeting LTFU HCV patients.LTFU HCV-infected patients were identified using laboratory and patient records. Subsequently, the Municipal Personal Records database was queried to identify individuals eligible for retrieval, defined as being alive and with a known address in the Netherlands. These individuals were invited for re-evaluation. The primary endpoint was the number of patients successfully re-linked to care.Retrieval was implemented in 45 sites in the Netherlands. Of 20,183 ever-diagnosed patients, 13,198 (65%) were known to be cured or still in care and 1,537 (8%) were LTFU and eligible for retrieval. Contact was established with 888/1,537 (58%) invited individuals; 369 (24%) had received prior successful treatment elsewhere, 131 (9%) refused re-evaluation and 251 (16%) were referred for re-evaluation. Finally, 219 (14%) were re-evaluated, of whom 172 (79%) approved additional data collection. HCV-RNA was positive in 143/172 (83%), of whom 38/143 (27%) had advanced fibrosis or cirrhosis and 123/143 (86%) commenced antiviral treatment.Our nationwide micro-elimination strategy accurately mapped the ever-diagnosed HCV population in the Netherlands and indicates that 27% of LTFU HCV-infected patients re-linked to care have advanced fibrosis or cirrhosis. This emphasizes the potential value of systematic retrieval for HCV elimination.
AbstractCiprofloxacin in low doses is, in volunteers, effective for decontaminating the digestive tract [elimination of aerobic Gram-negative bacilli (GNB)] without disturbing colonization resistance. Before using this concept in neutropenic patients, we investigated if a low dose quinolone is still effective when the colonization resistance is disturbed by another antimicrobial agent. Ciprofloxacin 20 mg daily was effective in eliminating Gram-negative bacilli from the digestive tract in 4/5 volunteers, in 1 volunteer the GNB persisted in low concentration. No colonization with exogenous resistant GNB occurred. Following impairment of colonization resistance by addition of clindamycin 300 mg daily, 3/5 volunteers became colonized by spontaneously acquired exogenous GNB resistant to ciprofloxacin. We conclude that selective decontamination with a quinolone in low dosage cannot be recommended in neutropenic patients because there is, in the case of disturbed colonization resistance, a real risk of acquisition of quinolone-resistant strains.
Melioidosis, caused by the Gram-negative bacterium Burkholderia pseudomallei, is an opportunistic infection across the tropics. Here, we provide a systematic overview of imported human cases in a non-endemic country over a 25-year period. All 55 Dutch microbiology laboratories were contacted in order to identify all B. pseudomallei positive cultures from 1990 to 2018. A response rate of 100% was achieved. Additionally, a systematic literature search was performed, medical-charts reviewed, and tissue/autopsy specimens were re-assessed. Thirty-three travelers with melioidosis were identified: 70% male with a median-age of 54 years. Risk factors were present in most patients (n = 23, 70%), most notably diabetes (n = 8, 24%) and cystic fibrosis (n = 3, 9%). Countries of acquisition included Thailand, Brazil, Indonesia, Panama, and The Gambia. Disease manifestations included pneumonia, intra-abdominal abscesses, otitis externa, genitourinary, skin-, CNS-, and thyroid gland infections. Twelve (36%) patients developed sepsis and/or septic shock. Repeat episodes of active infection were observed in five (15%) and mortality in four (12%) patients. Post-mortem analysis showed extensive metastatic (micro)abscesses amongst other sites in the adrenal gland and bone marrow. The number of imported melioidosis is likely to increase, given rising numbers of (immunocompromised) travelers, and increased vigilance of the condition. This first systematic retrospective surveillance study in a non-endemic melioidosis country shows that imported cases can serve as sentinels to provide information about disease activity in areas visited and inform pre-travel advice and post-travel clinical management.
Journal Article The release of endotoxin from antibiotic-treated Escherichia coli and the production of tumour necrosis factor by human monocytes Get access A. S. M. Dofferhoff, A. S. M. Dofferhoff aDepartment of Internal Medicine, Canisius-Wilhelmina HospitalWeg door Jonkerbos 100, P.O. Box 9015, 6500 GS Nijmegen Search for other works by this author on: Oxford Academic PubMed Google Scholar M. T. Esselink, M. T. Esselink bDepartment of Internal Medicine, Division of Hematology, University Hospital GroningenThe Netherlands Search for other works by this author on: Oxford Academic PubMed Google Scholar H. G. de Vries-Hospers, H. G. de Vries-Hospers cLaboratory of Medical Microbiology, University Hospital GroningenThe Netherlands Search for other works by this author on: Oxford Academic PubMed Google Scholar A. v. Zanten, A. v. Zanten dDepartment of Nuclear Medicine, University Hospital GroningenThe Netherlands Search for other works by this author on: Oxford Academic PubMed Google Scholar V. J. J. Bom, V. J. J. Bom bDepartment of Internal Medicine, Division of Hematology, University Hospital GroningenThe Netherlands Search for other works by this author on: Oxford Academic PubMed Google Scholar J. Weits, J. Weits eDepartment of Internal Medicine, Division of Infectious Diseases, University Hospital GroningenThe Netherlands Search for other works by this author on: Oxford Academic PubMed Google Scholar E. Vellenga E. Vellenga bDepartment of Internal Medicine, Division of Hematology, University Hospital GroningenThe Netherlands Search for other works by this author on: Oxford Academic PubMed Google Scholar Journal of Antimicrobial Chemotherapy, Volume 31, Issue 3, March 1993, Pages 373–384, https://doi.org/10.1093/jac/31.3.373 Published: 01 March 1993 Article history Received: 29 June 1992 Accepted: 19 November 1992 Published: 01 March 1993
'%3e%3cpath fill='%23012169' d='M0 0v30h60V0z'/%3e%3cpath stroke='%23fff' stroke-width='6' d='m0 0 60 30m0-30L0 30'/%3e%3cpath stroke='%23C8102E' stroke-width='4' d='m0 0 60 30m0-30L0 30' clip-path='url(%23b)'/%3e%3cpath stroke='%23fff' stroke-width='10' d='M30 0v30M0 15h60'/%3e%3cpath stroke='%23C8102E' stroke-width='6' d='M30 0v30M0 15h60'/%3e%3c/g%3e%3c/svg%3e)
