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ABSTRACT: An important role in the treatment regimens for Mycoplasma pneumoniae infections is played by macrolide (ML) antibiotics. In the past few years, however, a steady increase has been detected in the worldwide prevalence of ML-resistant (ML(r)) M. pneumoniae strains. It is obvious that this increase necessitates a continuous monitoring of ML(r) and, when detected, modification of antibiotic treatment modalities. Previously, we developed a pyrosequencing-based assay system for the genetic determination of ML(r) as well as molecular typing of M. pneumoniae. In this study, the sensitivity of this system was improved by the inclusion of a nested-PCR protocol. The modified system was applied to 114 M. pneumoniae-positive specimens that were obtained from a collection of 4,390 samples from patients with acute respiratory tract infections. These samples were collected between 1997 and 2008 in The Netherlands. The pyrosequencing system produced reliable data in 86% of the specimens that contained >500 M. pneumoniae genome copies/ml of patient sample. Each of these samples contained DNA of the ML-sensitive genotype. While 43% of the samples were found to harbor the M. pneumoniae subtype 1 genotype, 57% contained the subtype 2 genotype. We conclude that the pyrosequencing-based assay system is a useful tool for ML(r) determination and molecular typing of M. pneumoniae in patient samples. ML(r)-associated M. pneumoniae genotypes, however, were not found in the current study population.
Journal of clinical microbiology 04/2012; 50(6):1999-2004. · 4.16 Impact Factor
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ABSTRACT: The DNA recombination and repair machineries of Mycoplasma genitalium and Mycoplasma pneumoniae differ considerably from those of gram-positive and gram-negative bacteria. Most notably, M. pneumoniae is unable to express a functional RecU Holliday junction (HJ) resolvase. In addition, the RuvB homologues from both M. pneumoniae and M. genitalium only exhibit DNA helicase activity but not HJ branch migration activity in vitro. To identify a putative role of the RuvA homologues of these mycoplasmas in DNA recombination, both proteins (RuvA(Mpn) and RuvA(Mge), respectively) were studied for their ability to bind DNA and to interact with RuvB and RecU. In spite of a high level of sequence conservation between RuvA(Mpn) and RuvA(Mge) (68.8% identity), substantial differences were found between these proteins in their activities. First, RuvA(Mge) was found to preferentially bind to HJs, whereas RuvA(Mpn) displayed similar affinities for both HJs and single-stranded DNA. Second, while RuvA(Mpn) is able to form two distinct complexes with HJs, RuvA(Mge) only produced a single HJ complex. Third, RuvA(Mge) stimulated the DNA helicase and ATPase activities of RuvB(Mge), whereas RuvA(Mpn) did not augment RuvB activity. Finally, while both RuvA(Mge) and RecU(Mge) efficiently bind to HJs, they did not compete with each other for HJ binding, but formed stable complexes with HJs over a wide protein concentration range. This interaction, however, resulted in inhibition of the HJ resolution activity of RecU(Mge).
PLoS ONE 01/2012; 7(5):e38301. · 4.09 Impact Factor
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Journal of clinical microbiology 10/2011; 49(10):3723; author reply 3723-4. · 4.16 Impact Factor
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ABSTRACT: Homologous recombination between repeated DNA elements in the genomes of Mycoplasma species has been hypothesized to be a crucial causal factor in sequence variation of antigenic proteins at the bacterial surface. To investigate this notion, studies were initiated to identify and characterize the proteins that form part of the homologous DNA recombination machinery in Mycoplasma pneumoniae as well as Mycoplasma genitalium. Among the most likely participants of this machinery are homologs of the Holliday junction migration motor protein RuvB. In both M. pneumoniae and M. genitalium, genes have been identified that have the capacity to encode RuvB homologs (MPN536 and MG359, respectively). Here, the characteristics of the MPN536- and MG359-encoded proteins (the RuvB proteins from M. pneumoniae strain FH [RuvB(FH)] and M. genitalium [RuvB(Mge)], respectively) are described. Both RuvB(FH) and RuvB(Mge) were found to have ATPase activity and to bind DNA. In addition, both proteins displayed divalent cation- and ATP-dependent DNA helicase activity on partially double-stranded DNA substrates. The helicase activity of RuvB(Mge), however, was significantly lower than that of RuvB(FH). Interestingly, we found RuvB(FH) to be expressed exclusively by subtype 2 strains of M. pneumoniae. In strains belonging to the other major subtype (subtype 1), a version of the protein is expressed (the RuvB protein from M. pneumoniae strain M129 [RuvB(M129)]) that differs from RuvB(FH) in a single amino acid residue (at position 140). In contrast to RuvB(FH), RuvB(M129) displayed only marginal levels of DNA-unwinding activity. These results demonstrate that M. pneumoniae strains (as well as closely related Mycoplasma spp.) can differ significantly in the function of components of their DNA recombination and repair machinery.
Journal of bacteriology 09/2011; 193(23):6425-35. · 3.94 Impact Factor
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ABSTRACT: Infection with seasonal influenza A viruses induces immunity to potentially pandemic influenza A viruses of other subtypes (heterosubtypic immunity). We recently demonstrated that vaccination against seasonal influenza prevented the induction of heterosubtypic immunity against influenza A/H5N1 virus induced by infection with seasonal influenza in animal models, which correlated with the absence of virus-specific CD8(+) T cell responses. Annual vaccination of all healthy children against influenza has been recommended, but the impact of vaccination on the development of the virus-specific CD8(+) T cell immunity in children is currently unknown. Here we compared the virus-specific CD8(+) T cell immunity in children vaccinated annually with that in unvaccinated children. In the present study, we compared influenza A virus-specific cellular and humoral responses of unvaccinated healthy control children with those of children with cystic fibrosis (CF) who were vaccinated annually. Similar virus-specific CD4(+) T cell and antibody responses were observed, while an age-dependent increase of the virus-specific CD8(+) T cell response that was absent in vaccinated CF children was observed in unvaccinated healthy control children. Our results indicate that annual influenza vaccination is effective against seasonal influenza but hampers the development of virus-specific CD8(+) T cell responses. The consequences of these findings are discussed in the light of the development of protective immunity to seasonal and future pandemic influenza viruses.
Journal of Virology 08/2011; 85(22):11995-2000. · 5.40 Impact Factor
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ABSTRACT: The RecU protein from Mycoplasma genitalium, RecU(Mge), is a 19.4-kDa Holliday junction (HJ) resolvase that binds in a nonspecific fashion to HJ substrates and, in the presence of Mn(2+), cleaves these substrates at a specific sequence (5'-G/TC↓C/TTA/GG-3'). To identify amino acid residues that are crucial for HJ binding and/or cleavage, we generated a series of 16 deletion mutants (9 N- and 7 C-terminal deletion mutants) and 31 point mutants of RecU(Mge). The point mutations were introduced at amino acid positions that are highly conserved among bacterial RecU-like sequences. All mutants were purified and tested for the ability to bind to, and cleave, HJ substrates. We found the five N-terminal and three C-terminal amino acid residues of RecU(Mge) to be dispensable for its catalytic activities. Among the 31 point mutants, 7 mutants were found to be inactive in both HJ binding and cleavage. Interestingly, in 12 other mutants, these two activities were uncoupled; while these proteins displayed HJ-binding characteristics similar to those of wild-type RecU(Mge), they were unable to cleave HJ substrates. Thus, 12 amino acid residues were identified (E11, K31, D57, Y58, Y66, D68, E70, K72, T74, K76, Q88, and L92) that may play either a direct or indirect role in the catalysis of HJ resolution.
Journal of bacteriology 06/2011; 193(15):3941-8. · 3.94 Impact Factor
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ABSTRACT: Mycoplasma pneumoniae is a human pathogen that causes a range of respiratory tract infections. The first step in infection is adherence of the bacteria to the respiratory epithelium. This step is mediated by a specialized organelle, which contains several proteins (cytadhesins) that have an important function in adherence. Two of these cytadhesins, P40 and P90, represent the proteolytic products from a single 130 kDa protein precursor, which is encoded by the MPN142 gene. Interestingly, MPN142 contains a repetitive DNA element, termed RepMP5, of which homologues are found at seven other loci within the M. pneumoniae genome. It has been hypothesized that these RepMP5 elements, which are similar but not identical in sequence, recombine with their counterpart within MPN142 and thereby provide a source of sequence variation for this gene. As this variation may give rise to amino acid changes within P40 and P90, the recombination between RepMP5 elements may constitute the basis of antigenic variation and, possibly, immune evasion by M. pneumoniae. To investigate the sequence variation of MPN142 in relation to inter-RepMP5 recombination, we determined the sequences of all RepMP5 elements in a collection of 25 strains. The results indicate that: (i) inter-RepMP5 recombination events have occurred in seven of the strains, and (ii) putative RepMP5 recombination events involving MPN142 have induced amino acid changes in a surface-exposed part of the P40 protein in two of the strains. We conclude that recombination between RepMP5 elements is a common phenomenon that may lead to sequence variation of MPN142-encoded proteins.
Microbiology 10/2010; 157(Pt 2):473-83. · 3.06 Impact Factor
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ABSTRACT: The first choice antibiotics for treatment of Mycoplasma pneumoniae infections are macrolides. Several recent studies, however, have indicated that the prevalence of macrolide (ML)-resistance, which is determined by mutations in the bacterial 23S rRNA, is increasing among M. pneumoniae isolates. Consequently, it is imperative that ML-resistance in M. pneumoniae is rapidly detected to allow appropriate and timely treatment of patients. We therefore set out to determine the utility of pyrosequencing as a convenient technique to assess ML-resistance. In addition, we studied whether pyrosequencing could be useful for molecular typing of M. pneumoniae isolates. To this end, a total of four separate pyrosequencing assays were developed. These assays were designed such as to determine a short genomic sequence from four different sites, i.e. two locations within the 23S rRNA gene, one within the MPN141 (or P1) gene and one within the MPN528a gene. While the 23S rRNA regions were employed to determine ML-resistance, the latter two were used for molecular typing. The pyrosequencing assays were performed on a collection of 108 M. pneumoniae isolates. The ML-resistant isolates within the collection (n=4) were readily identified by pyrosequencing. Moreover, each strain was correctly typed as either a subtype 1 or subtype 2 strain by both the MPN141 and MPN528a pyrosequencing test. Interestingly, two recent isolates from our collection, which were identified as subtype 2 strains by the pyrosequencing assays, were found to carry novel variants of the MPN141 gene, having rearrangements in each of the two repetitive elements (RepMP4 and RepMP2/3) within the gene. In conclusion, pyrosequencing is a convenient technique for ML-resistance determination as well as molecular typing of M. pneumoniae isolates.
Journal of microbiological methods 09/2010; 82(3):214-22. · 2.43 Impact Factor
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ABSTRACT: Recombination between repeated DNA elements in the genomes of Mycoplasma species appears to lie at the basis of antigenic variation of several essential surface proteins. It is therefore imperative that the DNA recombinatorial pathways in mycoplasmas be unravelled. Here, we describe the proteins encoded by the Mycoplasma genitalium MG352 and Mycoplasma pneumoniae MPN528a genes (RecU(Mge) and RecU(Mpn) respectively), which share sequence similarity with RecU Holliday junction (HJ) resolvases. RecU(Mge) was found to: (i) bind HJ substrates and large double-stranded DNA molecules and (ii) cleave HJ substrates at the sequence 5'-(G) /(T) C↓(C) /(T) T(A) /(G) G-3' in the presence of Mn(2+). Interestingly, RecU(Mpn) (from M. pneumoniae subtype 2 strains) did not possess obvious DNA binding or cleavage activities, which was found to be caused by the presence of a glutamic acid residue at position 67 of the protein, which is not conserved in RecU(Mge). Additionally, RecU(Mpn) appears not to be expressed by subtype 1 M. pneumoniae strains, as these possess a TAA translation termination codon at position 181-183 of MPN528a. We conclude that RecU(Mge) is a HJ resolvase that may play a central role in recombination in M. genitalium.
Molecular Microbiology 09/2010; 77(5):1261-77. · 5.01 Impact Factor
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Journal of clinical microbiology 02/2010; 48(2):680; author reply 680. · 4.16 Impact Factor
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ABSTRACT: The P1, P40, and P90 proteins of Mycoplasma pneumoniae and the MgPa and P110 proteins of Mycoplasma genitalium are immunogenic adhesion proteins that display sequence variation. Consequently, these proteins are thought to play eminent roles in immune evasive strategies. For each of the five proteins, a similar underlying molecular mechanism for sequence variation was hypothesized, i.e., modification of the DNA sequences of their respective genes. This modification is thought to result from homologous recombination of parts of these genes with repeat elements (RepMp and MgPar elements in M. pneumoniae and M. genitalium, respectively) that are dispersed throughout the bacterial genome. Proteins that are potentially involved in homologous DNA recombination have been suggested to be implicated in recombination between these repeat elements and thereby in antigenic variation. To investigate this notion, we set out to study the function of the RecA homologs that are encoded by the M. pneumoniae MPN490 and M. genitalium MG339 genes. Both proteins, which are 79% identical on the amino acid level, were found to promote recombination between homologous DNA substrates in an ATP-dependent fashion. The recombinational activities of both proteins were Mg2+ and pH dependent and were strongly supported by the presence of single-stranded DNA binding protein, either from M. pneumoniae or from Escherichia coli. We conclude that the MPN490- and MG339-encoded proteins are RecA homologs that have the capacity to recombine homologous DNA substrates. Thus, they may play a central role in recombination between repetitive elements in both M. pneumoniae and M. genitalium.
Infection and immunity 10/2009; 77(11):4905-11. · 4.21 Impact Factor
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ABSTRACT: Several guidelines are available to guide the initiation of highly active antiretroviral therapy (HAART) in human immunodeficiency virus (HIV)-infected children. The recommendations in these guidelines show significant variability. Because there is no well-established evidence on when to start HAART, it is left to the discretion of the pediatrician which guidelines to follow. We conducted a survey concerning the indications for starting antiretroviral therapy among pediatricians involved in the treatment of HIV-infected patients in Europe and the United States. We compared the results of this survey with the guidelines available at the time, the recently adapted guidelines and literature evidence. Our results indicate that in clinical practice HAART was initiated at higher viral loads and lower CD4 counts than recommended by the guidelines. American guidelines recommended and still recommend more aggressive treatment than the European guidelines, and this is reflected in clinical practice. Until recently all guidelines were based on long term risk analyses of progression to acquired immunodeficiency syndrome (AIDS) and death performed in cohort data. A recent short term risk analysis makes it possible to calculate the 6 or 12-month risk for progression to AIDS or death for an individual child. Because viral load and CD4 count are typically measured every 3 months, one can argue that it is clinically more relevant to base the decision of when to start HAART on the short term probability of disease progression. Guidelines in Europe are now based on this type of analysis. The American guidelines only adopted the thresholds for CD4 and viral load. The short term risk analysis also shows that the risk for developing AIDS varies markedly with age. This should be reflected in all guidelines. Determining the acceptable risk of disease progression is difficult and influenced by patient-, doctor- and culture-related factors. The controversy over whether or not to treat asymptomatic infants is unresolved as well. All infants have a very high risk of disease progression regardless of their viral load or CD4 count, but lifelong treatment with a potential for significant toxicities and risk of developing resistance is also not an appealing option. We recommend an attempt to achieve a consensus among the different working groups to reduce the number of different guidelines, which should be based on the literature evidence. Because all risk analyses are based on information from the pre-HAART era, a head-to-head trial comparing early versus deferred HAART would be useful. This may be difficult to accomplish. The first step could be an analysis of retrospective data from collaborative cohort data.
The Pediatric Infectious Disease Journal 12/2006; 25(11):987-94. · 3.58 Impact Factor
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ABSTRACT: We report the data from a long-term study of 31 human immunodeficiency virus type 1 (HIV-1)-infected children who were treated with highly active antiretroviral therapy. A high proportion of the children had undetectable HIV-1 RNA levels. CD4+ T cell counts recovered and remained stable. Adverse events were observed frequently but were mostly mild.
Clinical Infectious Diseases 03/2005; 40(4):604-8. · 9.15 Impact Factor
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Mette D Hazenberg,
Sigrid A Otto, Annemarie M C van Rossum,
Henriëtte J Scherpbier,
Ronald de Groot,
Taco W Kuijpers,
Joep M A Lange,
Dörte Hamann,
Rob J de Boer,
José A M Borghans,
Frank Miedema
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ABSTRACT: Current understanding of how the T-cell pool is established in children and how this is affected by HIV infection is limited. It is widely believed that the thymus is the main source for T cells during childhood. Here we show, however, that healthy children had an age-related increase in total body numbers of naive and memory T cells, whereas absolute numbers of T-cell receptor excision circles (TRECs) did not increase. This suggests that expansion of the naive T-cell pool after birth is more dependent on T-cell proliferation than was previously recognized. Indeed, the proportion of dividing naive T cells was high, especially in younger children, which is consistent with expansion through proliferation, in addition to antigen-mediated naive T-cell activation leading to formation of the memory T-cell pool. In untreated children infected with HIV-1, total body numbers of T cells and TRECs were low and stable, whereas T-cell division levels were significantly higher than in healthy children. We postulate that in children infected with HIV, similar to adults infected with HIV, continuous activation of naive T cells leads to erosion of the naive T-cell pool and may be a major factor in lowering CD4(+) T-cell numbers.
Blood 01/2005; 104(12):3513-9. · 9.90 Impact Factor
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ABSTRACT: Zidovudine is often administered every 12 h in HIV-infected children, but so far no pharmacokinetic data are available for the administration of this agent every 12 h. We have evaluated the plasma pharmacokinetics of zidovudine administered every 8 h versus every 12 h in HIV-1-infected children.
In HIV-1-infected children who switched from zidovudine every 8 h to every 12 h, a pharmacokinetic curve was recorded both before and after the switch. Zidovudine plasma levels were measured by HPLC. Pharmacokinetic parameters were calculated by non-compartmental methods.
Six HIV-1-infected children [median age (range) 7.8 (2.5-13.4) years] were included. In these patients, geometric mean ratios of AUC(0-24) and C(max) for zidovudine every 12 h versus every 8 h were not significantly different from 1.0.
The plasma pharmacokinetic parameters of zidovudine taken every 8 h and every 12 h were not significantly different and therefore suggest bioequivalence of these two dose frequencies.
Journal of Antimicrobial Chemotherapy 12/2004; 54(6):1152-4. · 5.07 Impact Factor
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ABSTRACT: We studied a nucleoside reverse transcriptase inhibitor (NRTI)-sparing regimen for the treatment of children infected with NRTI-resistant HIV-1. The combination of lopinavir/ritonavir and efavirenz suppressed HIV-1 levels for a prolonged period and resulted in a significant increase in CD4+ T cell numbers despite an extensive prior treatment with NRTI (>4 years). Observed side effects were transient with the exception of dyslipidaemia.
Antiviral therapy 05/2004; 9(2):297-9. · 3.16 Impact Factor
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ABSTRACT: We have developed a new method based on matrix-assisted laser desorption/ionization time-of-flight (MALDI-TOF) mass spectrometry (MS) for analysis of zidovudine-triphosphate and (deoxy)nucleotide-triphosphates, which ultimately can be used for nucleoside reverse transcriptase inhibitor (NRTI) treatment monitoring in HIV-1 infected children and adults. Four different matrices were compared for sensitivity and reproducibility of zidovudine-triphosphate detection and anthranilic acid mixed with nicotinic acid (AA/NA) was selected as most suitable matrix. Solutions of zidovudine-triphosphate, ATP, and dGTP were detected up to 0.5fmol per sample. Furthermore, intracellular zidovudine-triphosphate, ATP, and dGTP were detected in peripheral blood mononuclear cells (PBMCs). Zidovudine-triphosphate, ATP, and dGTP yield identical mass spectra, however MALDI-TOF post-source decay analysis can be used for discrimination between these compounds. We conclude that this method based on MALDI-TOF MS can be used for analysis of intracellular zidovudine-triphosphate and (deoxy)nucleotide-triphosphates in PBMCs.
Biochemical and Biophysical Research Communications 03/2004; 315(1):151-9. · 2.48 Impact Factor
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ABSTRACT: The study describes the pharmacokinetics (PK) of the protease inhibitor nelfinavir and its active metabolite M8 in children and evaluates the influence of patient-related factors on nelfinavir plasma levels.
HIV-1-infected children treated with nelfinavir every 8 h (q8h) were eligible for inclusion in this retrospective study. 0-8 h intensive plasma pharmacokinetics (PK) sampling was performed at steady state. Nelfinavir maximum concentration (Cmax), area under the plasma concentration-time curve in 0-8 h (AUC0-8), trough level at the 8 h time point (C8) and relative apparent oral clearance (CI*F/kg) were calculated.
Twenty-four children (median age: 4.5 years, median nelfinavir dose: 28 mg/kg q8h) were included. Nelfinavir PK were highly variable: 10/24 children had an AUC0-8 below the value of 12.5 mg/l x h, which has previously been associated with an increased virological failure rate in children. With children aged < 2 years and a dose of 20 mg/kg q8h, a non-significant trend was observed to more AUC0-8 < 12.5 mg/l x h [odds ratio (OR) (95% CI): 2.44 (0.41-14.7) and 8.7 (0.79-95), respectively]. Nelfinavir C8 correlated strongly with AUC0-8 (r = 0.89, P < 0.001). C8 > 0.69 mg/l predicted an AUC0-8 > 12.5 mg/l x h with 71% sensitivity and 80% specificity. Dose of nelfinavir per body surface area was a better predictor of AUC0-8 than dose per body weight.
Nelfinavir PK show high interindividual variability in children. Children < 2 years old tend to be at increased risk for low nelfinavir levels. These data show that the nelfinavir dose of 20 mg/kg q8h is inadequate in most children. Also, these data suggest that paediatric dosing of nelfinavir based on body surface area should be considered. Therapeutic drug monitoring (TDM) can detect abnormal plasma levels and is therefore useful in optimizing nelfinavir therapy in HIV-infected children. However, further research is needed to more firmly establish a therapeutic range for nelfinavir in children.
Antiviral therapy 06/2003; 8(3):215-22. · 3.16 Impact Factor
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Jeanne P Dieleman, Annemarie M C van Rossum,
Bruno C H Stricker,
Miriam C J M Sturkenboom,
Ronald de Groot,
Denise Telgt,
Willem L Blok,
David M Burger,
Bert G Blijenberg,
Robert Zietse,
Inge C Gyssens
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ABSTRACT: Symptomatic nephrotoxicity is a well-known complication of indinavir treatment. However, little is known about the relevance of other abnormalities, such as leukocyturia during use of indinavir. We determined the prevalence, risk factors, and consequences of persistent leukocyturia in a prospectively monitored cohort of indinavir users in three adult outpatient clinics. Patients were monitored for nephrotoxicity at regular visits (every 3 months) between August 1998 and September 2000. Monitoring involved urine dipstick analysis and microscopy for pH, erythrocytes, leukocytes, and indinavir crystals. The urine albumin concentration/creatinine concentration ratio and serum creatinine and indinavir plasma concentrations were measured, and urinary tract infection was excluded. Urologic symptoms were retrieved from medical records. Of 184 patients with at least one assessment, 35% had leukocyturia (i.e., >75 cells/microL) at least once during the study period, which coincided with mild increase in the serum albumin level, erythrocyturia, and crystalluria. Thirty-two (24%) of 134 patients with two or more assessments had persistent leukocyturia (i.e., on two or more occasions). Risk factors were indinavir plasma concentration of >9 mg/L, urine pH of >5.7, and crystalluria. Persistent leukocyturia was associated with a gradual loss of renal function but not with urologic symptoms. The data show that leukocyturia is a frequent finding and emphasize the need for monitoring renal function during indinavir treatment, even in the absence of urologic symptoms.
JAIDS Journal of Acquired Immune Deficiency Syndromes 02/2003; 32(2):135-42. · 4.43 Impact Factor
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ABSTRACT: Prolonged administration of indinavir is associated with the occurrence of a variety of renal complications in adults. These well-documented side effects have restricted the use of this potent protease inhibitor in children.
A prospective study to monitor indinavir-related nephrotoxicity in a cohort of 30 human immunodeficiency virus type 1-infected children treated with indinavir.
Urinary pH, albumin, creatinine, the presence of erythrocytes, leukocytes, bacteria and crystals, and culture were analyzed every 3 months for 96 weeks. Serum creatinine levels were routinely determined at the same time points. Steady-state pharmacokinetics of indinavir were done at week 4 after the initiation of indinavir.
The cumulative incidence of persistent sterile leukocyturia (> or =75 cells/ micro L in at least 2 consecutive visits) after 96 weeks was 53%. Persistent sterile leukocyturia was frequently associated with a mild increase in the urine albumin/creatinine ratio and by microscopic hematuria. The cumulative incidence of serum creatinine levels >50% above normal was 33% after 96 weeks. Children with persistent sterile leukocyturia more frequently had serum creatinine levels of 50% above normal than those children without persistent sterile leukocyturia. In children younger than 5.6 years, persistent sterile leukocyturia was significantly more frequent than in older children. A higher cumulative incidence of persistent leukocyturia was found in children with an area under the curve >19 mg/L x h or a peak serum level of indinavir >12 mg/L. In 4 children, indinavir was discontinued because of nephrotoxicity. Subsequently, the serum creatinine levels decreased, the urine albumin/creatinine ratios returned to zero, and the leukocyturia disappeared within 3 months.
Children treated with indinavir have a high cumulative incidence of persistent sterile leukocyturia. Children with persistent sterile leukocyturia more frequently had an increase in serum creatinine levels of >50% above normal. Younger children have an additional risk for renal complications. The impairment of the renal function in these children occurred in the absence of clinical symptoms of nephrolithiasis. Indinavir-associated nephrotoxicity must be monitored closely, especially in children with risk factors such as persistent sterile leukocyturia, age <5.6 years, an area under the curve of indinavir >19 mg/L x h, and a C(max) >12 mg/L.
PEDIATRICS 08/2002; 110(2 Pt 1):e19. · 4.47 Impact Factor
