Pharmacokinetic/pharmacodynamic evaluation of the antimicrobial therapy of pneumococcal invasive disease in adults in post-PCV13 vaccine period in Madrid, Spain.

The objective of our study was to evaluate by pharmacokinetic/pharmacodynamic (PK/PD) analysis, if the antimicrobials used for the treatment of invasive pneumococcal disease (IPD) in adults, including meningitis, are adequate considering the susceptibility profile of S. pneumoniae in Spain after the implantation of PVC13 vaccine. Pharmacokinetic parameters of benzylpenicillin and cefotaxime were obtained from the literature, and susceptibility data of invasive S. pneumoniae strains recovered in 2017 (post-PCV13 vaccination period) were provided by the Public Health Regional Laboratory of Madrid. We have also studied levofloxacin because it is used to treat pneumococcal pneumonia previously to be diagnosed as bacteremic pneumonia. Monte Carlo simulation was used to estimate the probability of target attainment (PTA) and the cumulative fraction of response (CFR). All doses of benzylpenicillin except 2 mU q6h provide a high probability of treatment success for MIC values ≤ 1 mg/L; 4 mU q4h is even useful for MIC values up to 4 mg/L. This high dose, used for the treatment of meningitis, also provides high probability of treatment success for MIC ≤ 0.5 mg/L. At the susceptibility EUCAST breakpoint (≤ 0.5 mg/L), cefotaxime provides a high rate of PD target achievement, even at the lowest dose (1 g q8h). For meningitis, 2 g q6h ensures probabilities of target attainment ≥90% for MIC up to 1 mg/L. Our study confirms that after the implementation of PCV13 vaccine, the treatment with benzylpenicillin and cefotaxime provides high probability of the therapy success of IPD, including meningitis.

Moraxella osloensis infection among adults and children: A pediatric case and literature review.

Moraxella osloensis has been reported in the literature as a human pathogen, particularly among immunocompromised adults. In contrast to the adult population, most pediatric cases are among patients with no underlying immunological defect; however, no patient underwent further investigation and no data about the long-term follow-up are available. We report the case of a 2-month-old previously healthy girl infected with Moraxella osloensis. Here, we review case reports and case series of children and adults with Moraxella osloensis infection and compare them with our experience. On the basis of our findings, we recommend further investigations (immunological or other underlying diseases) when a child is found to be infected with these bacteria.

Case Report: First Case of Cefotaxime-Sulbactam-Induced Acute Intravascular Hemolysis in a Newborn With ABO Blood Type Incompatibility by the Mechanism of Non-Immunologic Protein Adsorption.

Background: ABO blood type incompatibility hemolytic disease of newborn (ABO-HDN) and drug-induced immune hemolytic anemia (DIIHA) due to non-immunologic protein adsorption (NIPA) mainly cause extravascular hemolysis. All the reported severe DIIHA were caused by drug-induced antibodies, and rare report of acute intravascular hemolysis was caused by the NIPA mechanism or ABO-HDN. Case presentation: We report the first case of acute intravascular hemolysis induced by cefotaxime sodium - sulbactam sodium (CTX - SBT) in a case of ABO-HDN which resulted in death at 55 h after birth. The mother's blood type was O and RhD-positive, and the newborn's blood type was B and RhD-positive. No irregular red blood cell (RBC) antibodies or drug-dependent antibodies related to CTX or SBT was detected in the mother's plasma and the plasma or the RBC acid eluent of the newborn. Before the newborn received CTX - SBT treatment, the result of direct antiglobulin test (DAT) was negative while anti-B was positive (2 +) in both plasma and acid eluent. After the newborn received CTX - SBT treatment, the results of DAT for anti-IgG and anti-C3d were both positive, while anti-B was not detected in plasma, but stronger anti-B (3 +) was detected in acid eluent. In vitro experiments confirmed that NIPA of SBT promoted the specific binding of maternal-derived IgG anti-B to B antigen on RBCs of the newborn, thereby inducing acute intravascular hemolysis. Conclusion: The NIPA effect of SBT promoted the specific binding of mother-derived IgG anti-B in newborn's plasma to the newborn's RBC B antigens and formed an immune complex, and then activated complement, which led to acute intravascular hemolysis. Drugs such as SBT with NIPA effect should not be used for newborns with HDN.

Curative effects of vancomycin and cefotaxime combined with gamma globulin respectively in neonatal septicemia and their influences on PCT, CRP and hs-CRP.

OBJECTIVE: To explore the curative effects of vancomycin and cefotaxime combined with gamma globulin respectively in neonatal septicemia and their influences on PCT, CRP, and hs-CRP, so as to provide references for clinical treatment. PATIENTS AND METHODS: 181 patients with neonatal septicemia admitted to Huangshi Maternity and Child Health Hospital from April 2012 to August 2014 were selected as the study subjects. Patients treated with vancomycin combined with gamma globulin were selected as group A (96 cases) and those treated with cefotaxime combined with gamma globulin were selected as group B (85 cases). The improvement time of clinical symptoms (milk rejection, nervous system symptoms, body temperature), hospital stays, mortality, medicine curative effects, adverse reactions, complications, and levels of serum CRP, PCT, and hs-CRP of patients before and after treatment were compared between the two groups. RESULTS: The improvement time of clinical symptoms like body temperature, milk rejection, and neurological symptoms, as well as hospital stays in group A were lower than those in group B (p<0.05); the total effective rate of medicine curative effects in group B was better than that in group A (p<0.05); there was no significant difference in levels of serum CRP, PCT, and hs-CRP between the two groups before treatment (p>0.05); after treatment, levels of serum CRP, PCT, and hs-CRP in both groups decreased significantly, and levels of serum CRP, PCT, and hs-CRP in group B decreased more significantly than those in group A (p<0.05). CONCLUSIONS: Cefotaxime combined with gamma globulin in the treatment of patients with neonatal septicemia has short improvement time in clinical symptoms, high total effective rate of drugs, low mortality, fewer adverse reactions and complications, and can significantly reduce levels of serum CRP, PCT, and hs-CRP, which is worthy of further promotion and application in clinical practice.

Osteomielitis pélvica y piomiositis del músculo obturador interno. Revisión del tratamiento a propósito de un caso / Pelvic osteomyelitis and obturator internus muscle pyomyositis. Revision of the treatment with regard to a case

La osteomielitis pélvica asociada a infección del músculo obturador interno es una infección poco difundida en la literatura científica. Presentamos el caso de un adolescente con ambas infecciones y una revisión del abordaje terapéutico de ambas patologías

Pelvic osteomyelitis associated with pyomyositis of the obturador internus muscle is rarely reported. We present the case of a teenager with both infections and a review of the therapeutic approach of both pathologies

Pediatric acute dacryocystitis due to Eikenella corrodens: A case report.

Eikenella corrodens is a facultatively anaerobic gram-negative rod bacterium in the oropharynx and respiratory tract. It is a member of HACEK (Haemophilus spp., Aggregatibacter spp., Cardiobacterium hominis, E. corrodens, and Kingella kingae) group commonly associated with endocarditis and craniofacial infections. It is usually susceptible to penicillin, second and third-generation cephalosporins, and carbapenem, but has variable susceptibility to first-generation cephalosporin. We herein provide a description of the first case of pediatric acute dacryocystitis caused by E. corrodens. The patient did not respond to oral cephalexin and required surgical drainage followed by intravenous cefotaxime. Also provided is a brief review of the current literature.

Entamoeba histolytica liver abscess case: could stool PCR avoid it?

Background Liver abscess is the most common extraintestinal manifestation of Entamoeba histolytica. Clinical manifestations could appear after returning from an endemic area or several years after the exposure. The diagnosis usually requires microbiological confirmation. Case presentation We present a case of a 55-year-old woman diagnosed with Crohn's disease treated with immunosuppressive drugs, who was admitted to the Emergency Service with liver parenchyma abscesses. Computed tomography (CT)-guided puncture showed pus, and both Gram staining and fresh parasite visualization were negative. Hepatic pus bacteriological culture was reported as negative and parasite multiplex polymerase chain reaction (PCR) was performed, being positive for E. histolytica. The same PCR was performed on blood, pleural fluid and stool samples, all of them being positive for E. histolytica. Conclusions Reviewing the clinical history of this patient, it was observed that parasite detection in three stool samples was negative 2 months before the current admission. Due to the lack of sensitivity of the microscopy techniques, we propose to routinely perform parasite detection in stools using molecular techniques, especially in immunocompromised patients.

Effect of antimicrobial peptides HNP-1 and hBD-1 on Staphylococcus aureus strains in vitro and in vivo.

The aims of this study were: (i) To investigate the activity of recombinant AMPs HNP-1 and hBD-1 in combination with cefotaxime against Staphylococcus aureus strains (MSSA and MRSA) in vitro using checkerboard method; (ii) To investigate the activity of HNP-1 and hBD-1 encapsulated in silicon nanoparticles (niosomes) in the treatment of MRSA-infected wound in rats. For this S. aureus strains (MSSA and MRSA) were isolated from patients with diabetic foot infection. Cefotaxime, recombinant HNP-1 and hBD-1 (in all possible combinations with each other) were used for testing by the checkerboard method. Two niosomal topical gels with HNP-1/hBD-1 were prepared to treat MRSA-infected wounds in rats. Gels were administered once a day, the control group-without treatment. Wound healing rate was calculated on the 4th, 9th and 16th days of the experiment and compared using one-way ANOVA with Bonferroni correction. MIC of HNP-1 for MSSA and MRSA was the same-1 mg/L. MIC of hBD-1 for MSSA and MRSA was also the same-0.5 mg/L. Topical gels with niosomal HNP-1 (or hBD-1) showed a significantly faster wound healing in comparison with the control. The data obtained open up prospects for use of AMPs encapsulated in silica nanoparticles for the development of new antibiotics.

Continuous versus intermittent infusion of cefotaxime in critically ill patients: a randomized controlled trial comparing plasma concentrations.

BACKGROUND: In critical care patients, reaching optimal ß-lactam concentrations poses challenges, as infections are caused more often by microorganisms associated with higher MICs, and critically ill patients typically have an unpredictable pharmacokinetic/pharmacodynamic profile. Conventional intermittent dosing frequently yields inadequate drug concentrations, while continuous dosing might result in better target attainment. Few studies address cefotaxime concentrations in this population. OBJECTIVES: To assess total and unbound serum levels of cefotaxime and an active metabolite, desacetylcefotaxime, in critically ill patients treated with either continuously or intermittently dosed cefotaxime. METHODS: Adult critical care patients with indication for treatment with cefotaxime were randomized to treatment with either intermittent dosing (1 g every 6 h) or continuous dosing (4 g/24 h, after a loading dose of 1 g). We defined a preset target of reaching and maintaining a total cefotaxime concentration of 4 mg/L from 1 h after start of treatment. CCMO trial registration number NL50809.042.14, Clinicaltrials.gov NCT02560207. RESULTS: Twenty-nine and 30 patients, respectively, were included in the continuous dosing group and the intermittent dosing group. A total of 642 samples were available for analysis. In the continuous dosing arm, 89.3% met our preset target, compared with 50% in the intermittent dosing arm. Patients not reaching this target had a significantly higher creatinine clearance on the day of admission. CONCLUSIONS: These results support the application of a continuous dosing strategy of ß-lactams in critical care patients and the practice of therapeutic drug monitoring in a subset of patients with higher renal clearance and need for prolonged treatment for further optimization, where using total cefotaxime concentrations should suffice.

Meropenem versus Cefotaxime and Ampicillin as Empirical Antibiotic Treatment in Adult Bacterial Meningitis: a Quality Registry Study, 2008 to 2016.

Cefotaxime, alone or with ampicillin, is frequently used in empirical treatment of acute bacterial meningitis (ABM). Meropenem is a less extensively investigated alternative. The aim of the study was to investigate the effects of empirical treatment with meropenem compared to cefotaxime plus ampicillin on outcome in ABM. The study was based on data from the Swedish quality register for ABM collected between January 2008 and December 2016. Propensity score matching was performed to adjust for baseline differences between the groups. Mortality within 30 days was the primary outcome. The treatment regimens of interest were administered to 623 patients; 328 were given cefotaxime plus ampicillin whereas 295 received meropenem. Using propensity score matching, the 30-day mortality rates were 3.2% in the cefotaxime plus ampicillin group and 3.6% in the meropenem group. For matched cases, the odds ratio (OR) for 30-day mortality for meropenem versus cefotaxime plus ampicillin was 1.15 (confidence interval [CI], 0.41 to 3.22; P = 0.79). The OR for 90-day mortality was 1.47 (CI, 0.62 to 3.52; P = 0.38) and for unfavorable outcome was 1.10 (CI, 0.75 to 1.63; P = 0.62). The findings of our study indicate that meropenem is an effective empirical treatment option for adults with community-acquired ABM. However, to spare carbapenems, guidelines should continue to recommend third-generation cephalosporins as an empirical treatment for the majority of patients with ABM.

PHARMECMO: Therapeutic drug monitoring and adequacy of current dosing regimens of antibiotics in patients on Extracorporeal Life Support.

INTRODUCTION: Optimisation of antibiotic therapy for extracorporeal membrane oxygenation (ECMO) patients remains a pharmacological challenge. The objective of this study was to observe the plasma concentrations of commonly used antibiotics in intensive care for patients treated with extracorporeal membrane oxygenation. PATIENTS AND METHODS: The PHARMECMO study was a pilot, prospective study, conducted in a cardiac surgery intensive care unit. Every adult patient under ECMO support, with known or suspected sepsis and receiving antibiotic therapy, was eligible for inclusion. Plasma concentrations of antibiotics were determined by a combination of liquid chromatography and mass spectrometry. RESULTS: Forty-four eligible patients were enrolled for 68 inclusions on a twelve-month period. For the association piperacillin-tazobactam (n=19), 68.7% of CT50 and 93.7% of Cmin reached the pharmacokinetic goals defined (64 mg.L-1 for CT50 and 16 mg.L-1 for Cmin). For cefotaxime (n=12), the pharmacokinetic goals (4 mg.L-1 for CT50 and 1 mg.L-1 for Cmin) were achieved in 100% of the cases for CT50 and in 81.8% of the cases for Cmin. Regarding imipenem (n=10), the pharmacokinetic goals were 16 mg.L-1 for CT50 and 4 mg.L-1 for Cmin. Only one CT50 was above 16 mg.L-1. For Cmin, 60% of the doses did not reach the target concentration. In our 10 patients, only one patient was considered as reaching the pharmacokinetic goals. Finally, for amikacin (n=6), four Cmax (66.7%) were infra-therapeutics for a target between 60 and 80 mg.L-1. CONCLUSION: These preliminary results suggest that therapeutic drug monitoring could optimise the achievement of pharmacokinetic objectives associated with an effective antibiotic therapy. For most patients, the recommended doses of imipenem and amikacin did not achieve the pK targets.

Streptococcus bovis - unusual etiology of meningitis in a neonate with Down syndrome: a case report.

BACKGROUND: Common etiological agents of neonatal meningitis include group B Streptococcus, Escherichia coli, and Staphylococcus aureus. Here we report a rare pathogen - Streptococcus bovis - causing meningitis in a premature neonate with Down syndrome. CASE PRESENTATION: A 26-day-old Asian male neonate with Down syndrome presented with a history of high-grade fever, poor sucking, poor cry, and reduced activity. On admission, he was febrile and had features of circulatory collapse. A cerebrospinal fluid examination confirmed bacterial meningitis and blood culture isolated the causative organism: group D Streptococcus, which was verified as Streptococcus bovis biotype 2. An echocardiogram did not show evidence of infective endocarditis. CONCLUSIONS: This is probably the first report of neonatal meningitis due to Streptococcus bovis in a child with Down syndrome. Although our patient did not show features of overt immunodeficiency, subtle abnormalities in his immune system would have predisposed him to infection with this unusual organism. This case highlights the need for considering unusual pathogens when managing serious infections in children with Down syndrome.

Cephalosporin-resistant Escherichia coli isolated from farm workers and pigs in northern Vietnam.

OBJECTIVE: Antimicrobial-resistant bacteria may be transmitted between farm workers and livestock. This study aimed to determine and compare the prevalence and the genetic determinants of cefotaxime-resistant and ESBL-producing Escherichia coli in faecal isolates from workers and pigs at 100 farms in northern Vietnam. METHODS: Farmers were interviewed about antimicrobial usage in livestock. Escherichia coli isolated on MacConkey agar containing 2 mg/l of cefotaxime (CTX) were tested for susceptibility to different cephalosporins by disc diffusion and screened for occurrence of ESBL-encoding genes by PCR. RESULTS: Antimicrobial usage was widespread and included classes regarded of critical or high importance in human medicine. Dosages were 0.5-2 times higher than recommended, and antimicrobials were often administered right until slaughter. Prevalence of CTX-resistant E. coli was 86% in farm workers and 89% in pigs. In 76% of farms, CTX-resistant E. coli were shared by pigs and farm workers. ESBL-producing E. coli were detected from pigs and workers at 66 and 69 farms, respectively. The ESBL phenotype was mainly mediated by CTX-M and to a lesser extent by TEM. Occurrence of blaCTX-M was similar in E. coli from pigs (66.7%) and humans (68.5%). CONCLUSION: The high occurrence of ESBL-producing E. coli in pig farmers and pigs could present a risk for spillover of these bacteria from pig farms into the community. Genomic studies are needed to elucidate reservoirs and transmission routes of ESBL-producing E. coli at livestock farms.

Population Pharmacokinetics of Cefotaxime and Dosage Recommendations in Children with Sickle Cell Disease.

The pharmacokinetic profile of most drugs is dependent on the patient's covariates and may be influenced by the disease. Cefotaxime is frequently prescribed in pediatric patients with sickle cell disease (SCD), characterized by vaso-occlusive complications, chronic hemolytic anemia, and a defective immunological function predisposing the individual to severe infection. Data on the impact of the disease on the disposition of cefotaxime are missing. In the present study, our aims were to determine cefotaxime pharmacokinetics when prescribed to children with SCD for suspected or proven bacterial infection, identify significant covariates, and perform Monte Carlo simulations to optimize the drug dosage. Cefotaxime serum concentrations were measured in 78 pediatric SCD patients receiving cefotaxime intravenously at a daily dose of 200 mg/kg of body weight in three or four divided doses over 30 min. A total of 107 concentrations were available for pharmacokinetic analysis. A population pharmacokinetic model was developed with NONMEM software and used for Monte Carlo simulations. Cefotaxime concentrations ranged from 0.05 to 103.7 mg/liter. Cefotaxime pharmacokinetics were best described by a one-compartment model: the median estimated weight-normalized volume of distribution and clearance were 0.42 liter/kg (range, 0.2 to 1.1 liter/kg) and 0.38 liter/h/kg (range, 0.1 to 1.2 liter/h/kg). Cefotaxime clearance increased by 22% in patients with acute chest syndrome. Dosing optimization, performed using EUCAST MIC susceptibility breakpoints, showed that a dose of 100 mg/kg/6 h should be used, depending on the patient's characteristics and clinical presentation, in order to reach a value of the percentage of time that the drug concentration exceeded the MIC under steady-state pharmacokinetic conditions of 80% in 80% of the patients when targeting sensitive Gram-positive cocci and Gram-negative bacilli with MICs of 1 mg/liter or below.

Extended-spectrum ß-lactamase-producing Escherichia coli contributes to the survival of cefotaxime-susceptible E. coli under high concentrations of cefotaxime by acquisition of increased AmpC expression.

Extended-spectrum ß-lactamase-producing Escherichia coli (ESBL-E) are becoming increasingly widespread in Vietnam. Antibiotics are detected in many Vietnamese foods; however, the effect of ESBL-E and antibiotic consumption on intestinal bacteria has not been studied sufficiently. Here, we investigated the effect of oral administration of ESBL-E (TB19) and cefotaxime on luminescence-emitting cefotaxime-sensitive E. coli (X14). Mice were given water containing TB19 and then received three injections of 1.0 × 108 CFU of X14 harboring a luciferase gene. The mice were administered 100 µg of cefotaxime and luminescent bacteria were monitored over 24 h, following which luminescent bacteria were isolated from mouse feces. Luminescence continued to be detected in mice administered TB19 24 h after cefotaxime ingestion. Fecal analysis revealed two types of luminescent colonies: cefoxitin-resistant E. coli (X14-R) and Pseudomonas aeruginosa. Pulse-field gel electrophoresis confirmed that X14-R was a clonal strain of X14, suggesting that X14 survived using ESBLs originating from TB19 and acquired cefoxitin resistance due to cefotaxime consumption. Moreover, in vitro analysis of X14 indicated that expression of the ampC gene was upregulated by cefotaxime. Overall, ESBL-E and cefotaxime promoted the expansion of cefoxitin-resistant E. coli in the absence of plasmid-mediated gene transfer.

Population Pharmacokinetic Model to Optimize Cefotaxime Dosing Regimen in Critically Ill Children.

BACKGROUND: During sepsis, optimal plasma antibiotic concentrations are mandatory. Modifications of pharmacokinetic parameters could lead to low drug concentrations and therefore, insufficient therapeutic levels. OBJECTIVE: The aim of this study was to build a population pharmacokinetic model for cefotaxime and its metabolite desacetylcefotaxime in order to optimize individual dosing regimens for critically ill children. METHODS: All children aged < 18 years, weighing more than 2.5 kg, and receiving intermittent cefotaxime infusions were included in this study. Cefotaxime and desacetylcefotaxime were quantified by high-performance liquid chromatography. Pharmacokinetics were described using the non-linear mixed-effect modeling software MONOLIX, and Monte Carlo simulations were used to optimize dosing regimen in order to maintain serum concentrations above the target concentration (defined at 2 mg·L-1) throughout the dosing interval. RESULTS: We included 49 children with a median (range) postnatal age of 23.7 (0.2-229) months, and median body weight (range) of 10.9 (2.5-68) kg. A one-compartment model with first-order elimination adequately described the data. Median (range) values for cefotaxime clearance, desacetylcefotaxime clearance, and volume of distribution were 0.97 (0.3-7.1) L·h-1, 3.2 (0.6-16.3) L·h-1, and 0.3 (0.2-0.41) L·kg-1, respectively. Body weight and postnatal age were statistically significant covariates. Cefotaxime-calculated residual concentrations were low, and no patient succeeded in attaining the target. Unlike intermittent administration, a dosing regimen of 100 mg·kg-1·day-1 administered by continuous infusion provided a probability of target attainment of 100%, regardless of age and weight. CONCLUSIONS: Standard intermittent cefotaxime dosing regimens in critically ill children are not adequate to reach the target. We showed that, for the same daily dose, continuous infusion was the only administration that enabled the target to be attained, for children over 1 month of age. As continuous administration is achievable in the pediatric intensive care unit, it should be considered for clinical practice. TRIAL REGISTRATION NUMBER: Registered at http://www.clinicaltrials.gov , NCT02539407.

Nanosized Liposomes Containing Bile Salt: A Vesicular Nanocarrier for Enhancing Oral Bioavailability of BCS Class III Drug.

PURPOSE: Liposomes have been studied as a colloidal carrier in drug delivery systems, especially for oral administration. However, their low structural integrity in the gut is still a major shortcoming. Membrane disruptive effects of physiological bile salts in the small intestine result in premature drug release prior to intestinal absorption. Thus, we analyzed the stabilizing effect of sodium deoxycholate when incorporated into nano-sized liposomes. METHOD: Cefotaxime-loaded liposomes were prepared with different sodium deoxycholate concentrations (3.75- 30 mM) by rotary film evaporation followed by nano-size reduction. The physical integrity of liposomes was evaluated by monitoring cefotaxime leakage, particle sizes in different simulated physiological media. The oral bioavailability and pharmacokinetics of cefotaxime was assessed in rats (n = 6 per group) after single dose of drug-encapsulated in liposomes containing bile salt, drug in conventional liposomes, and cefotaxime solution (oral and intravenous). RESULTS: Simulated gastric fluid with low pH showed less effect on the stability of liposomes in comparison to media containing physiological bile salts.  Liposomes containing 15 mM sodium deoxycholate were most stable in size and retained the majority of encapsulated cefotaxime even in fed state of simulated intestinal fluid being the most destructive media. Pharmacokinetics data showed an increase in Cmax and AUC0-inf in the following order: cefotaxime solution < conventional liposomes < liposomes made with bile salts. The total oral bioavailability of cefotaxime in liposomes containing bile salt was found to be 5-times higher compared to cefotaxime solution and twice as much as in conventional liposomes. CONCLUSION: Incorporation of bile salts, initially used as membrane permeation enhancer, also acted as a stabilizer against physiological bile salts. The nano-sized liposomes containing sodium deoxycholate were able to reduce the leakage of encapsulated cefotaxime in the gut due to the improved vesicle stability and to enhance the oral bioavailability of acid-labile drugs up to 5-fold. This article is open to POST-PUBLICATION REVIEW. Registered readers (see "For Readers") may comment by clicking on ABSTRACT on the issue's contents page.

Severe hemolysis after plasma transfusion in a neonate with necrotizing enterocolitis, Clostridium perfringens infection, and red blood cell T-polyagglutination.

BACKGROUND: Red blood cell (RBC) Thomsen-Friedenreich antigen exposure (T activation) in infants with necrotizing enterocolitis (NEC) has occasionally been associated with posttransfusional intravascular hemolysis thought to be due to anti-T antibodies in the donor plasma. STUDY DESIGN AND METHODS: We describe an infant with NEC and Clostridium perfringens infection complicated by severe hemolysis after plasma transfusion. After this case, infants with confirmed NEC were prospectively evaluated for T activation. We checked for hemolysis in patients with T activation receiving plasma-containing blood products. RESULTS: The infant had received 80 mL of fresh-frozen plasma (FFP). His RBCs displayed strong T activation, and agglutination was observed with four of six ABO-compatible FFP units. A direct antiglobulin test was negative. IgM-class anti-T antibodies were present in small amounts (titer of 8) in the transfused FFP. Anti-T antibodies from the blood donor were not hemolytic in vitro. In the prospective study, T activation was observed in three of 28 infants with NEC (11%). One infant presented moderate T activation and two infants presented very strong T activation but only moderate decreases in sialic acid expression on the RBC membrane. These three infants presented no signs of hemolysis after transfusion with unwashed blood products or FFP. CONCLUSION: Anti-T antibodies are unlikely to be the etiologic factor for the hemolytic reactions observed in infants with NEC and T activation. Massive RBC desialylation and the direct action of bacterial toxins are more probable causes. Strict avoidance of plasma-containing blood products does not seem justified in these infants.

Mixed Micelles Loaded with Bile Salt: An Approach to Enhance Intestinal Transport of the BCS Class III Drug Cefotaxime in Rats.

BACKGROUND AND OBJECTIVES: Cefotaxime is a class III drug according to the Biopharmaceutical Classification System due to low intestinal permeability based on poor oral bioavailability. Bile salt compounds have been shown to be effective additive for drug permeation through several biological membranes. The main purpose of this study was to investigate the ability of a mixed micelles made of phosphatidylcholine, sodium deoxycholate, and loaded with a cefotaxime-3α,7α-dihydroxy-12-keto-5ß-cholanate complex to enhance the oral bioavailability of cefotaxime in rats. METHODS: Thin-film hydration method was used to prepare cefotaxime-loaded mixed micelles using different bile salt concentrations (0.87-25 mM of sodium deoxycholate). Overall, micelle sizes ranging from 86.9 to 155.6 nm were produced with negative zeta potential values from -15.9 to -19.5 mV and drug loading from 10.5 to 18.9 %. The oral bioavailability of cefotaxime in mixed micellar formulation was assessed and the pharmacokinetic parameters were compared with cefotaxime-3α,7α-dihydroxy-12-keto-5ß-cholanate complex and cefotaxime aqueous solution. 24 Male Wistar rats were randomly allocated into four groups (n = 6, per group) to receive the following: (1) a single intravenous dose of cefotaxime (25 mg/kg) in sterilized normal saline solution for injection; (2) a single oral dose of mixed micelles (100 mg/kg of cefotaxime) in phosphate buffered saline administered by oral gavage; (3) a single oral dose of cefotaxime-3α,7α-dihydroxy-12-keto-5ß-cholanate complex (100 mg/kg of cefotaxime) in phosphate buffered saline administered by oral gavage; (4) a single oral dose of free cefotaxime (100 mg/kg) in aqueous solution administered by oral gavage. Blood samples were collected for up to 24 h and cefotaxime analyzed using a validated HPLC assay. RESULTS: Pharmacokinetic data showed that the oral bioavailability of cefotaxime in mixed micelles was found to be 4.91 % higher compared to the cefotaxime in aqueous solution (1.30 %). Maximum concentration (C max) of cefotaxime in mixed micellar formulation was higher (1.08 ± 0.1 µg/ml) compared to the cefotaxime-3α,7α-dihydroxy-12-keto-5ß-cholanate complex (0.69 ± 0.1 µg/ml) and cefotaxime in aqueous solution (0.52 ± 0.1 µg/ml). Similarly, the mean values for area under the plasma concentration-time curve extrapolated to infinity (AUC0-∞) of cefotaxime in the mixed micellar formulation was higher (3.89 ± 0.9 µg·h/mL) compared to the cefotaxime-3α,7α-dihydroxy-12-keto-5ß-cholanate complex (1.52 ± 0.2 µg·h/mL) and cefotaxime in aqueous solution (1.03 ± 0.4 µg·h/mL), respectively. CONCLUSION: The mixed micellar formulation was able to increase the oral bioavailability of the BCS Class III drug cefotaxime up to fourfold by enhancing drug permeation through the mucosal membrane of the small intestine.