Modelled Target Attainment after Temocillin Treatment in Severe Pneumonia: Systemic and Epithelial Lining Fluid Pharmacokinetics of Continuous versus Intermittent Infusions.

The objective of this article is to describe the population pharmacokinetics (PK) of temocillin administered via continuous infusion (CI) versus intermittent infusion (II) in critically ill patients with pneumonia. Secondary objectives included characterization of epithelial lining fluid (ELF)/plasma penetration ratios and determination of the probability of target attainment (PTA) for a range of MICs. Thirty-two mechanically ventilated patients who were treated for pneumonia with 6 g of temocillin daily for in vitro sensitive pathogens were assigned to either the II (2 g every 8 h over 0.5 h) or the CI (6 g over 24 h after a loading dose of 2 g) group. A population pharmacokinetic model was developed using unbound plasma, and total ELF concentrations of temocillin and related Monte Carlo simulations were performed to assess PTAs. The area under the concentration-time curve from 0 to 24 h (AUC0-24) ELF/plasma penetration ratio was 0.73, at steady state, for both modes of infusion and whatever the level of creatinine clearance. Monte Carlo simulations showed that for the minimal pharmacodynamic (PD) targets of 50% T > 1× MIC (II group) and 100% T > 1× MIC (CI group), PK/PD breakpoints were 4 mg/L in plasma and 2 mg/L in ELF and 4 mg/L in plasma and ELF, respectively. The breakpoint was 8 mg/L in ELF for both modes of infusion in patients with creatinine clearance (CLCR) < 60 mL/min/1.73 m2. While CI provides better PKPD indexes, the latter remain below available recommendations for systemic infections, except in the case of moderate renal impairment, thereby warranting future clinical studies in order to determine the efficacy of temocillin in severe pneumonia.

[Drug-induced acute angle closure glaucoma]. / Quels sont les médicaments à risque de précipiter un glaucome aigu par fermeture de l'angle ?

Acute angle closure glaucoma is an ophthalmic emergency that can lead to blindness in some cases. The presenting signs are often suggestive, like ocular pain and blurred vision accompanied by headache, nausea and vomiting. These symptoms must be recognized as soon as possible, and the patient must be addressed, urgently, to an ophthalmologist for treatment. Many drugs may lead to an acute angle closure glaucoma in patients with risk factors. This article aims to remind the anatomical risk factors as well as the drugs that may induce an acute angle closure glaucoma. For a better understanding, this article will provide a brief reminder of the pathophysiological mechanism of acute angle closure glaucoma.

Le glaucome aigu par fermeture de l'angle, appelé communément crise de glaucome, est une urgence ophtalmologique pouvant potentiellement conduire à la cécité. Les symptômes sont assez bruyants, les manifestations les plus fréquentes sont une douleur oculaire et une vision floue accompagnées de céphalées, de nausées et de vomissements. Ces symptômes doivent être reconnus le plus rapidement possible afin de référer le patient chez un ophtalmologue pour une prise en charge urgente. Plusieurs médicaments peuvent précipiter la survenue d'une crise chez un patient prédisposé. Il convient donc de rappeler les facteurs de risque anatomiques ainsi que les médicaments pouvant précipiter un glaucome aigu par fermeture de l'angle. Pour une meilleure compréhension, cet article fait un rappel succinct des mécanismes physiopathologiques impliqués dans la survenue d'un glaucome aigu par fermeture de l'angle.

Sequential Time-Kill, a Simple Experimental Trick To Discriminate between Pharmacokinetics/Pharmacodynamics Models with Distinct Heterogeneous Subpopulations versus Homogenous Population with Adaptive Resistance.

Experiments were conducted with polymyxin B and two Klebsiella pneumonia isogenic strains (the wild type, KP_WT, and its transconjugant carrying the mobile colistin resistance gene, KP_MCR-1) to demonstrate that conducting two consecutive time-kill experiments (sequential TK) represents a simple approach to discriminate between pharmacokinetics/pharmacodynamics models with two heterogeneous subpopulations or adaptive resistance.

Population Pharmacokinetics of Colistin Methanesulfonate and Colistin in Critically Ill Patients with Acute Renal Failure Requiring Intermittent Hemodialysis.

Colistin is increasingly used as a last option for the treatment of severe infections due to Gram-negative bacteria in critically ill patients requiring intermittent hemodialysis (HD) for acute renal failure. Our objective was to characterize the pharmacokinetics (PK) of colistin and its prodrug colistin methanesulfonate (CMS) in this population and to suggest dosing regimen recommendations. Eight intensive care unit (ICU) patients who were under intermittent HD and who were treated by CMS (Colimycine) were included. Blood samples were collected between two consecutive HD sessions. CMS and colistin concentrations were measured by a specific chromatographic assay and were analyzed using a PK population approach (Monolix software). Monte Carlo simulations were conducted to predict the probability of target attainment (PTA). CMS nonrenal clearance was increased in ICU-HD patients. Compared with that of ICU patients included in the same clinical trial but with preserved renal function, colistin exposure was increased by 3-fold in ICU-HD patients. This is probably because a greater fraction of the CMS converted into colistin. To maintain colistin plasma concentrations high enough (>3 mg/liter) for high PTA values (area under the concentration-time curve for the free, unbound fraction of a drug [fAUC]/MIC of >10 and fAUC/MIC of >50 for systemic and lung infections, respectively), at least for MICs lower than 1.5 mg/liter (nonpulmonary infection) or 0.5 mg/liter (pulmonary infection), the dosing regimen of CMS should be 1.5 million international units (MIU) twice daily on non-HD days. HD should be conducted at the end of a dosing interval, and a supplemental dose of 1.5 MIU should be administered after the HD session (i.e., total of 4.5 MIU for HD days). This study has confirmed and complemented previously published data and suggests an a priori clear and easy to follow dosing strategy for CMS in ICU-HD patients.

Co-purification of arrestin like proteins with alpha-enolase from bovine myocardial tissues and the possible role in heart diseases as an autoantigen.

AIM: Previously, we reported that visual arrestin co-purified with glycolytic enzymes. The aim of this study was to analyze the co-purification of arrestin like proteins (ALP) in bovine cardiac tissues with enolases. METHODS: The soluble extract of bovine myocardial tissues from different regions such as left and right atriums and ventricles of the bovine heart (n = 3) was analyzed by ACA-34 gel filtration, immuno-affinity column, SDS-PAGE, ELISA, western blot and a sandwich immune assay for quantification of ALP and sequence analysis. RESULTS: We observed that; 1) The cardiac muscle contained a 50 kDa ALP at a concentration of 751 pg/mg of soluble protein extract, 2) ALP purified, by immunoaffinity, contained alpha-enolase of 48 kDa confirmed by protein sequence analysis; 3) Cardiomyocyte cells exposed to anti arrestin and anti enolase monoclonal antibodies showed decreased proliferation in vitro, 4) High level of autoantibodies were detected by ELISA (3.57% for arrestin and 9.12% for α-enolase) in serum of patients with infarcted heart disease. CONCLUSION: We suggest a possible interaction between ALP and alpha-enolases yielding a complex that may be involved in the induction of cardiac autoimmune diseases.

New colistin population pharmacokinetic data in critically ill patients suggesting an alternative loading dose rationale.

Colistin is an old antibiotic that has recently gained a considerable renewal of interest as the last-line defense therapy against multidrug-resistant Gram-negative bacteria. It is administered as colistin methanesulfonate (CMS), an inactive prodrug, and it was shown that due to slow CMS conversion, colistin plasma concentrations increase very slowly after treatment initiation, which constitutes the rationale for a loading dose in critically ill patients. However, faster CMS conversion was observed in healthy volunteers but using a different CMS brand, which may also have a major impact on colistin pharmacokinetics. Seventy-three critically ill patients not undergoing dialysis received multiple doses of CMS. The CMS concentrations were measured by liquid chromatography-tandem mass spectrometry (LC-MS/MS), and a pharmacokinetic analysis was conducted using a population approach. We confirmed that CMS renal clearance and colistin concentrations at steady state are mostly governed by creatinine clearance, but we predict a typical maximum concentration of drug in serum (Cmax) of colistin close to 2 mg/liter, occurring 3 h after an initial dose of 2 million international units (MIU) of CMS. Accordingly, the estimated colistin half-life (t1/2) was relatively short (3.1 h), with rapid attainment of steady state. Our results are only partially consistent with other recently published results. We confirm that the CMS maintenance dose should be adjusted according to renal function in critically ill patients. However, much higher than expected colistin concentrations were observed after the initial CMS dose, with rapid steady-state achievement. These discrepancies challenge the pharmacokinetic rationale for a loading dose, which may still be appropriate for rapid bacterial eradication and an improved clinical cure rate.

[High-throughput sequencing for infectious disease diagnoses: Example of shotgun metagenomics in central nervous system infections]. / Séquençage à haut débit pour le diagnostic en maladies infectieuses : exemple de la métagénomique shotgun dans les infections du système nerveux central.

The advent of high-throughput sequencing in clinical microbiology is opening the way to new diagnostic and prognostic approaches in infectious diseases. Detection, identification and characterisation of pathogenic microorganisms are essential steps in diagnosis and implementation of appropriate antimicrobial therapy. However, standard methods of microbiological diagnosis are failing in some cases. In addition, the emergence of new infections, facilitated by international travel and global warming, requires the implementation of innovative diagnostic methods. Among the different strategies used in clinical microbiology and reviewed in this article, shotgun metagenomics is the only technique that allows today a panpathogenic and unbiased detection of all microorganisms potentially responsible for an infectious disease, including those still unknown. The aims of this article are to present the different possible strategies of high-throughput sequencing used in the microbiological diagnosis of infectious diseases and to highlight the diagnostic contribution of shotgun metagenomics in the field of central nervous system infections.

A gene related to Caenorhabditis elegans spermatogenesis factor fer-1 is mutated in limb-girdle muscular dystrophy type 2B.

The limb-girdle muscular dystrophies are a genetically heterogeneous group of inherited progressive muscle disorders that affect mainly the proximal musculature, with evidence for at least three autosomal dominant and eight autosomal recessive loci. The latter mostly involve mutations in genes encoding components of the dystrophin-associated complex; another form is caused by mutations in the gene for the muscle-specific protease calpain 3. Using a positional cloning approach, we have identified the gene for a form of limb-girdle muscular dystrophy that we previously mapped to chromosome 2p13 (LGMD2B). This gene shows no homology to any known mammalian gene, but its predicted product is related to the C. elegans spermatogenesis factor fer-1. We have identified two homozygous frameshift mutations in this gene, resulting in muscular dystrophy of either proximal or distal onset in nine families. The proposed name 'dysferlin' combines the role of the gene in producing muscular dystrophy with its C. elegans homology.

Targeting lung macrophages for fungal and parasitic pulmonary infections with innovative amphotericin B dry powder inhalers.

The incidence of fungal pulmonary infections is known to be on the increase, and yet there is an alarming gap in terms of marketed antifungal therapies that are available for pulmonary administration. Amphotericin B (AmB) is a highly efficient broad-spectrum antifungal only marketed as an intravenous formulation. Based on the lack of effective antifungal and antiparasitic pulmonary treatments, the aim of this study was to develop a carbohydrate-based AmB dry powder inhaler (DPI) formulation, prepared by spray drying. Amorphous AmB microparticles were developed by combining 39.7 % AmB with 39.7 % γ-cyclodextrin, 8.1 % mannose and 12.5 % leucine. An increase in the mannose concentration from 8.1 to 29.8 %, led to partial drug crystallisation. Both formulations showed good in vitro lung deposition characteristics (80 % FPF < 5 µm and MMAD < 3 µm) at different air flow rates (60 and 30 L/min) when used with a DPI, but also during nebulisation upon reconstitution in water.

Severity of parechovirus infections in infants under 3 months of age and comparison with enterovirus infections: A French retrospective study.

While enteroviruses (EV) are a well-recognized cause of aseptic meningitis in children, human parechoviruses (HPeV), especially genotype 3, have been increasingly reported as a frequent cause of sepsis-like illness and meningitis among young infants. The aim of this study was to describe the epidemiological, clinical, and laboratory characteristics of HPeV infections in infants and to compare them with those of well-known EV infections. This monocentric retrospective study was carried out at the pediatric unit of Nantes University Hospital from January 2015 to August 2018. All patients under 18 years of age with diagnosis codes referring to fever, for whom viral infection was suspected and cerebrospinal fluid (CSF) specimens were collected, were included. All CSF specimens were screened by duplex real-time polymerase chain reaction (PCR) assay that allows for the simultaneous detection of EV and HPeV in clinical samples. During the study period, 1373 CSF specimens from patients under 18 were included. A total of 312 CSF samples were positive for HPeV (n=34) or EV (n=278). Among the 34 HPeV-positive patients, 97% (33/34) were under 3 months of age, whereas the rate was 54% (149/278) for EV-positive patients (P<0.001); thus, patients under 3 months of age were defined as the study population for the rest of this work. A review of the medical records was carried out for the positive cases. In this population, the HPeV detection rate was 5.6% versus 25.3% (P<0.001) for EV. All but one of the HPeV samples available for genotyping were HPeV-3. No seasonality was observed for HPeV infections. Length of hospital stay tended to be longer for children infected with HPeV compared with those infected by EV (3 days vs. 2 days, P=0.05). Clinicians reported more severe illness presentations among HPeV-infected infants, with more frequent administration of fluid bolus (P<0.02). Regarding laboratory characteristics, a significant lack of cellular reaction in the CSF (P=0.004) as well as lower C-reactive protein (CRP) levels (P=0.006) and neutrophil counts (P<0.001) were noted for HPeV infections compared with EV infections. Our results confirm the early onset of HPeV infections (more than 95% of patients aged under 3 months). The clinical presentation and laboratory characteristics of the two infections was similar. However, some higher clinical severity criteria and a lack of CSF pleocytosis were regularly observed in patients with HPeV infections. Considering the significant proportion (5.6%; 95% CI, 3.7-7.5) of all CSF samples in our series, HPeV detection should be systematically included in the microbiological diagnosis of febrile children under 3 months of age.

Pain Modulation Mechanisms in ASD Adults.

We tested endogenous pain modulation mechanisms in adults with autism spectrum disorders (ASD). Nineteen ASD adults without intellectual disabilities were included, matched with 19 healthy volunteers on the basis of sex and chronological age. An experimental pain model was used to measure excitatory and inhibitory pain mechanisms in a single session. Statistical analyses indicated that endogenous pain modulation mechanisms in ASD group did not differ significantly from those of healthy adults. The pain scores were very disparate in ASD group with a greater range of extreme scores than in control group. Unlike schizophrenic patients, there was no systematic dysfunction of endogenous excitatory pain modulation mechanisms, but the high variability requires to be wise to interpret the results and formulate conclusion.

Semi-mechanistic PK/PD modelling of combined polymyxin B and minocycline against a polymyxin-resistant strain of Acinetobacter baumannii.

OBJECTIVES: To expand on previous reports of synergy between polymyxin B (PMB) and minocycline (MIN) against Acinetobacter baumannii; and to gain insight into the qualitative and quantitative determinants of their synergy. METHODS: A semi-mechanistic pharmacokinetic/pharmacodynamic (PK/PD) model was developed on the basis of data from in vitro time-kill experiments with determination of resistant bacterial count to describe the effects of PMB and MIN alone and in combination. The model was enriched by complementary experiments providing information on the characteristics of the resistant subpopulation. RESULTS: The model successfully described the data and made possible quantification of the strength of interaction between the two drugs and formulation of hypotheses about the mechanisms of the observed interaction. The effect of the combination was driven by MIN, with PMB acting as an helper drug; simulations at clinically achievable concentrations showed that 1.5 mg/L MIN +0.2 mg/L PMB is expected to produce sustained killing over 30 hours, while 0.3 mg/L MIN +1 mg/L PMB is met by bacterial regrowth. Interaction equations showed that maximal synergy is reached for PMB concentrations ≥0.1 mg/L and MIN concentrations ≥1 mg/L. CONCLUSIONS: Semi-mechanistic PK/PD modelling was used to investigate the quantitative determinants of synergy between PMB and MIN on a PMB-resistant A. baumannii strain. The developed model, improving on usual study techniques, showed asymmetry in the drug interaction, as PMB acted mostly as a helper to MIN, and provided simulations as a tool for future studies.

Loss of calpain 3 proteolytic activity leads to muscular dystrophy and to apoptosis-associated IkappaBalpha/nuclear factor kappaB pathway perturbation in mice.

Calpain 3 is known as the skeletal muscle-specific member of the calpains, a family of intracellular nonlysosomal cysteine proteases. It was previously shown that defects in the human calpain 3 gene are responsible for limb girdle muscular dystrophy type 2A (LGMD2A), an inherited disease affecting predominantly the proximal limb muscles. To better understand the function of calpain 3 and the pathophysiological mechanisms of LGMD2A and also to develop an adequate model for therapy research, we generated capn3-deficient mice by gene targeting. capn3-deficient mice are fully fertile and viable. Allele transmission in intercross progeny demonstrated a statistically significant departure from Mendel's law. capn3-deficient mice show a mild progressive muscular dystrophy that affects a specific group of muscles. The age of appearance of myopathic features varies with the genetic background, suggesting the involvement of modifier genes. Affected muscles manifest a similar apoptosis-associated perturbation of the IkappaBalpha/nuclear factor kappaB pathway as seen in LGMD2A patients. In addition, Evans blue staining of muscle fibers reveals that the pathological process due to calpain 3 deficiency is associated with membrane alterations.

Pharmacodynamic modelling of ß-lactam/ß-lactamase inhibitor checkerboard data: illustration with aztreonam-avibactam.

OBJECTIVES: Checkerboard experiments followed by fractional inhibitory concentration (FIC) index determinations are commonly used to assess in vitro pharmacodynamic interactions between combined antibiotics, but FIC index cannot be determined in case of antibiotic/non-active compound combinations. The aim of this study was to use a simple modelling approach to quantify the in vitro activity of aztreonam-avibactam, a new ß-lactam-ß-lactamase inhibitor combination. METHODS: MIC checkerboard experiments were performed with 12 Enterobacteriaceae with diverse ß-lactamases profiles. Aztreonam MICs in the absence and presence of avibactam at different concentrations (ranging from 0.0625 to 4 mg/L) were determined. Aztreonam MIC versus avibactam concentrations were fitted by an inhibitory Emax model with a baseline effect parameter. RESULTS: A concentration-dependent relationship was observed with a steep initial reduction of aztreonam MIC at low avibactam concentrations and reaching a maximum at higher avibactam concentrations that was adequately fitted by the model. Maximum avibactam effect was characterized by the ratio of aztreonam MICs in the absence of avibactam (MIC0) and when avibactam concentration tends toward infinity (MIC∞), and this ratio ranged between 90 and 10 068 depending on the strain. Avibactam potency was characterized by avibactam concentrations corresponding to 50% of the maximum effect (IC50 values between 0.00022 and 0.053 mg/L). CONCLUSIONS: An inhibitory Emax model with a baseline effect could quantify maximum avibactam effect and potency among various strains. This simple modelling approach can be used to compare the activity of other combinations of antibiotics with non-antibiotic drugs when FIC index is inappropriate.

Sex differences in opioid-mediated pain inhibitory mechanisms during the interphase in the formalin test.

Many chronic pain conditions are more prevalent in women than men and both fundamental and clinical research supports the implication of endogenous pain inhibitory mechanisms. The goal of this study was to verify if sex differences on endogenous pain inhibitory mechanisms during the formalin test are opioidergic and modulated by sex hormones. Formalin tests were performed with naloxone hydrochloride, a non-selective opioid antagonist in intact and gonadectomized Sprague-Dawley rats of both sexes. Considering the sexual dimorphisms we found, where naloxone preferentially blocked the interphase in female rats, injections of all the possible combinations of mu- (naltrexone hydrochloride), delta- (naltrindole hydrochloride) and kappa-selective antagonists (norbinaltorphimine dihydrochloride) were given to evaluate the contribution of these opioid-receptor subtypes to the inhibitory mechanism during the interphase in intact females. Finally, the systemic administration of naloxone methiodide and intrathecal administration of naloxone hydrochloride in intact females allowed us to verify if the action of endogenous opioids that are liberated during the interphase takes place at the periphery or spinally, respectively. The results show that the interphase was almost completely inhibited by naloxone in females while it produced only a slight blockade in males. These results permitted us to conclude that opioids play a major role in the pain inhibitory mechanism of the interphase in females while a non-opioid mechanism seems to be responsible for this inhibitory pathway in males. Using gonadectomized animals of both sexes, we demonstrated the modulation of the opioidergic system of the interphase by sex hormones. The administration of different combinations of selective antagonists for mu-, kappa- and delta-opioid receptors in intact females permitted us to conclude that only the combination of kappa- and delta-selective antagonists significantly blocked the interphase. The same result was obtained with the combination of the three antagonists, confirming the results with systemic naloxone hydrochloride. Finally, intrathecal administration permitted us to support that the action of naloxone is primarily at the spinal level, even if a supraspinal action cannot be ruled out. These results are of particular interest in showing sexual dimorphisms in endogenous pain modulation mechanisms during the interphase of the formalin test. A clearer understanding of the difference between male and female endogenous pain inhibitory pathways should lead to a better understanding of the role of endogenous pain modulation deficits in certain chronic pain conditions.

Endogenous pain modulation during the formalin test in estrogen receptor beta knockout mice.

The involvement of estrogen in pain has been investigated in many ways. However the specific role played by estrogen receptors remains elusive. Estrogen receptors alpha and beta mediate different physiological functions. For example, estrogen receptor beta is more closely related to non-reproductive effects than the alpha subtype is. To verify the involvement of estrogen receptor beta on acute and persistent pain as well as on endogenous pain inhibitory mechanisms, hotplate and formalin tests were carried out in wild type (WT) and estrogen receptor beta knockout (ERbeta KO) mice of both sexes. Ovariectomies followed by estrogen and progesterone replacement were performed in female groups to insure comparable sex hormone levels. We found that nociceptive responses are lower in ERbeta KO female than in WT female mice during the interphase and early tonic phase II of the formalin test but not during acute and late tonic phases. Moreover, behavioral and spinal (c-Fos) differences were only observed in females. ERbeta KO females had lower c-Fos expression in laminae I-II and IV-V of the spinal cord than WT females. These results suggest that estrogen, through its actions on ERbeta, dampens the efficacy of endogenous pain modulation mechanisms during the interphase and/or inflammation process in the early phase II, triggering an increase in spinal nociceptive neuronal activity. This confirms our previous observations that estrogen specifically influences nociceptive responses during the interphase of the formalin test and demonstrates a role for ERbeta on endogenous pain modulation systems.

[Evaluation of thymopoiesis: clinical applications]. / Evaluation de la thymopoïèse: applications cliniques.

In the precedent article, we have described how T-cell generation in the thymus (thymopoiesis) may be currently evaluated through quantification by PCR of T-cell receptor excision circles (TREC) generated by intrathymic random recombination of the gene segments coding for variable parts of T-cell receptor for antigen (TCR). In hematology, TREC methodology helps in a better understanding of immune reconstitution after graft of hematopoietic stem cells: first there is a proliferation of mature T cells present in the graft, then a differentiation of naive T cells. In geriatrics, the homeostasis of the peripheral T-cell repertoire is maintained through proliferation of peripheral memory T cells rather than through thymic generation of naive T cells. In addition, TREC quantification constitutes a novel major tool for deciphering the tight control of thymopoiesis by the neuroendocrine system.

[Clinical evaluation of thymic function]. / Evaluation clinique de la fonction du thymus.

The essential role of the thymus is to install an extremely diverse repertoire of T lymphocytes that are self-tolerant and competent against non-self, as well as to generate self-antigen specific regulatory T cells (Treg) able to inactivate in periphery self-reactive T cells having escaped the thymic censorship. Although indirect, techniques of medical imaging and phenotyping of peripheral T cells may help in the investigation of thymic function. Nowadays however, thymopoiesis is better evaluated through quantification by PCR of T-cell receptor excision circles (TREC) generated by intrathymic random recombination of the gene segments coding for the variable parts of the T-cell receptor for antigen (TCR). The TREC methodology is very valuable in the circumstances not associated with intense proliferation or apoptosis of peripheral T lymphocytes.

[Post-licensure safety surveillance for Prevenar 13® in France]. / Bilan français des effets indésirables du vaccin Prévenar 13®.

OBJECTIVE: To describe the profile and the incidence of adverse events (AEs) reported with Prevenar 13® since its commercialization. METHOD: Analysis of all adverse events reported with Prevenar 13® in France between 1st July 2010 and 31 October 2014. RESULTS: In 4 years and 4 months, 376 AEs, including 252 severe (67%), were recorded, 83 of which occurred following an injection of Prevenar 13® alone: 39 cutaneous AEs, 16 neurological AEs, four cases of collapse or shock, nine cases of fever, and one of thrombocytopenia. For the serious AEs, the outcome was favorable in 88% of cases and none of the 12 reported deaths were attributed to a side effect of vaccination. Fifty-nine cases of pneumococcal disease that suggest an ineffective vaccine were reported, but only 16 can be considered as a real failure of the vaccination. DISCUSSION: In many cases, Prevenar 13® was administered on the same day as a hexavalent vaccine with which the AEs reported were expected. The profile of AEs reported following Prevenar 13® alone is similar to that seen with Prevenar 7®. CONCLUSION: Since its release in 2010, the Prevenar 13® pharmacovigilance survey, which includes more than 11,800,000 distributed doses, did not show any new information in terms of tolerance safety.