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1.
J Med Case Rep ; 16(1): 344, 2022 Sep 29.
Article in English | MEDLINE | ID: mdl-36171586

ABSTRACT

BACKGROUND: After the introduction of antibiotics, pneumococcal pericarditis has become a rare finding. However, this severe condition with high mortality and complication rates requires rapid recognition and intervention. Herein, we describe a patient that presents with this rare disease resulting in an unusual, fatal outcome. CASE PRESENTATION: A previously healthy, 68-year-old, Caucasian male presented with progressive fatigue, dyspnea, and appetite loss since 12 days. He was diagnosed with diabetes mellitus 5 days before presentation but had not started treatment. After echocardiography revealed pericardial effusion, pericardiocentesis was performed with immediate drainage of a large volume of purulent fluid suggestive of bacterial pericarditis. On the basis of cultures showing Streptococcus pneumoniae as the causative organism, a regimen of intravenous penicillin was initiated. Additionally, antidiabetic drugs were started as his diabetes also predisposed him to invasive infectious disease. No other primary source of the infection, such as pneumonia, was found. Though the patient was found to be severely ill on admission, his clinical condition improved. A total of 1235 mL of pericardial fluid was drained, and adequate drainage was confirmed by daily, bedside echocardiography. However, 6 days post-admission, the patient suddenly developed intrapericardial bleeding with blood clot formation on the right chamber with subsequent cardiac tamponade. With the blood clot precluding adequate drainage through the catheter, the patient suffered cardiac arrest and died before surgical intervention could be attempted. CONCLUSIONS: Pneumococcal pericarditis is a very rare but life-threatening disease that necessitates immediate intervention with antibiotics and drainage of the pericardial effusion. Thus, although symptoms may be variable and aspecific, early recognition of this condition is critical. The present case illustrates the presentation, diagnosis, and clinical course of a patient presenting with pneumococcal pericarditis in current clinical practice. Through this report, we aimed to increase awareness among clinicians both of the existence of this phenomenon and of its uncertain clinical course. As is highlighted by the case, patients with pneumococcal pericarditis are at high risk for complications and should be closely monitored.


Subject(s)
Bacterial Infections , Diabetes Mellitus , Pericardial Effusion , Pericarditis , Aged , Anti-Bacterial Agents/therapeutic use , Bacterial Infections/complications , Diabetes Mellitus/drug therapy , Humans , Hypoglycemic Agents/therapeutic use , Male , Mediastinitis , Penicillins/therapeutic use , Pericardial Effusion/diagnostic imaging , Pericardial Effusion/etiology , Pericardial Effusion/therapy , Pericarditis/complications , Pericarditis/therapy , Sclerosis
2.
PLoS One ; 17(4): e0267140, 2022.
Article in English | MEDLINE | ID: mdl-35436301

ABSTRACT

BACKGROUND: The ability to accurately distinguish bacterial from viral infection would help clinicians better target antimicrobial therapy during suspected lower respiratory tract infections (LRTI). Although technological developments make it feasible to rapidly generate patient-specific microbiota profiles, evidence is required to show the clinical value of using microbiota data for infection diagnosis. In this study, we investigated whether adding nasal cavity microbiota profiles to readily available clinical information could improve machine learning classifiers to distinguish bacterial from viral infection in patients with LRTI. RESULTS: Various multi-parametric Random Forests classifiers were evaluated on the clinical and microbiota data of 293 LRTI patients for their prediction accuracies to differentiate bacterial from viral infection. The most predictive variable was C-reactive protein (CRP). We observed a marginal prediction improvement when 7 most prevalent nasal microbiota genera were added to the CRP model. In contrast, adding three clinical variables, absolute neutrophil count, consolidation on X-ray, and age group to the CRP model significantly improved the prediction. The best model correctly predicted 85% of the 'bacterial' patients and 82% of the 'viral' patients using 13 clinical and 3 nasal cavity microbiota genera (Staphylococcus, Moraxella, and Streptococcus). CONCLUSIONS: We developed high-accuracy multi-parametric machine learning classifiers to differentiate bacterial from viral infections in LRTI patients of various ages. We demonstrated the predictive value of four easy-to-collect clinical variables which facilitate personalized and accurate clinical decision-making. We observed that nasal cavity microbiota correlate with the clinical variables and thus may not add significant value to diagnostic algorithms that aim to differentiate bacterial from viral infections.


Subject(s)
Bacterial Infections , Microbiota , Respiratory Tract Infections , Virus Diseases , Bacterial Infections/drug therapy , C-Reactive Protein/metabolism , Humans , Nose/microbiology , Respiratory Tract Infections/drug therapy , Virus Diseases/diagnosis
3.
Lancet Infect Dis ; 22(2): 274-283, 2022 02.
Article in English | MEDLINE | ID: mdl-34627499

ABSTRACT

BACKGROUND: Adults hospitalised to a non-intensive care unit (ICU) ward with moderately severe community-acquired pneumonia are frequently treated with broad-spectrum antibiotics, despite Dutch guidelines recommending narrow-spectrum antibiotics. Therefore, we investigated whether an antibiotic stewardship intervention would reduce the use of broad-spectrum antibiotics in patients with moderately severe community-acquired pneumonia without compromising their safety. METHODS: In this cross-sectional, stepped-wedge, cluster-randomised, non-inferiority trial (CAP-PACT) done in 12 hospitals in the Netherlands, we enrolled immunocompetent adults (≥18 years) who were admitted to a non-ICU ward and had a working diagnosis of moderately severe community-acquired pneumonia. All participating hospitals started in a control period and every 3 months a block of two hospitals transitioned from the control to the intervention period, with all hospitals eventually ending in the intervention period. The unit of randomisation was the hospital (cluster), and electronic randomisation (by an independent data manager) decided the sequence (the time of intervention) by which hospitals would cross over from the control period to the intervention period. Blinding was not possible. The antimicrobial stewardship intervention was a bundle targeting health-care providers and comprised education, engaging opinion leaders, and prospective audit and feedback of antibiotic use. The co-primary outcomes were broad-spectrum days of therapy per patient, tested by superiority, and 90-day all-cause mortality, tested by non-inferiority with a non-inferiority margin of 3%, and were analysed in the intention-to-treat population, comprising all patients who were enrolled in the control and intervention periods. This trial was prospectively registered at ClinicalTrials.gov, NCT02604628. FINDINGS: Between Nov 1, 2015, and Nov 1, 2017, 5683 patients were assessed for eligibility, of whom 4084 (2235 in the control period and 1849 in the intervention period) were included in the intention-to-treat analysis. The adjusted mean broad-spectrum days of therapy per patient were reduced from 6·5 days in the control period to 4·8 days in the intervention period, yielding an absolute reduction of -1·7 days (95% CI -2·4 to -1·1) and a relative reduction of 26·6% (95% CI 18·0-35·3). Crude 90-day mortality was 10·9% (242 of 2228 died) in the control period and 10·8% (199 of 1841) in the intervention period, yielding an adjusted absolute risk difference of 0·4% (90% CI -2·7 to 2·4), indicating non-inferiority. INTERPRETATION: In patients hospitalised with moderately severe community-acquired pneumonia, a multifaceted antibiotic stewardship intervention might safely reduce broad-spectrum antibiotic use. FUNDING: None.


Subject(s)
Antimicrobial Stewardship , Community-Acquired Infections , Pneumonia , Adult , Anti-Bacterial Agents/therapeutic use , Community-Acquired Infections/drug therapy , Cross-Sectional Studies , Humans , Pneumonia/drug therapy
4.
Ned Tijdschr Geneeskd ; 1642020 05 20.
Article in Dutch | MEDLINE | ID: mdl-32613785

ABSTRACT

BACKGROUND: Scombroid food poisoning is caused by eating fish with a high concentration of histamine. Histamine is converted from histidine in fish of the Scombroidea family if it is not stored at a sufficiently low temperature. The clinical picture resembles an allergic reaction. CASE DESCRIPTION: Twenty-one of our hospital personnel went to the ER, mostly reporting flushing, headache, palpitations and gastro-intestinal symptoms. They had all eaten tuna salad in the staff canteen. The symptoms appeared to be caused by scombroid food poisoning. CONCLUSION: As a result of early recognition of the clinical picture and prompt crisis management we were able to prevent the outbreak spreading further.


Subject(s)
Disease Outbreaks/prevention & control , Food Preservation , Foodborne Diseases , Gastrointestinal Diseases , Histamine/poisoning , Marine Toxins/poisoning , Tuna , Animals , Emergency Medical Services , Flushing/diagnosis , Flushing/etiology , Food Preservation/methods , Food Preservation/standards , Foodborne Diseases/diagnosis , Foodborne Diseases/epidemiology , Foodborne Diseases/etiology , Foodborne Diseases/physiopathology , Gastrointestinal Diseases/diagnosis , Gastrointestinal Diseases/etiology , Headache/diagnosis , Headache/etiology , Humans , Personnel, Hospital
5.
Eur J Clin Microbiol Infect Dis ; 38(3): 505-514, 2019 Mar.
Article in English | MEDLINE | ID: mdl-30707378

ABSTRACT

Respiratory tract infections (RTI) are more commonly caused by viral pathogens in children than in adults. Surprisingly, little is known about antibiotic use in children as compared to adults with RTI. This prospective study aimed to determine antibiotic misuse in children and adults with RTI, using an expert panel reference standard, in order to prioritise the target age population for antibiotic stewardship interventions. We recruited children and adults who presented at the emergency department or were hospitalised with clinical presentation of RTI in The Netherlands and Israel. A panel of three experienced physicians adjudicated a reference standard diagnosis (i.e. bacterial or viral infection) for all the patients using all available clinical and laboratory information, including a 28-day follow-up assessment. The cohort included 284 children and 232 adults with RTI (median age, 1.3 years and 64.5 years, respectively). The proportion of viral infections was larger in children than in adults (209(74%) versus 89(38%), p < 0.001). In case of viral RTI, antibiotics were prescribed (i.e. overuse) less frequently in children than in adults (77/209 (37%) versus 74/89 (83%), p < 0.001). One (1%) child and three (2%) adults with bacterial infection were not treated with antibiotics (i.e. underuse); all were mild cases. This international, prospective study confirms major antibiotic overuse in patients with RTI. Viral infection is more common in children, but antibiotic overuse is more frequent in adults with viral RTI. Together, these findings support the need for effective interventions to decrease antibiotic overuse in RTI patients of all ages.


Subject(s)
Anti-Bacterial Agents/therapeutic use , Antimicrobial Stewardship/standards , Inappropriate Prescribing/statistics & numerical data , Respiratory Tract Infections/drug therapy , Aged , Bacterial Infections/diagnosis , Bacterial Infections/drug therapy , Bacterial Infections/epidemiology , Child, Preschool , Female , Humans , Infant , Israel/epidemiology , Male , Middle Aged , Netherlands/epidemiology , Prospective Studies , Reference Standards , Respiratory Tract Infections/diagnosis , Respiratory Tract Infections/epidemiology , Virus Diseases/diagnosis , Virus Diseases/drug therapy , Virus Diseases/epidemiology
7.
Infect Dis (Lond) ; 47(12): 862-8, 2015.
Article in English | MEDLINE | ID: mdl-26211497

ABSTRACT

BACKGROUND: Corynebacterium pseudodiphtheriticum may be present as commensal flora of the respiratory tract and therefore it may be difficult to assess clinical relevance when it is cultured from lower respiratory tract specimens. Our objective was to determine the clinical relevance of C. pseudodiphtheriticum as a lower respiratory tract pathogen and to define patients at risk of developing lower respiratory tract infections caused by C. pseudodiphtheriticum. METHODS: We retrospectively identified all lower respiratory tract cultures positive for C. pseudodiphtheriticum over a 10-year period and assessed clinical relevance by predefined criteria. RESULTS: Clinical relevance was likely or possible in 86% of patients. Pre-existent comorbidity was present in 86% of patients, mostly underlying cardiac or pulmonary disease. All isolates were susceptible to amoxicillin. CONCLUSION: C. pseudodiphtheriticum should be considered a clinically relevant pathogen when cultured from the lower respiratory tract in symptomatic patients.


Subject(s)
Corynebacterium Infections/microbiology , Corynebacterium/isolation & purification , Respiratory Tract Infections/microbiology , Adult , Aged , Aged, 80 and over , Amoxicillin/pharmacology , Anti-Bacterial Agents/pharmacology , Bronchoalveolar Lavage Fluid/microbiology , Corynebacterium/drug effects , Corynebacterium/pathogenicity , Female , Heart Diseases/complications , Humans , Lung Diseases/complications , Male , Middle Aged , Pleural Effusion/microbiology , Pneumonia/microbiology , Retrospective Studies , Risk Factors , Sputum/microbiology , Young Adult
8.
Ned Tijdschr Geneeskd ; 157(42): A6375, 2013.
Article in Dutch | MEDLINE | ID: mdl-24128598

ABSTRACT

BACKGROUND: The pathogen Mycoplasma pneumonia is a frequent cause of respiratory tract infections, especially in adolescents. Less well known is that this infection may also be associated with extrapulmonary manifestations including M. pneumonia associated mucositis (MPAM). CASE DESCRIPTION: A 19-year-old Dutch man was admitted to the hospital with severe mucositis, stomatitis, bilateral conjunctivitis, urethritis and mild exanthema on his arms. He had a one-week history of coughing and fever. Thorough microbiological investigations were implemented. After a few days both the IgM titre and polymerase chain reaction investigations for M. pneumonia from a throat swab taken on admission proved to be positive. Treatment with doxycycline resulted in rapid improvement in clinical condition. All mucosal lesions almost healed within two weeks. CONCLUSION: M. pneumonia infections may be associated with the triad of stomatitis, conjunctivitis and urethritis in the absence of extensive skin manifestations. The prognosis is favourable.


Subject(s)
Anti-Bacterial Agents/therapeutic use , Doxycycline/therapeutic use , Mucositis/diagnosis , Mycoplasma pneumoniae/isolation & purification , Pneumonia, Mycoplasma/diagnosis , Diagnosis, Differential , Humans , Male , Mucositis/complications , Mucositis/drug therapy , Mucositis/microbiology , Pneumonia, Mycoplasma/complications , Pneumonia, Mycoplasma/drug therapy , Polymerase Chain Reaction/methods , Treatment Outcome , Young Adult
9.
Am J Trop Med Hyg ; 89(3): 527-30, 2013 Sep.
Article in English | MEDLINE | ID: mdl-23857021

ABSTRACT

Recently, two patients of African origin were given a diagnosis of Plasmodium falciparum malaria without recent travel to a malaria-endemic country. This observation highlights the importance for clinicians to consider tropical malaria in patients with fever. Possible transmission routes of P. falciparum to these patients will be discussed. From a public health perspective, international collaboration is crucial when potential cases of European autochthonous P. falciparum malaria in Europe re considered.


Subject(s)
Malaria, Falciparum/diagnosis , Malaria, Falciparum/transmission , Plasmodium falciparum/isolation & purification , Administration, Intravenous , Adult , Antimalarials/therapeutic use , Female , Fever/drug therapy , Humans , Malaria, Falciparum/drug therapy , Male , Netherlands , Public Health , Quinine/therapeutic use , Travel , Treatment Outcome , Young Adult
10.
J Acquir Immune Defic Syndr ; 62(5): 546-9, 2013 Apr 15.
Article in English | MEDLINE | ID: mdl-23314415

ABSTRACT

BACKGROUND: In HIV-negative patients, radiotherapy (RT) decreases CD4 T-cell counts. We studied the effects of RT in HIV-1 positive patients. METHODS: HIV-1 positive patients with a subsequent diagnosis of a solid tumor were selected from the Dutch national observational HIV cohort, Aids Therapy Evaluation in the Netherlands (ATHENA). The patients were grouped according to whether they had received RT or not. Primary endpoint of the study was the time from baseline to reaching CD4 cell counts higher than those at baseline. Kaplan-Meier estimates of the percentage of patients reaching the endpoint were calculated. RESULTS: Ninety patients were included of whom 36 received RT and 54 did not. Median duration of RT was 46 [interquartile range (IQR) 30-63] days. Median first CD4 cell count after stopping RT was 150 (IQR 30-270) × 10/L lower compared with baseline. In 13 of the 36 patients receiving RT, CD4 cell counts recovered to baseline, after a median of 469 (IQR 345-595) days. In 35 of the 54 patients without RT, the CD4 cell count recovered to baseline or higher, after a median of 112 (IQR 42-182) days. After 3 years, in 39% of patients who had RT compared with 71% of patients without RT, CD4 cell counts recovered to baseline or higher (P < 0.0001). In a Cox regression adjusted for potential confounders, RT was associated with a longer (hazard ratio 0.29; 95% confidence interval 0.13 to 0.63) and combination antiretroviral therapy use with a shorter time to return to baseline [hazard ratio 2.46 (95% confidence interval 1.11 to 5.48)]. CONCLUSIONS: RT resulted in a significant and prolonged decrease in CD4 cell counts.


Subject(s)
CD4-Positive T-Lymphocytes/immunology , CD4-Positive T-Lymphocytes/radiation effects , HIV Infections/immunology , HIV-1/isolation & purification , Neoplasms/radiotherapy , Neoplasms/virology , Adult , CD4 Lymphocyte Count , Cohort Studies , Female , HIV Infections/complications , HIV Infections/virology , Humans , Kaplan-Meier Estimate , Male , Middle Aged , Neoplasms/immunology , Netherlands , Proportional Hazards Models , Retrospective Studies
11.
Infect Control Hosp Epidemiol ; 33(5): 527-30, 2012 May.
Article in English | MEDLINE | ID: mdl-22476283

ABSTRACT

We conducted a retrospective cohort study to assess respiratory colonization before and after the use of chlorhexidine oral decontamination among a cohort of intensive care unit patients who received mechanical ventilation. We observed a decrease in the prevalence of Enterobacteriaceae and an increase in the incidence of fungal colonization. Chlorhexidine oral decontamination might have a differential effect on respiratory colonization.


Subject(s)
Chlorhexidine/administration & dosage , Decontamination/methods , Equipment Contamination , Mouthwashes/administration & dosage , Respiration, Artificial/instrumentation , Aged , Aged, 80 and over , Bacteria/drug effects , Female , Hospitals, Teaching , Humans , Male , Middle Aged , Netherlands , Retrospective Studies
12.
J Heart Valve Dis ; 20(1): 100-2, 2011 Jan.
Article in English | MEDLINE | ID: mdl-21404906

ABSTRACT

It has been suggested that 18F-fluorodeoxyglucose positron emission tomography (FDG-PET) might serve as a tool for the often difficult diagnosis of infective endocarditis. The case is described of a patient with a Bartonella henselae endocarditis with a negative FDG-PET. This case report demonstrates that negative FDG-PET findings do not rule out the presence of endocarditis.


Subject(s)
Aortic Valve/diagnostic imaging , Bartonella henselae/isolation & purification , Endocarditis, Subacute Bacterial/diagnostic imaging , Fluorodeoxyglucose F18 , Positron-Emission Tomography , Radiopharmaceuticals , Anti-Bacterial Agents/therapeutic use , Aortic Valve/microbiology , Aortic Valve/surgery , Echocardiography, Transesophageal , Endocarditis, Subacute Bacterial/microbiology , Endocarditis, Subacute Bacterial/therapy , Heart Valve Prosthesis Implantation , Humans , Male , Middle Aged , Predictive Value of Tests , Tomography, X-Ray Computed
13.
Transpl Int ; 21(11): 1066-71, 2008 Nov.
Article in English | MEDLINE | ID: mdl-18699845

ABSTRACT

To study if mycophenolic acid (MPA), the active metabolite of mycophenolate mofetil (MMF), indeed inhibits T-cell proliferation in kidney transplant recipients by lowering intracellular deoxyguanosine triphosphate (dGTP) and guanosine triphosphate (GTP) levels. Blood was drawn from 11 kidney transplant recipients. Ex vivo T-cell proliferation was measured by stimulation with phytohemagglutin (PHA) and anti-CD3 monoclonal antibody (mAb). Plasma MPA levels and intracellular dGTP and GTP in peripheral blood mononuclear cells were measured. MMF induces a significant decrease in T-lymphocyte proliferation at all time points (i.e. 24 h, 10 days and 8 weeks) after stimulation with both PHA (P = 0.001, 0.002 and 0.013 respectively) and anti-CD3 mAb (P = 0.004, 0.004 and 0.005 respectively). There was no significant change in intracellular dGTP (P = 0.31, 0.16 and 0.35) or GTP levels (P = 0.99, 0.32 and 0.49) between baseline and day 1, day 10 or week 8. All MPA levels were above the minimal required concentration for the inhibition of lymphocyte proliferation. MMF inhibits T-lymphocyte proliferation in kidney transplant recipients without lowering intracellular dGTP or GTP levels. This suggests another mechanism underlying its immunosuppressive capacity.


Subject(s)
Cell Proliferation/drug effects , Deoxyguanine Nucleotides/metabolism , Guanosine Triphosphate/metabolism , Kidney Transplantation , Mycophenolic Acid/analogs & derivatives , T-Lymphocytes/drug effects , Adult , Female , Humans , Male , Middle Aged , Mycophenolic Acid/pharmacokinetics , Mycophenolic Acid/therapeutic use
15.
AIDS Res Hum Retroviruses ; 23(1): 19-27, 2007 Jan.
Article in English | MEDLINE | ID: mdl-17263628

ABSTRACT

P-glycoprotein (P-gp) can compromise the antiretroviral effect of a protease inhibitor (PI)-containing regimen for HIV-1, but can also reduce HIV-1 replication. We studied the net effect of P-gp on the intracellular HIV-1 RNA and DNA load in vivo. CD4(+) T cells were isolated from 27 HIV-1 patients (13 without and 14 with a PI-containing regimen) and subsequently sorted in CD45RO(-) (naive) and CD45RO(+) (memory) subsets with either high (P-gp(high)) or low (P-gp(low)) P-gp activity. Unspliced HIV-1 RNA and HIV-1 DNA load were determined. For each patient P-gp(high) and P-gp(low) subsets were compared. In patients on a PI-containing regimen, intracellular unspliced HIV-1 RNA was significantly lower in P-gp(high)-naive CD4(+) cells compared to P-gp(low)-naive CD4(+) cells (p = 0.04). The same trend was seen in naive CD4(+) cells of treatment naive patients. In both treated and untreated patients HIV-1 DNA levels were significantly lower in P-gp(high) than in P-gp(low) memory CD4(+) cells (p = 0.02 and p = 0.04). High cellular P-gp activity coincided with a reduced intracellular HIV-1 load in vivo, both in therapy-naive and in PI-treated patients. Therefore we conclude that the potential efflux function of P-gp on PIs may be clinically less relevant than the effect of P-gp on intracellular HIV-1 replication.


Subject(s)
ATP Binding Cassette Transporter, Subfamily B, Member 1/metabolism , HIV Protease Inhibitors/pharmacology , HIV-1 , Indinavir/pharmacology , Nelfinavir/pharmacology , Adult , CD4-Positive T-Lymphocytes/drug effects , CD4-Positive T-Lymphocytes/metabolism , DNA, Viral/blood , Humans , Leukocytes, Mononuclear/metabolism , Middle Aged , Polymerase Chain Reaction , RNA, Viral/blood , Viral Load
16.
AIDS Res Hum Retroviruses ; 21(12): 991-6, 2005 Dec.
Article in English | MEDLINE | ID: mdl-16379601

ABSTRACT

Mycophenolate mofetil has been proposed for HIV-1 therapy because of its guanine-depleting effect, which is expected to interfere with HIV-1 replication directly by hampering reverse transcription and indirectly via inhibition of CD4+ T cell proliferation. However, treatment with mycophenolate mofetil might also compromise lymphocyte reconstitution and HIV-specific immunity. Therefore we longitudinally studied the effects of mycophenolate mofetil in combination with HAART on T cell proliferation, lymphocyte reconstitution, and HIV-specific CD4+ and CD8+ T cell responses in six therapy-naive, acute or chronic HIV-1-infected patients, as compared to eight patients treated with HAART alone. T cell proliferation in whole blood cultures of patients treated with mycophenolate mofetil was inhibited. Strikingly, ex vivo Ki67 expression within T cells was not influenced by treatment with mycophenolate mofetil. In vitro studies showed that Ki67 expression occurs at an early step of the cell cycle and was not inhibited by guanine depletion. When treatment with mycophenolate mofetil was stopped a transient increase in apoptosis and Ki67-expressing T cells was detected. This observation together with near complete inhibition of T cell proliferation in whole blood cultures during treatment with mycophenolate mofetil indicated that T cell proliferation was inhibited in patients treated with mycophenolate mofetil. Still, there was no evidence for detrimental effects of treatment with mycophenolate mofetil in addition to HAART on CD4+ T cell reconstitution or HIV-specific immunity.


Subject(s)
Antiretroviral Therapy, Highly Active , HIV Infections/drug therapy , HIV Infections/immunology , Immunosuppressive Agents/adverse effects , Mycophenolic Acid/analogs & derivatives , Acute Disease , Antiretroviral Therapy, Highly Active/adverse effects , CD4 Lymphocyte Count , CD4-Positive T-Lymphocytes/drug effects , CD4-Positive T-Lymphocytes/immunology , CD8-Positive T-Lymphocytes/drug effects , CD8-Positive T-Lymphocytes/immunology , Chronic Disease , Drug Therapy, Combination , HIV Infections/virology , HIV-1/drug effects , Humans , Immunosuppressive Agents/administration & dosage , Immunosuppressive Agents/therapeutic use , Lymphocyte Activation , Male , Mycophenolic Acid/administration & dosage , Mycophenolic Acid/adverse effects , Mycophenolic Acid/therapeutic use , Treatment Outcome
17.
Br J Clin Pharmacol ; 60(3): 276-86, 2005 Sep.
Article in English | MEDLINE | ID: mdl-16120066

ABSTRACT

AIMS: The aim of the study was to characterize the population pharmacokinetics of indinavir, define the relationship between the pharmacokinetics of indinavir and ritonavir, and to identify the factors influencing the pharmacokinetics of indinavir alone or when given with ritonavir. METHODS: HIV-1-infected patients being treated with an indinavir-containing regimen were included. During regular visits, 102 blood samples were collected for the determination of plasma indinavir and ritonavir concentrations. Full pharmacokinetic curves were available from 45 patients. Concentrations of indinavir and ritonavir were determined by liquid chromatography coupled with electrospray tandem mass spectrometry. Pharmacokinetic analysis was performed using nonlinear mixed effect modelling (NONMEM). RESULTS: The disposition of indinavir was best described by a single compartment model with first order absorption and elimination. Values for the clearance, volume of distribution and the absorption rate constant were 46.8 l h(-1) (24.2% IIV), 82.3 l (24.6% IIV) and 02.62 h(-1), respectively. An absorption lag-time of 0.485 h was detected in patients also taking ritonavir. Furthermore this drug, independent of dose (100-400 mg) or plasma concentration, decreased the clearance of indinavir by 64.6%. In contrast, co-administration of efavirenz or nevirapine increased the clearance of indinavir by 41%, irrespective of the presence or absence of ritonavir. Female patients had a 48% higher apparent bioavailability of indinavir than males. CONCLUSIONS: The pharmacokinetic parameters of indinavir were adequately described by our population model. Female gender and concomitant use of ritonavir and non-nucleoside reverse transcriptase inhibitors strongly influenced the pharmacokinetics of this drug. The results support the concept of ritonavir boosting, maximum inhibition of indinavir metabolized being observed at 100 mg.


Subject(s)
Anti-HIV Agents/pharmacokinetics , HIV Infections/drug therapy , HIV Protease Inhibitors/pharmacokinetics , Indinavir/pharmacokinetics , Ritonavir/pharmacokinetics , Adult , Drug Therapy, Combination , Female , HIV Protease Inhibitors/administration & dosage , Humans , Indinavir/administration & dosage , Male , Middle Aged , Netherlands , Ritonavir/administration & dosage
18.
AIDS ; 19(11): 1145-54, 2005 Jul 22.
Article in English | MEDLINE | ID: mdl-15990567

ABSTRACT

BACKGROUND: It has been reported that antiretroviral therapy (HAART) during acute HIV-1 infection may rescue HIV-1-specific CD4 T cell responses. OBJECTIVE: To determine the duration of this preserved response by investigating the long-term effects of HAART during acute infection on HIV-specific CD4 T cell function related to possible immune control during subsequent therapy interruption. METHODS: A longitudinal analysis followed HIV-specific CD4 T cell reactivity in 17 individuals with well-documented acute HIV-1 infection where five out of 11 HAART-treated patients stopped therapy and six were untreated. Peripheral blood mononuclear cells were stimulated with overlapping peptide pools derived from Gag and Nef. Production of interferon-gamma (IFN-gamma) and interleukin-2 (IL-2) by CD4 T cells was analysed together with proliferative responses. RESULTS: Absolute numbers, but not percentages, of Gag-specific IFN-gamma-, IL-2- or IFN-gamma/IL-2-producing CD4 T cells were increased in treated compared with untreated individuals up to 2 years after seroconversion. HAART during acute HIV-1 infection was associated with lower viral load but did not result in increased proliferation of HIV-specific CD4 T cells. One out of five individuals who discontinued therapy showed evidence for immune control. However, patients who failed to control viraemia also had measurable proliferative HIV-specific CD4 T cell responses and preserved numbers of cytokine-producing CD4 T cells. CONCLUSIONS: Early HAART during acute HIV-1 infection resulted in higher numbers of HIV-specific IFN-gamma- and IL-2-producing CD4 T cells, but this preservation in four out of five patients was not associated with control of viraemia upon treatment interruption.


Subject(s)
Antiretroviral Therapy, Highly Active , CD4-Positive T-Lymphocytes/immunology , HIV Infections/drug therapy , HIV-1/immunology , Acute Disease , CD4-Positive T-Lymphocytes/metabolism , Cell Proliferation , HIV Infections/immunology , Humans , Immunity, Cellular/immunology , Interferon-gamma/biosynthesis , Interleukin-2/biosynthesis , Prospective Studies , RNA, Viral/metabolism
19.
Clin Pharmacokinet ; 43(12): 823-32, 2004.
Article in English | MEDLINE | ID: mdl-15355127

ABSTRACT

OBJECTIVE: To study the effect of mycophenolate mofetil therapy on the pharmacokinetic parameters of a number of antiretroviral drugs, on intracellular pools of deoxycytidine triphosphate (dCTP) and deoxyguanosine triphosphate (dGTP), and on intracellular concentrations of the triphosphate of lamivudine (3TCTP). DESIGN: Randomised pharmacokinetic study. PARTICIPANTS: Nineteen HIV-1-infected patients. METHODS: Antiretroviral-naive men starting treatment with didanosine 400 mg once daily, lamivudine 150 mg twice daily, abacavir 300 mg twice daily, indinavir 800 mg twice daily, ritonavir 100 mg twice daily and nevirapine 200 mg twice daily were randomised to a group with or without mycophenolate mofetil 500 mg twice daily. After 8 weeks of therapy, the plasma pharmacokinetic profiles of mycophenolic acid (the active metabolite of mycophenolate mofetil), abacavir, indinavir and nevirapine, and triphosphate concentrations (dCTP, dGTP and 3TCTP) in peripheral blood mononuclear cells, were determined. RESULTS: Nine of the 19 patients received mycophenolate mofetil. There was no difference in plasma clearance of indinavir or abacavir between the two groups. The clearance of nevirapine was higher in patients using mycophenolate mofetil (p = 0.04). In 12 patients, of whom five also received mycophenolate mofetil, intracellular triphosphates were measured. There was no significant difference in intracellular dCTP, dGTP or 3TCTP concentrations between the two groups. CONCLUSION: In this small cohort of patients, mycophenolate mofetil therapy reduced the plasma concentration of nevirapine but had no effect on plasma concentrations of indinavir and abacavir. There were no consistent effects of mycophenolic acid on the intracellular concentrations of dCTP, dGTP or 3TCTP.


Subject(s)
Acquired Immunodeficiency Syndrome/drug therapy , Anti-Inflammatory Agents, Non-Steroidal/therapeutic use , Anti-Retroviral Agents/therapeutic use , Cytidine Triphosphate/analogs & derivatives , Cytidine Triphosphate/pharmacokinetics , Deoxycytosine Nucleotides/pharmacokinetics , Deoxyguanine Nucleotides/pharmacokinetics , HIV-1 , Lamivudine/analogs & derivatives , Lamivudine/pharmacokinetics , Mycophenolic Acid/analogs & derivatives , Mycophenolic Acid/therapeutic use , Acquired Immunodeficiency Syndrome/metabolism , Adult , Anti-Inflammatory Agents, Non-Steroidal/blood , Anti-Inflammatory Agents, Non-Steroidal/pharmacokinetics , Anti-Retroviral Agents/pharmacokinetics , Dideoxynucleotides , Drug Interactions , Humans , Male , Metabolic Clearance Rate , Middle Aged , Mycophenolic Acid/blood , Mycophenolic Acid/pharmacokinetics
20.
AIDS ; 18(14): 1925-31, 2004 Sep 24.
Article in English | MEDLINE | ID: mdl-15353978

ABSTRACT

OBJECTIVE: To study the effect of mycophenolate mofetil (MMF) on the decay rate of plasma HIV-1 RNA and the latently infected cellular reservoir in treatment-naive patients starting antiretroviral therapy. DESIGN: : Randomized trial. METHODS: A group of 19 HIV-1 infected patients (9 with a chronic and 10 with a primary infection) starting a triple antiretroviral drug regimen were randomized to a group with or without MMF. Plasma samples for HIV-1 RNA were taken and HLA-DR-CD4+ T cells were co-cultured for HIV-1 isolation. Slopes of plasma HIV-1 RNA and cellular viral load decay were calculated for the first 14 days and the first 24 weeks of treatment, respectively. RESULTS: The median plasma HIV-1 RNA daily decay rate in chronically infected patients was 0.25 log10 copies/ml [interquartile range (IQR), 0.18-0.30] with MMF and 0.28 log10 copies/ml (IQR, 0.22-0.32) without MMF (P = 0.56); in primary infected patients, it was 0.31 log10 copies/ml (IQR, 0.31-0.32) with MMF and 0.32 log10 copies/ml (IQR, 0.26-0.34) without MMF (P = 0.75). The median daily decay rate of latently infected cells was 0.017 and 0.004 infected cells/10 cells in patients with and without MMF, respectively (P = 0.89). The increase in CD4 T cells was comparable between patients with and without MMF. After stopping MMF, there was an increase in the cellular reservoir in six of eight patients. CONCLUSION: The addition of MMF to a triple class antiretroviral regimen in treatment-naive patients does not significantly increase the plasma HIV-1 RNA decay rate or the decay rate of the latently infected cellular reservoir.


Subject(s)
Enzyme Inhibitors/therapeutic use , HIV Infections/drug therapy , HIV-1 , Mycophenolic Acid/analogs & derivatives , Mycophenolic Acid/therapeutic use , Adult , Antiretroviral Therapy, Highly Active , Humans , Male , Middle Aged , RNA, Viral/blood
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