Correlation of the vancomycin 24-h area under the concentration-time curve (AUC24) and trough serum concentration in children with severe infection: A clinical pharmacokinetic study.

BACKGROUND: Vancomycin is a common drug used in children with severe infection. In adults, at least 15 mg/L of the optimal vancomycin trough concentration (Ctrough) is needed to generate the target 24-h area under the concentration-time curve (AUC24) to the minimum inhibitory concentration (MIC) of 400 for a pathogen with the MIC ≤1 mg/L. OBJECTIVES: To determine vancomycin PK in children with severe infection and to explore the correlation between vancomycin Ctrough and AUC24 in children, as well as to propose the appropriate vancomycin dosages using Monte Carlo simulation. MATERIALS AND METHODS: Children aged 2-18 years who were admitted to Chiang Mai University Hospital and received intravenous vancomycin for severe infection were included in the study. Serum samples for vancomycin PK were obtained before and serially after the administration of the first dose according to the protocol. Pharmacokinetic analyses were performed using Phoenix WinNonlin® 7.0 and NLME™7.0. RESULTS: Fourteen children with 64% males and age range from 2 to 13 years were included in this study. Non-compartmental analysis revealed the median volume of distribution, clearance, and elimination half-life of 0.58 L/kg, 2.82 mL/kg/min and 2.33 h, respectively. Vancomycin serum concentrations were best described by a two-compartmental model with first-order elimination.The observed Ctrough at 6 h correlated well with the AUC24. The median vancomycin Ctrough at steady state that correlated with the AUC24 ≥ 400 and <800 were 11.18, 9.50, 7.91 and 6.55 mg/L in simulated children receiving vancomycin 40, 60, 80 and 100 mg/kg/day, respectively. CONCLUSION: Correlation between vancomycin Ctrough and AUC24 values in children has been observed. However, the values of Ctrough that correlate with the target AUC24≥400 in children are lower than the values observed and targeted in adults.

Case report of congenital asplenia presenting with Haemophilus influenzae type a (Hia) sepsis: an emerging pediatric infection in Minnesota.

BACKGROUND: In the pre-vaccine era, invasive disease with Haemophilus influenzae, type b (Hib) commonly presented with osteoarticular involvement. Haemophilus influenzae, type a (Hia) sepsis is a rare but emerging problem in recent years. Here, we report a case of sepsis with concomitant osteoarthritis due to Hia that was the presenting infectious disease manifestation of isolated asplenia in a young child. This unique observation adds to our understanding of sepsis and asplenia in children. CASE PRESENTATION: A five-year-old girl developed acute Hia bacteremia and sepsis. The patient developed arthritis shortly after onset of septic shock. Arthrocentesis was culture-negative, but given the difficulty differentiating between septic and reactive arthritis, prolonged antibiotic administration was provided for presumed osteoarticular infection, and the patient had an uneventful recovery. The finding of Howell-Jolly bodies on blood smear at the time of presentation prompted an evaluation that revealed isolated congenital asplenia. Evaluation for known genetic causes of asplenia was unrevealing. Investigation by the Minnesota Department of Health revealed an emergence of Hia infections over the past 5 years, particularly in children with an American Indian background. CONCLUSIONS: Hia is an important pathogen in the differential diagnosis of invasive bacterial infections in children and shares overlap in clinical presentation and pathogenesis with Hib. Invasive Hia disease can be a presenting manifestation of asplenia in children. Hia is an emerging pathogen in American Indian children.

A case of severe TBCE-negative hypoparathyroidism-retardation-dysmorphism syndrome: Case report and literature review.

Hypoparathyroidism-retardation-dysmorphism syndrome (HRD) is a rare autosomal recessive disorder attributed to the mutations in the tubulin-specific chaperone E (TBCE) gene, which is vital for microtubule function during mitosis, organelle positioning, and neuronal cytokinesis. HRD is a congenital syndromic hypoparathyroidism associated with growth deficiency, microcephaly, intellectual disability, ocular anomalies, and facial dysmorphism. To our knowledge, there is only one published case of mild HRD-like syndrome with no identifiable genetic etiology. We report a case of severe TBCE-negative phenotypic HRD in a 4-year-old female from India presenting with hypocalcemic seizures due to congenital hypoparathyroidism, extreme microcephaly, growth deficiency, ocular anomalies, and facial dysmorphism. SNP microarray and whole exome sequencing (WES) did not detect any abnormalities in TBCE or other genes of interest. WES revealed two variants of unknown clinical significance in CASC5 gene, which codes for a protein in the kinetochore and, interestingly similar to TBCE, is essential for proper microtubule function during mitosis and cell proliferation and has been implicated in primary microcephaly disorders. However, further targeted sequencing in the parents revealed both variants inherited from the unaffected mother. Significant copy number variant noise in the proband and her parents limited further analysis. At this time the role of variants in the CASC5 gene is unclear and cannot explain our patient's phenotype. In conclusion, we report a severe case of phenotypic HRD syndrome, in which extensive genetic evaluation failed to reveal an etiology. Our case demonstrates that the pathogenesis of HRD may be genetically heterogenous, meriting further genetic investigations.

Pharmacokinetics and pharmacodynamics of meropenem in children with severe infection.

This study aimed to describe the pharmacokinetic (PK) characteristics of meropenem in children with severe infections and to assess the pharmacokinetic/pharmacodynamic (PK/PD) profiles of various meropenem dosage regimens in these patients. Fourteen children with severe infections received intravenous (i.v.) bolus doses of meropenem (20 mg/kg/dose) every 8 h (q8h). Serum samples were obtained before and serially after the second dose of meropenem, and a population PK analysis was performed. The final model was used to simulate serum concentration-time profiles with various dosage regimens. The PK/PD target was to achieve a serum meropenem concentration higher than the minimum inhibitory concentration (MIC) of the causative organism (i.e. Pseudomonas aeruginosa and Enterobacteriaceae) for ≥40% of the dosing interval (40%T>MIC). The median age and weight of the children were 6.0 years and 20.0 kg, respectively. Meropenem serum concentration-time profiles were best described by a two-compartmental model with first-order elimination. The simulations showed that the probabilities of target attainment (PTAs) for organisms with an MIC of 1 mg/L were 0.678 and 1.000 following i.v. bolus and 3-h infusion of meropenem (20 mg/kg/dose), respectively. Using a 3-h infusion of a 20 mg/kg/dose, the PTA was 0.999 and 0.765 for organisms with MICs of 4 mg/L and 8 mg/L, respectively. Meropenem given as i.v. bolus doses of 20 mg/kg/dose q8h appeared to be inadequate for PK/PD target attainment for organisms with an MIC of 1 mg/L. The simulations showed that meropenem administration via a 3-h infusion using the same dose improved the PTA.

A 9-year-old boy with severe diphtherial infection and cardiac complications.

The incidence of diphtheria has decreased since the introduction of an effective vaccine. However, in countries with low vaccination rates it has now become a re-emerging disease. Complications from diphtheria commonly include upper airway obstruction and cardiac complications. We present a 9-year-old boy who was diagnosed with diphtheria. He presented with fever, tonsilar plaques, respiratory failure and an incomplete vaccination history. He was endotracheal intubated and received diphtheria antitoxin and penicillin on the first day of hospitalisation. He developed progressive arrhythmias and fulminant myocarditis despite early identification and treatment with equine antitoxin and antibiotics. After a temporary transvenous pacemaker insertion due to third-degree atrioventricular block and hypotension for 1 week, he developed myocardial perforation from the pacemaker tip resulting in pericardial effusion. The treatment included emergency pericardiocentesis and pacemaker removal. His electrocardiogram showed a junctional rhythm with occasional premature ventricular complexes. He then developed ventricular tachycardia and cardiac arrest and finally died.

Dengue shock syndrome in an infant.

Dengue is a mosquito-borne infection affecting children and adults worldwide. In newborn infants, the dengue virus can cause diseases, especially in infants born to pregnant women hospitalised with dengue or postpartum women with fever. The authors report a case of a term newborn infant who presented with haemodynamic instability and thrombocytopaenia at the age of 7 days, without a history of clinical dengue infection in the mother. The physical examination revealed an afebrile and drowsy infant with a petechial rash all over the body and ecchymosis on both palms and soles. The authors confirmed the diagnosis using the dengue NS1 antigen on the first day of admission. The treatment included fluid management and platelet transfusion. The patient recovered well and was discharged from the hospital on the 10th day of hospitalisation.

An 11-year-old boy with Plasmodium falciparum malaria and dengue co-infection.

Malaria and dengue fever are major mosquito-borne public health problems in tropical countries. The authors report a malaria and dengue co-infection in an 11-year-old boy who presented with sustained fever for 10 days. The physical examination revealed a flushed face, injected conjunctivae and left submandibular lymphadenopathy. His peripheral blood smear showed few ring-form trophozoites of Plasmodium falciparum. His blood tests were positive for dengue NS-1 antigen and IgM antibody, and negative for IgG antibody. After the initiation of antimalarial treatment with artesunate and mefloquine, his clinical condition gradually improved. However, he still had low-grade fever that persisted for 6 days. Finally, he recovered well without fluid leakage, shock or severe bleeding. This case report emphasises that early recognition and concomitant treatment of malaria and dengue co-infection in endemic areas can improve clinical outcome and prevent serious complications.