Should we reconsider cefazolin for treating staphylococcal meningitis? A retrospective analysis of cefazolin and cloxacillin cerebrospinal fluid levels in patients treated for staphylococcal meningitis.

OBJECTIVES: To assess the meningeal penetration of cefazolin and cloxacillin in individuals treated for methicillin-susceptible staphylococcal meningitis. METHODS: We retrospectively identified individuals treated for Staphylococcus meningitis with measurements of cefazolin or cloxacillin concentrations in cerebrospinal fluid (CSF) using a validated assay of liquid chromatography coupled with mass spectrometry at the Nantes University Hospital between January 2009 and October 2019. Staphylococcus meningitis was defined by a compatible clinical presentation and a microbiological confirmation (positive CSF culture or positive specific PCR). Medical charts were retrospectively reviewed to collect microbiological and clinical data, and to assess therapeutic success. RESULTS: Among the 17 included individuals, eight (47%) were treated with cefazolin and nine (53%) with cloxacillin. Median daily dosages of cefazolin and cloxacillin were 8 g (range 6-12 g) and 12 g (range 10-13 g), respectively. Cefazolin and cloxacillin were mainly administered by continuous infusion. Eleven individuals (65%) were men, median (interquartile range (IQR)) age was 54 years (50; 70), 14 (82%) had postoperative meningitis and 3 (18%) had haematogenous meningitis. Median (IQR) antibiotic CSF concentrations were 2.8 mg/L (2.1; 5.2) and 0.66 mg/L (0.5; 0.9) for cefazolin and cloxacillin groups, respectively. Cloxacillin was discontinued in two individuals for therapeutic failure. CONCLUSIONS: Patients with staphylococcal meningitis treated with high-dose continuous intravenous infusion of cefazolin achieved therapeutic concentrations in CSF. Cefazolin appears to be a therapeutic candidate that should be properly evaluated in this indication.

PK/PD targets of amikacin and gentamicin in ICU patients.

OBJECTIVES: We aimed to evaluate the probability to achieve PK-PD targets in patients with sepsis hospitalized in the intensive care unit (ICU) after a single dose of 30mg/kg of amikacin or 8mg/kg of gentamicin. PATIENTS AND METHODS: This single-center prospective study included 138 ICU patients with severe sepsis or septic shock with an indication for intravenous amikacin (N=89) or gentamicin (N=49). Maximum concentration (Cmax) was measured 30 minutes after infusion completion. PK/PD objectives were respectively Cmax≥60mg/L and ≥30mg/L for amikacin and gentamicin for empirical therapy, and a Cmax/MIC ratio≥8, as per French guidelines. RESULTS: The median Simplified Acute Physiology Score II was 43 and ICU case fatality rate was 34.8%. A causative bacterial agent was identified in 94 patients (68.1%). Three pathogens had acquired aminoglycoside resistance and 15 were naturally resistant. The targeted Cmax for the first dose was achieved in 53 patients (59.6%) receiving amikacin, and one (2.2%) patient receiving gentamicin. Cmax/MIC ratio≥8 was obtained in all patients infected with susceptible pathogens (N=72). Factors associated with Cmax≥60mg/L of amikacin in multivariate analysis were dose per kg of adapted body weight (OR=1.39, P<0.001) and renal clearance estimated with CKD-EPI formula (OR=0.98, P=0.003). CONCLUSIONS: Despite high doses, amikacin and gentamicin first Cmax remain dramatically low in ICU patients. However, an adequate Cmax/MIC ratio was reached in all patients.

Maternal consumption of quinine-containing sodas may induce G6PD crises in breastfed children.

Glucose-6-phosphate dehydrogenase (G6PD) deficiency is the most common human enzyme defect often presenting with neonatal jaundice and/or hemolytic anemia. G6PD hemolytic events are linked with exposure to a pro-oxidant agent. We here report three cases of initial G6PD crises in breastfed children secondary to maternal consumption of a tonic drink which contains quinine. Quinine was found in breast milk of one of the mothers after she consumed tonic water. CONCLUSION: The amount of quinine that is transmitted through breast milk appears to be sufficient to induce G6PD crises in breastfed children. We hence recommend that consumption of quinine-containing sodas during breastfeeding should be avoided in populations with a high prevalence of G6PD deficiency. What is Known: • G6PD hemolytic events are linked with exposure to a pro-oxidant agent. • Ingestion of fava beans by a mother who was breastfeeding has been reported to induce a neonatal G6PD crisis. What is New: • Maternal consumption of tonic drink which contains quinine appears to be sufficient to induce G6PD crises in breastfed children. • Maternal consumption of quinine-containing sodas during breastfeeding should be avoided in populations with a high prevalence of G6PD deficiency.

Simultaneous determination of ceftaroline, daptomycin, linezolid and rifampicin concentrations in human plasma by on-line solid phase extraction coupled to high-performance liquid chromatography-tandem mass spectrometry.

Methicillin-resistant Staphylococcus aureus infection is a serious clinical problem worldwide. Ceftaroline, daptomycin, linezolid in combination with rifampicin are particularly used in this indication. To allow monitoring of these antibiotics, an on-line solid phase extraction coupled to high-performance liquid chromatography-tandem mass spectrometry assay requiring a 100 µL aliquot of human plasma has been developed. Besides, significance of 25-O-desacetylrifampicin concentrations was evaluated. Sample pre-treatment is limited to protein precipitation with methanol. After centrifugation 10 µL of supernatant are injected into the chromatographic system, which consists of an on-line solid phase extraction followed by a separation on a phenyl-hexyl column and detected by a tandem mass spectrometer. Plasma drug concentrations were determined by multiple reaction monitoring in positive ion mode, and assay performance was evaluated. 25-O-Desacetylrifampicin activity, was compared to rifampicin using a microbiological method. Sample preparation using methanol precipitation followed by solid-phase extraction yielded good recovery and ionization efficiency, with chromatographic separation achieved within 3 min per sample. Within-run and between-run precisions ranged respectively from 1.22% to 9.35% and from 1.61% to 9.36%. Lower limits of quantification were 0.04 mg/L for linezolid, 0.1mg/L for rifampicin, 0.2mg/L for ceftaroline and 0.5mg/L for daptomycin. It appears that 25-O-desacetylrifampicin displays a substantial intrinsic bactericidal activity against S. aureus. This assay provides simple, rapid, sensitive and accurate quantification of the four antibiotic drugs and one metabolite and can be routinely used to monitor drug concentration in methicillin-resistant S. aureus infected patients.

A liquid chromatography-tandem mass spectrometry assay for quantification of rilpivirine and dolutegravir in human plasma.

A liquid chromatography-tandem mass spectrometry assay requiring a 100µL aliquot of human plasma for simultaneous determination of rilpivirine, a second generation non-nucleoside reverse transcriptase inhibitors of HIV and dolutegravir, a novel integrase stand transfer inhibitors of HIV concentrations has been developed. Sample pre-treatment is limited to protein precipitation with a mixture of methanol and zinc sulfate. After centrifugation the supernatant is injected in the chromatographic system, which consists of on-line solid phase extraction followed by separation on a phenyl-hexyl column. This 2.5min method, with its simple sample preparation provides sensitive (the limit of quantitation is 25ng/mL for each compound), accurate and precise (the intra-day and inter-day imprecision and inaccuracy are lower than 15%) quantification of the plasma concentration of these drugs and can be used for therapeutic drug monitoring in patients infected with HIV.

Pharmacokinetics of ertapenem in burns patients.

The aims of this study were to evaluate pharmacokinetic (PK) parameters of total and unbound ertapenem (ERT) in burns patients and to identify which covariates influence these PK parameters. ERT plasma concentrations were measured in burns patients (n = 8) who received a 0.5-h infusion of ERT (1000 mg) every 24 h. PK parameters were estimated by a non-compartmental approach and the influence of covariates was estimated by multivariate analysis using a population approach. Clearance (CL) and the volume of distribution (V) of total ERT were lower than the results for unbound ERT [CL, 22.2 ± 5.6 mL/min vs. 279.4 ± 208.2 mL/min; V, 9.7 ± 1.4L vs. 120.6 ± 130.6L (mean ± standard deviation)]. Creatinine clearance (CL(Cr)) and the burned surface area (BSA) were the covariates identified that significantly (P<0.01) affected the pharmacokinetics of total ERT [CL (L/h)=0.373 +{0.00666 x CL(Cr) (mL/min)}] and unbound ERT [peripheral volume of distribution (L) = 3.05 + {0.959 x BSA (% of the total body surface)}], respectively. The influences of albuminaemia, glomerular filtration and burn wound on ERT pharmacokinetics are proposed to explain these results. These first results support that the ERT plasma concentration should be closely monitored particularly for patients with high values of BSA and/or CL(Cr) to avoid suboptimal exposure.

A liquid chromatography assay for a quantification of doripenem, ertapenem, imipenem, meropenem concentrations in human plasma: application to a clinical pharmacokinetic study.

A simple chromatographic assay based on ultra high performance liquid chromatography with ultraviolet detection at 295 nm is proposed to determinate simultaneously human plasma concentrations of imipenem, doripenem, meropenem and ertapenem. After deproteinization by acetonitrile, carbapenems are separated on a PentaFluoroPhenyl column with a binary gradient elution. This method is specific, accurate, precise (the intra-day and inter-day imprecision and inaccuracy are lower than 15%), sensitive (the limit of quantitation is equal to 0.50 mg/L for imipenem, doripenem, ertapenem, meropenem) and not time consuming (run time=7 min). An application of this method to measure ertapenem plasma concentrations in burn patients is presented.

A liquid chromatography-tandem mass spectrometry assay for quantification of nevirapine, indinavir, atazanavir, amprenavir, saquinavir, ritonavir, lopinavir, efavirenz, tipranavir, darunavir and maraviroc in the plasma of patients infected with HIV.

A liquid chromatography-tandem mass spectrometry assay for simultaneous determination of the plasma concentration of 11 antiretroviral agents (nevirapine, indinavir, atazanavir, amprenavir, saquinavir, ritonavir, lopinavir, efavirenz, tipranavir, darunavir and maraviroc) has been developed. Sample pre-treatment is limited to protein precipitation with a mixture of methanol and zinc sulfate. After centrifugation the supernatant is injected in the chromatographic system, which consists of on-line solid phase extraction followed by separation on a phenyl-hexyl column. This method, with its simple sample preparation provides sensitive, accurate and precise quantification of the plasma concentration of antiretroviral drugs and can be used for therapeutic drug monitoring in patients infected with HIV.

Influence of darunavir coadministration on nevirapine pharmacokinetics in HIV-infected patients: a population approach.

OBJECTIVE: The influence of ritonavir-boosted darunavir coadministration on nevirapine pharmacokinetics was investigated in HIV-infected patients using a population-based approach. METHODS: The population was composed of 51 patients (89 samples; 42 patients treated with an antiretroviral regimen containing nevirapine and nucleoside/nucleotide reverse transcriptase inhibitors and nine patients treated with a regimen containing a combination of nevirapine and darunavir). A one-compartment model with first-order absorption was fitted to the data using nonmem version V (GloboMax, Ellicott City, MD, USA). RESULTS: Relationships were established between nevirapine clearance (Cl) and age (Cl/F=2.42+47.2/age, where F denotes bioavailability) and between nevirapine volume of distribution (V(d)) and the presence of darunavir in the antiretroviral regimen [V(d)/F=38.0+75.0 (1 - darunavir coadministration), where darunavir coadministration is 1 for patients treated with a combination of nevirapine and darunavir and 0 for other patients]. According to this final model, a significant decrease in the means of Cl/F (3.84 +/- 0.92 vs. 2.76 +/- 1.00 L/h; P<0.05) and V(d)/F (93.2 +/- 31.10 vs. 39.8 +/- 6.97 L; P<0.0001) and an increase in the mean of nevirapine trough plasma concentrations (3.68 +/- 1.69 vs. 5.35 +/- 3.20 mg/L; P<0.05) are observed if nevirapine is used in combination with darunavir. CONCLUSIONS: These results suggest that nevirapine exposure is increased when nevirapine is administered in combination with darunavir and that therapeutic drug monitoring of nevirapine should be performed if this antiretroviral regimen is considered.

Comparison between a liquid chromatography-tandem mass spectrometry assay and a fluorescent polarization immunoassay to measure whole blood everolimus concentration in heart and renal transplantations.

Various methods [fluorescent polarization immunoassay (FPIA) and liquid chromatography-tandem mass spectrometry (LC-MS/MS) assay] are used for therapeutic drug monitoring of everolimus. The aim of this study is to compare these assays in renal and heart transplantation. The correlation between results was investigated by linear regression in 44 patients (24 heart recipients and 20 renal recipients--137 samples). The comparison between assays was performed by a paired t-test. A highly significant correlation was found between FPIA and LC-MS/MS in heart and renal recipients [FPIA=0.851 x LC-MS/MS+1.773r(2)=0.8738 (P<0.001)]. Paired t-tests did not show a significant difference between everolimus whole blood concentrations in the populations of heart and renal recipients or heart recipients or renal recipients. FPIA and LC-MS/MS assays gave consistent overall results although some significant differences were observed in some samples between these methods indicating that FPIA assay has limitations that deserve further investigations.