Fosfomycin-induced agranulocytosis: a case report and review of the literature.

BACKGROUND: The intravenous form of fosfomycin, a bactericide antibiotic used to treat multiresistant bacterial infections is little prescribed. The most common reported adverse effects are hypokaliemia and hypernatremia. We describe a case of agranulocytosis, a rarely described side effect that may be fatal. CASE PRESENTATION: A 45 year-old woman was admitted to the intensive care unit for post-surgical meningitis following meningioma resection. Meropenem and vancomycin were first introduced. A DRESS-syndrom with meropenem was suspected. Neutropenia was diagnosed three days after the introduction of parenteral fosfomycin and agranulocytosis four days later. Eosinophilia was also observed. A bone marrow aspiration was performed showing a disappearance of the neutrophil granulocyte line and a significant eosinophilia. Meropenem was discontinued. Fosfomycin was maintained and filgrastim was added. As filgrastim had no effect, the relationship with fosfomycin was suspected, so it was then withheld. An increase of the neutrophil count was observed. Because of the complexity of the case, the unfavorable course of the illness and the urgent need for revision surgery, a rechallenge with fosfomycin was done followed by a decrease of the neutrophil count. CONCLUSION: This is the third paper reporting agranulocytosis induced by fosfomycin, and the first detailed description of a case. Based on chronological and semiological criteria and bibliographic data, the event was qualified as probable with the Naranjo adverse drug probability scale. Literature data is scarce. The summary of product characteristics mentions that only a few cases of transient neutropenia and agranulocytosis have been reported. An analysis of the FDA Adverse Event Reporting System Database highlighted a higher than expected frequency of agranulocytosis in patients treated with fosfomycin. Parenteral fosfomycin is often used in patients receiving other medications, so that it is rarely the only suspect. In our case, the results of the bone marrow aspiration, the sudden drop of the neutrophil count with concomitant eosinophilia and the absence of improvement despite the dose decrease, point towards an immuno-allergic mechanism. However, the overlap between the suspected DRESS induced by meropenem and the agranulocytosis do not allow to conclude with certainty on the causality. Awareness should be raised about this side effect.

Immunogenicity and safety of the combined vaccine for measles, mumps, and rubella isolated or combined with the varicella component administered at 3-month intervals: randomised study.

BACKGROUND: Field testing required to license the combined measles, mumps, and rubella (MMR) vaccine must take into account the current recommendation of the vaccine in Brazil: first dose at 12 months and second dose at 15 months of age in combination with a varicella vaccine. OBJECTIVES: This study aimed to evaluate the clinical consistency, immunogenicity, and reactogenicity of three batches of MMR vaccine prepared with active pharmaceutical ingredients (API) from Bio-Manguinhos, Fiocruz (MMR-Bio), and compare it to a vaccine (MMR produced by GlaxoSmithKline) with different API. METHODS: This was a phase III, randomised, double-blind, non-inferiority study of the MMR-Bio administered in infants immunised at health care units in Pará, Brazil, from February 2015 to January 2016. Antibody levels were titrated by immunoenzymatic assays. Adverse events were recorded in diaries. FINDINGS: Seropositivity levels after MMR-Bio were 97.6% for measles, 84.7% for mumps, and 98.0% for rubella. After the MMRV vaccine, seroconversion rates and GMT increased substantially for mumps. In contrast, approximately 35% of the children had no detectable antibodies to varicella. Systemic adverse events were more frequent than local events. CONCLUSION: The demonstration of batch consistency and non-inferiority of the Bio-MMR vaccine completed the technology transfer. This is a significant technological achievement with implications for immunisation programs.

Relationship between microaspiration and ventilator-associated events: A post-hoc analysis of a randomized controlled trial.

OBJECTIVE: The relationship between ventilator-associated events (VAE) and microaspiration in intubated patients has not be studied. The objective of this study was to evaluate the relationship between abundant microaspiration of oropharyngeal secretions or gastric contents and the incidence of VAE. PATIENTS AND METHODS: This was a post hoc analysis of the BESTCUFF study, which was a multicenter, cluster randomized, cross-over, controlled, open-label trial in adult patients ventilated for over 48 h. All tracheal aspirates were sampled for 48 h following enrollment, with quantitative measurement of pepsin and alpha-amylase. VAE were identified using National Healthcare Safety Network criteria, based on PEEP or FiO2 variations compared to stable parameters in previous days. The primary objective was to assess the relationship between abundant global microaspiration and the incidence of VAE, adjusted for pre-specified confounding factors (sex, SAPS II score and Glasgow coma scale). RESULTS: 261 patients were included, of which 31 (11.9%) developed VAE, with an overall median age of 65 (interquartile range 52-74), a majority of male patients (164, 62.8%), a median SAPS II score of 50 [40-61], a median SOFA score of 8 [5-11], and acute respiratory failure as main reason for ICU admission (117, 44.8%).The incidence of VAE was not significantly associated with abundant global microaspiration (adjusted cause-specific hazard ratio (cHR): 1.55 [0.46-5.17), abundant gastric microaspiration (adjusted cHR: 1.24 [0.61-2.53), or with abundant oropharyngeal microaspiration (adjusted HR: 1.07 [0.47-2.42]). CONCLUSIONS: Our results suggest no significant association between abundant global, gastric or oropharyngeal microaspiration and the incidence of VAE. IMPLICATIONS FOR CLINICAL PRACTICE: This study underscores that measuring microaspiration in intubated critically ill patients might not be useful to predict the diagnosis of VAE or to evaluate interventions aiming at preventing these complications.

Impact of tapered-cuff tracheal tube on microaspiration of gastric contents in intubated critically ill patients: a multicenter cluster-randomized cross-over controlled trial.

PURPOSE: Studies on the impact of tapered-cuff tracheal tubes on rates of microaspiration and ventilator-associated pneumonia (VAP) in intubated patients have reported conflicting results. The aim of this study was to determine the influence of this shape of tracheal cuff on abundant microaspiration of gastric contents in critically ill patients. METHODS: All patients intubated in the intensive care unit (ICU) and requiring mechanical ventilation for at least 48 h were eligible for this multicenter cluster-randomized controlled cross-over open-label study. The primary outcome was abundant microaspiration of gastric contents, defined by the presence of pepsin at significant level in >30% of tracheal aspirates. Quantitative measurement of pepsin and salivary amylase was performed in all tracheal aspirates during the 48 h following enrollment. RESULTS: A total of 326 patients were enrolled in the ten participating ICUs (162 in the PVC tapered-cuff group and 164 in the standard-cuff group). Patient characteristics were similar in the two study groups. The proportion of patients with abundant microaspiration of gastric contents was 53.5% in the tapered-cuff and 51.0% in the standard-cuff group (odds ratio 1.14, 95% CI 0.72-1.82). While abundant microaspiration of oropharyngeal secretions was not significantly different (77.4 vs 68.6%, p = 0.095), the proportion of patients with tracheobronchial colonization was significantly lower (29.6 vs 43.3%, p = 0.01) in the tapered-cuff than in the standard-cuff group. No significant difference between the two groups was found for other secondary outcomes, including ventilator-associated events and VAP. CONCLUSIONS: This trial showed no significant impact of tapered-cuff tracheal tubes on abundant microaspiration of gastric contents. TRIAL REGISTRATION: ClinicalTrials.gov, number NCT01948635.

Impact of tracheal cuff shape on microaspiration of gastric contents in intubated critically ill patients: study protocol for a randomized controlled trial.

BACKGROUND: Ventilator-associated pneumonia (VAP) is the most common infection in intubated critically ill patients. Microaspiration of the contaminated gastric and oropharyngeal secretions is the main mechanism involved in the pathophysiology of VAP. Tracheal cuff plays an important role in stopping the progression of contaminated secretions into the lower respiratory tract. Previous in vitro studies suggested that conical cuff shape might be helpful in improving tracheal sealing. However, clinical studies found conflicting results. The aim of this study is to determine the impact of conical tracheal cuff shape on the microaspiration of gastric contents in critically ill patients. METHODS/DESIGN: This prospective cluster randomized controlled crossover open-label trial is currently being conducted in ten French intensive care units (ICUs). Patients are allocated to intubation with a polyvinyl chloride (PVC) standard (barrel)-shaped or a PVC conical-shaped tracheal tube. The primary objective is to determine the impact of the conical shaped tracheal cuff on abundant microaspiration of gastric contents. Secondary outcomes include the incidence of microaspiration of oropharyngeal secretions, tracheobronchial colonization, VAP and ventilator-associated events. Abundant microaspiration is defined as the presence of pepsin at significant level (>200 ng/ml) in at least 30 % of the tracheal aspirates. Pepsin and amylase are quantitatively measured in all tracheal aspirates during the 48 h following inclusion. Quantitative tracheal aspirate culture is performed at inclusion and twice weekly. We plan to recruit 312 patients in the participating ICUs. DISCUSSION: BEST Cuff is the first randomized controlled study evaluating the impact of PVC tracheal-cuff shape on gastric microaspirations in patients receiving invasive mechanical ventilation. Enrollment began in June 2014 and is expected to end in October 2015. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT01948635 (registered 31 August 2013).

Immunogenicity and safety of the combined vaccine for measles, mumps, and rubella isolated or combined with the varicella component administered at 3-month intervals: randomised study

BACKGROUND Field testing required to license the combined measles, mumps, and rubella (MMR) vaccine must take into account the current recommendation of the vaccine in Brazil: first dose at 12 months and second dose at 15 months of age in combination with a varicella vaccine. OBJECTIVES This study aimed to evaluate the clinical consistency, immunogenicity, and reactogenicity of three batches of MMR vaccine prepared with active pharmaceutical ingredients (API) from Bio-Manguinhos, Fiocruz (MMR-Bio), and compare it to a vaccine (MMR produced by GlaxoSmithKline) with different API. METHODS This was a phase III, randomised, double-blind, non-inferiority study of the MMR-Bio administered in infants immunised at health care units in Pará, Brazil, from February 2015 to January 2016. Antibody levels were titrated by immunoenzymatic assays. Adverse events were recorded in diaries. FINDINGS Seropositivity levels after MMR-Bio were 97.6% for measles, 84.7% for mumps, and 98.0% for rubella. After the MMRV vaccine, seroconversion rates and GMT increased substantially for mumps. In contrast, approximately 35% of the children had no detectable antibodies to varicella. Systemic adverse events were more frequent than local events. CONCLUSION The demonstration of batch consistency and non-inferiority of the Bio-MMR vaccine completed the technology transfer. This is a significant technological achievement with implications for immunisation programs.

Activated protein C improves macrovascular and microvascular reactivity in human severe sepsis and septic shock.

We tested the effects of activated protein C (APC) in macrovascular and microvascular beds within 60 min of treatment. Twelve patients treated with APC for severe sepsis were included. We assessed macrovascular reactivity by phenylephrine arterial dose response. Pharmacological modeling (EC50, Emax, and Hill coefficient) and individual dose-response curve were tested. Microvascular reactivity was tested with skin laser Doppler by using postocclusive reactive hyperemia with measurements of peak, time to peak (Tmax), time to half recovery (T1/2R), and myogenic and sympathetic tones. All measurements were done 30 min before, just before, and 30 and 60 min after APC infusion. Microvascular reactivity was also tested in eight healthy volunteers. In patients, arterial pressure did not increase significantly. However, 60 min after the beginning of APC infusion, reactivity to α-1 stimulation was improved: EC50 decreased from 15.3 (0.9-56) to 3.1 (1.0-6.2) (P = 0.04), and 5 of 12 patients improved their dose-response curve. As for microcirculatory parameters, as early as 30 min after the beginning of APC infusion, postocclusive reactive hyperemia peak increased from 102 (40-168) to 162 (35-196) (P = 0.04), Tmax was shorter: 30 s (14-52 s) versus 56 s (22-83 s) (P = 0.03), and the T1/2R also decreased, from 72.4 s (41.9-134.6 s) to 49.8 s (31.0-129.8 s) (P = 0.02). Myogenic tone increased (P = 0.03), whereas sympathetic tone decreased (P = 0.03), and myogenic tone was lower than controls before but not after APC treatment. In conclusion, APC improves vascular reactivity both at macrocirculatory and microcirculatory levels very quickly, suggesting that this is not due to protein synthesis or anticoagulant effect. The myogenic properties of vessels could partly drive this effect.

Manual compression of the abdomen to assess expiratory flow limitation during mechanical ventilation.

PURPOSE: The aim of this study was to evaluate the manual compression of the abdomen (MCA) during expiration as a simple bedside method to detect expiratory flow limitation (EFL) during daily clinical practice of mechanical ventilation (MV). METHODS: We studied 44 semirecumbent intubated and sedated critically ill patients. Flow-volume loops obtained during MCA were superimposed upon the preceding breaths and recorded with the ventilator. Expiratory flow limitation was expressed as percentage of expiratory tidal volume without any increase in flow during MCA (MCA [%V(T)]). In the first 13 patients, MCA was validated by comparison with the negative expiratory pressure (NEP) technique. Esophageal pressure changes during MCA and intrinsic positive end-expiratory pressure were also recorded in all the patients. RESULTS: Manual compression of the abdomen and NEP agreed in all cases in detecting EFL with a bias of -0.16%. Percentage of expiratory tidal volume without any increase in flow during MCA is highly correlated with percentage of expiratory tidal volume without any increase in flow during NEP (n = 13, P < .0001, r(2) = 0.99) and intrinsic positive end-expiratory pressure (n = 44, P < .001, r(2) = 0.78), with a good repeatability (n = 44; within-subject SD, 5.7%) and reproducibility (n = 13; within-subject SD, 2.41%). Two third of the patients were flow limited, among whom one third had no previously known respiratory disease. CONCLUSIONS: Manual compression of the abdomen provides a simple, rapid, and safe bedside reliable maneuver to detect and quantify EFL during mechanical ventilation.

Impact of polyurethane on variations in tracheal cuff pressure in critically ill patients: a prospective observational study.

OBJECTIVE: To determine the impact of polyurethane (PU) on variations in cuff pressure (P (cuff)) in intubated critically ill patients. METHODS: Prospective observational before-after study performed in a ten-bed ICU. Cuff pressure was continuously recorded for 24 h in 76 intubated patients, including 26 with polyvinyl chloride (PVC), 22 with cylindrical polyurethane (CPU), and 28 with tapered polyurethane (TPU)-cuffed tracheal tubes. P (cuff) was manually adjusted every 8 h by nurses and was maintained around 25 cmH(2)O. Time spent with cuff underinflation and overinflation was continuously measured. In addition, pepsin, a proxy for microaspiration of gastric contents, was quantitatively measured in tracheal secretions at the end of recording period. RESULTS: A total of 1,824 h of continuous recording of cuff pressure was analyzed. Patient characteristics were similar in the three groups. No significant difference was found in percentage of time spent with underinflation (mean +/- SD, 26 +/- 22, 28 +/- 12, 30 +/- 13% in PVC, CPU, and TPU groups, respectively) and overinflation [median (IQR), 7 (2-14), 6 (3-14), 11% (5-20)] among the three groups. However, a significant difference was found in the coefficient of variation of P (cuff) (mean +/- SD, 82 +/- 48, 92 +/- 47, 135 +/- 67, p = 0.002). While the coefficient of P (cuff) variation was significantly (p < 0.017) higher in the TPU compared to CPU and PVC groups, no significant difference was found between the CPU and PVC groups. The pepsin level was significantly different among the three groups (408 +/- 282, 217 +/- 159, 178 +/- 126 ng/ml; p < 0.001). In fact, the pepsin level was significantly lower in the CPU and TPU groups compared with the PVC group. CONCLUSION: PU does not impact variations in P (cuff) in critically ill patients.

Acute delirium in a critically ill patient may be a wolf in sheep's clothing.

Acute delirium is a commonly encountered problem in the intensive care unit (ICU), which has a myriad of causes and contributes to poor outcomes. We present the case of an alcoholic critically ill patient who developed prolonged acute ICU delirium wrongly diagnosed as sedation and alcohol withdrawal. Protracted vomiting, swallowing disorders and continuous aspirations prevented him from enteral feeding and discontinuation of mechanical ventilation. After several days, it became clear that the patient had been misdiagnosed. Fortunately, nystagmus and ophthalmoplegia then allowed the recognition of Wernicke's encephalopathy, confirmed by cerebral MRIs. After thiamine supplementation, his state improved but he was discharged only on day 32. Wernicke's encephalopathy is an acute reversible neuropsychiatric emergency, which is falsely considered as uncommon, and is largely misdiagnosed, especially in critically ill patients. Thiamine should be systematically given to all critically ill alcoholic patients, especially those with protracted vomiting.