Aurélie Lavergne

Cécile Vigneau

Elisabeth Polard

Louise Triquet

Nathalie Rioux-Leclercq

Pierre Tattevin
email: pierre.tattevin@chu-rennes.fr

Léonard Golbin

Acute kidney injury during treatment with high-dose cloxacillin A report of 23 cases and literature review

Keywords: acute kidney injury, nephrotoxicity, cloxacillin, high-dose, therapeutic drug monitoring

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Cloxacillin, a member of the isoxazolyl penicillin group with oxacillin, dicloxacillin, and flucloxacillin, is a major anti-staphylococcal agent, recommended as first line treatment for a broad range of severe infections due to meticillin-susceptible Staphylococcus aureus (MSSA), and included on the World Health Organization (WHO) list of essential medicines. According to the cloxacillin prescribing information, the maximum dose is 6 g/day, but doses recommended by the European Society of Cardiology for infective endocarditis [START_REF] Habib | ESC Guidelines for the management of infective endocarditis: The Task Force for the Management of Infective Endocarditis of the European Society of Cardiology. Endorsed by: European Association for Cardio-Thoracic Surgery (EACTS), the European Association of Nuclear Medicine (EANM)[END_REF], or the French Society of Infectious Diseases for osteoarticular infections [START_REF]Société de Pathologie Infectieuse de Langue Française (SPILF), Collège des Universitaires de Maladies Infectieuses et Tropicales (CMIT), Groupe de Pathologie Infectieuse Pédiatrique (GPIP), Société Française d'Anesthésie et de Réanimation (SFAR[END_REF] are 8-12 g/day, intravenously, for 2-6 weeks. These higher doses are justified by the need to reach effective concentrations within difficult-to-reach infected foci (e.g. bone, cardiac valves and vegetations, brain), and their acceptable tolerability. Accordingly, no dose adjustment is recommended for patients with renal impairment if estimated glomerular filtration rate (eGFR) is >30 mL/min, while daily dose must be reduced by 50% for patients with eGFR<30 mL/min.

Although few cases of acute kidney injury (AKI) imputable to cloxacillin have been reported following its approval in the early 1980's, increasing use of high doses, in an ageing population, with comorbidities, and concomitant use of potentially nephrotoxic drugs, may change the overall good tolerability of this old drug. Recent reports have suggested an emergence of AKI with different extended-spectrum penicillins [START_REF] Hammond | Systematic Review and Meta-Analysis of Acute Kidney Injury Associated with Concomitant Vancomycin and Piperacillin/tazobactam[END_REF]. However, little is known about the respective nephrotoxicity of currently recommended antistaphylococcal agents (penicillinase-resistant penicillins, or cefazolin), and the risk factors for AKI associated with these treatments. We report a contemporary case series of 23 consecutive patients with AKI associated with high-dose cloxacillin, to better define the characteristics, the mechanisms, and the outcome of this emerging severe adverse event.

A C C E P T E D

M A N U S C R I P T 5 2. METHODS

Patients

The study was conducted in Pontchaillou, a university-affiliated hospital that serves as a referral center for the area of Rennes, Bretagne, in western France. All suspicion of cloxacillin-induced AKI registered by the pharmacovigilance center in Pontchaillou hospital between January 1 st , 2009 and December 31 st , 2015 were retrieved. Cases were identified through passive surveillance (voluntary notification), and through systematic queries in biomedical data warehouse, using ICD-10 (International Classification of Diseases 10th Revision) codes or codes combinations suggestive of drug-induced kidney injury, described elsewhere [START_REF] Osmont | Use of the PMSI for the detection of adverse drug reactions[END_REF].

Clinical and biological data

Data were collected on a standardized questionnaire from medical files, including: age, sex, comorbidities, treatment received within two weeks before AKI onset, including iodinated contrast media. Doses, duration, and indication for cloxacillin were collected. Clinical data recorded included: hemodynamic instability (defined as systolic blood pressure <90 mmHg requiring volume expansion and/or vasopressive drugs), hypersensitivity signs (cutaneous eruption, fever of acute onset more than 48 h after cloxacillin start, arthralgia). Cloxacillin plasma concentration was determined by high-performance liquid chromatography method with UV detection, as previously described [START_REF] Verdier | Simultaneous Determination of 12 beta-Lactam Antibiotics in Human Plasma by High-Performance Liquid Chromatography with UV Detection: Application to Therapeutic Drug Monitoring[END_REF]. The target range of trough concentration (or steady-state concentration, in case of continuous administration), was 20-50 µg/mL, as previously described [START_REF] Neuville | Systematic overdosing of oxa-and cloxacillin in severe infections treated in ICU: risk factors and side effects[END_REF].

We systematically recorded serum creatinine (SCr, µmol/L) before cloxacillin start and 1, 3 and 6 months after cloxacillin treatment, as well as white blood cells count (including

A C C E P T E D M A N U S C R I P T 6
eosinophil count), platelets, and hemoglobin level by the time of AKI. Serum levels of aspartate and alanine aminotransferases (AST, ALT), alkaline phosphatases, and bilirubin were collected. Urinalysis with urine dipstick, proteinuria by 24-h collection or on sample and estimated in g/g of urinary creatinine, and crystalluria were recorded when available. For dipstick analysis, thresholds were 5 erythrocytes/µL for microscopic hematuria, 5 white blood cells/µL for leukocyturia, and 1 +, or 25 mg/dL for proteinuria.

Definitions

AKI was defined according to Kidney Disease: Improving Global Outcomes (KDIGO) guidelines, through increase in SCr by 26.5 µmol/L, or 1.5 times baseline [START_REF] Kdigo Aki | KDIGO clinical practice guideline for acute kidney injury[END_REF]. The Risk, Injury, Failure, Loss of function, End stage renal disease (RIFLE) score was used for AKI classification [START_REF] Kdigo Aki | KDIGO clinical practice guideline for acute kidney injury[END_REF]. Because urine output was not available for each patient, only SCr maximal value was used to determine the RIFLE score. An increase of SCr by a factor of 1.5, 2 or 3, was used to classify AKI as, respectively, stage Risk, Injury, or Failure. eGFR using the Cockcroft and Gault formula was calculated only once before cloxacillin start. Chronic kidney disease (CKD) stage was determined for each value at baseline, as well as 3 and 6 months after AKI. Cases were classified as complete recovery if CKD stage after AKI was 1 or 2, or if CKD stage after AKI was equal to baseline CKD stage. Recovery was analyzed 3 months after AKI or as soon as creatinine returned to baseline level. Anemia was defined as Hb <12 g/dL, thrombocytopenia as platelets count <150 G/L, and hypereosinophilia as eosinophils count >0.6 G/L. Hepatic cytolysis was defined as AST or ALT >2 upper normal values (N); cholestasis as alkaline phosphatases >2 N. When performed, results of renal biopsy were collected, as was the number of renal replacement therapy sessions.

Statistics

A C C E P T E

Ethics/regulatory issues

In France, any suspicion of severe adverse events must be reported to the drug safety surveillance department (pharmacovigilance). Cases are investigated by the local department, anonymized, and recorded in a national database that ensures data privacy. This study has been approved by the institutional review board of Rennes University hospital. An information letter was sent to each patient, who was offered the opportunity to decline participation in this study.

RESULTS

Patients characteristics

Twenty-five cases of AKI suspected to be related to high-dose cloxacillin were registered by the drug safety surveillance system during the study period. Two were excluded, because review of medical records found that AKI started before cloxacillin was introduced. Hence,

A C C E P T E D M A N U S C R I P T 8
23 cases were enrolled (16 men, 7 women), with a median age of 75 years (IQR, 66-80).

Patients characteristics are detailed in Table 1. Of note, no patient should have received reduced cloxacillin dose according to current guidelines, as all had eGFR >30 mL/min when cloxacillin was started, whatever the method used to estimate GFR. All cases were classified as 'AKI possibly or probably related to cloxacillin' by the drug safety surveillance department.

Acute kidney injury

AKI occurred after a median cloxacillin treatment duration of 4 days (IQR, 3-7 days).

According to RIFLE criteria, 3 patients (13%) were scored 'Injury', and 20 patients (87%) 'Failure'. The median SCr at peak was 339 µmol/L (IQR, 249-503). Five patients required renal replacement therapy, with a median number of 4 (IQR, 3-5) sessions of intermittent hemodialysis, over a maximum duration of three weeks. No patient presented clinical signs of hypersensitivity, with the possible exception of one patient with unexplained back pain of acute onset, that resolved when cloxacillin dose was reduced.

Urinalysis was available for 19 patients (83%): 16 patients (70%) had microscopic hematuria, 3 (13%) had aseptic leukocyturia, and 10 (44%) had proteinuria on dipstick.

Proteinuria was quantified in 12 patients, with a median of 0.825 g/g (IQR 0.75-0.97). Only one patient had proteinuria >3 g/g, with normal serum albumin level. Seven patients presented urinalysis compatible with tubular disease, with proteinuria dosage on sample higher than by the dipstick. Crystalluria was investigated in four patients, and positive for one. One patient underwent renal biopsy that revealed acute tubulointerstitial nephritis, with lymphocytic infiltrate and acute tubular necrosis (figure 1).

Cofactors for AKI

A 13 patients with cloxacillin trough plasma concentration >50 µg/mL, 7 were documented at the same time as AKI onset, 3 were observed before AKI, and 3 were observed after AKI.

Outcome

Only the patient with AIN biopsy-proven received steroids. AKI improved in all patients: for 21 (91%), SCr decreased after cloxacillin was discontinued, with a median delay of 5 days (IQR, 1-7) between last dose of cloxacillin and the beginning of renal function improvement.

In 2 patients with simultaneous cloxacillin plasma concentration >50 µg/mL and AKI, cloxacillin daily dose reduction led to a stabilization of kidney function in one patient, and significant improvement for the other. Evolution of kidney function is detailed on Table 2.

Finally, considering the last SCr value available, complete recovery was observed for 13 patients (57%). The infectious diseases that motivated high-dose cloxacillin were finally controlled in all patients initially, and all patients could be discharged. However, one patient had a recurrence of endocarditis and died 3 months later.

Estimates of AKI incidence in patients treated with high-dose cloxacillin

During the study period (2009-2015), 137,675 defined daily doses (275,350 g) of cloxacillin were administered in our institution. With a mean daily dose of 9.7 g, and a mean duration of treatment of 10.5 days, the number of patients who received intravenous cloxacillin during the study period is estimated at 676. Hence, these 23 cases of AKI would translate into a cumulative risk of AKI of 3.4% per patient treated with cloxacillin, and an incidence rate of 0.3% per treatment-day.

DISCUSSION

A C C E P T E D M A N U S C R I P T 11

To the best of our knowledge, this is the first case series of AKI associated with cloxacillin. AKI occurred early after cloxacillin start (i.e. median, 4 days (IQR, 3-7), primarily in elderlies (median age 75 years, IQR, 66-80), and was often serious: 20 cases were classified as 'failure' according to RIFLE, and 5 patients required renal replacement therapy.

Renal function had returned to baseline value at the end of follow-up for 57% of patients.

Renal toxicity of cloxacillin has been rarely reported: In 1989, 7 years after cloxacillin was approved for use, Grimm et al. reported the first case of acute renal failure with eosinophiliuria in a four-year-old child after 10 days of oral cloxacillin [START_REF] Grimm | Interstitial nephritis induced by cloxacillin[END_REF]. Renal function totally recovered following cloxacillin discontinuation, and a three-day course of corticosteroids. Although no renal biopsy was performed, this observation was highly suggestive of acute interstitial nephritis (AIN). Three other cases of cloxacillin-induced AIN were reported in 1991-1992 [START_REF] García-Ortiz | Cloxacillin-induced acute tubulo interstitial nephritis[END_REF][START_REF] Billip-Tomecka | Reversible renal failure in female patients with acute interstitial nephritis caused by cloxacillin][END_REF][START_REF] Bruckheimer | Cloxacillin-induced interstitial nephritis[END_REF], including one case of AIN documented by biopsy in a 15year-old child, after a three-month course of oral cloxacillin [START_REF] García-Ortiz | Cloxacillin-induced acute tubulo interstitial nephritis[END_REF]. This child required 4 sessions of peritoneal dialysis, and recovered normal renal function 21 days after cloxacillin discontinuation, without corticosteroids. Lastly, an observational study on the risk of AKI associated with antimicrobial agents found that among 40 patients treated with cloxacillin, one developed AKI [START_REF] Khalili | Antibiotics induced acute kidney injury: incidence, risk factors, onset time and outcome[END_REF], with an estimated risk of 2.5% in patients treated with cloxacillin, quite similar to the 3.4% estimated in our study. Of note, similar incidence rates have been reported with the other isoxazolyl penicillins currently licensed (i.e. oxacillin, dicloxacillin, and flucloxacillin), and the primary mechanism suspected or documented was AIN [START_REF] Loubet | Cefazolin versus anti-staphylococcal penicillins for treatment of methicillin-susceptible Staphylococcus aureus bacteremia: a narrative review[END_REF].

Although most cases of cloxacillin-induced nephropathy reported to date were suspected or documented to be immuno-allergic [START_REF] Grimm | Interstitial nephritis induced by cloxacillin[END_REF][START_REF] García-Ortiz | Cloxacillin-induced acute tubulo interstitial nephritis[END_REF][START_REF] Billip-Tomecka | Reversible renal failure in female patients with acute interstitial nephritis caused by cloxacillin][END_REF][START_REF] Bruckheimer | Cloxacillin-induced interstitial nephritis[END_REF], the cases reported herein suggest that other mechanisms may be involved. Although AIN was documented for the only patient who underwent kidney biopsy, several points argue against a primarily immuno-allergic pathway,

A C C E P T E D M A N U S C R I P T
and suggest other possible mechanisms for cloxacillin-induced AKI. Firstly, all patients except one were receiving high-dose cloxacillin, and more than half had cloxacillin plasma concentration >50 µg/mL. Secondly, for 2 patients, renal function improved or stabilized while cloxacillin was continued, at a lower dose. These two facts are suggestive of doserelated, direct tubular toxicity. Thirdly, few patients had clinical or biological signs of hypersensitivity (e.g. only three had hypereosinophilia). Fourthly, crystalluria was documented in one patient, suggesting that tubular precipitation of cloxacillin may occur, as reported with other penicillins [START_REF] Labriola | Massive amoxicillin crystalluria causing anuric acute renal failure[END_REF][START_REF] Yarlagadda | Drug-induced crystal nephropathy: an update[END_REF][START_REF] Zeller | Amoxicillin crystalluria, an emerging complication with an old and well-known antibiotic[END_REF]. Similar hypothesis were raised regarding nephrotoxicity of flucloxacillin, an isoxazolyl penicillin structurally close to cloxacillin [START_REF] Sutherland | Flucloxacillin, a new isoxazolyl penicillin, compared with oxacillin, cloxacillin, and dicloxacillin[END_REF].

For the latter, a dose effect was recently demonstrated, with an higher risk of AKI in patients who received high-dose flucloxacillin prophylaxis before knee surgery, as compared to standard dose [START_REF] Challagundla | Renal impairment after high-dose flucloxacillin and single-dose gentamicin prophylaxis in patients undergoing elective hip and knee replacement[END_REF].

Whatever the mechanism, our case series underlines that almost all patients who developed AKI during cloxacillin treatment had other risk factors for AKI, including hemodynamic instability and concomitant use of nephrotoxic drugs or iodinated contrast media. More than half were receiving ACE inhibitors, ARB, or diuretics. As intravenous cloxacillin is mainly eliminated by urinary route, and actively excreted by renal tubules [START_REF] Barza | Pharmacokinetics of the penicillins in man[END_REF],

drugs that modify renal hemodynamic, may increase the risk of AKI during cloxacillin treatment. In addition, 19 patients (83%) were also receiving gentamicin, and 3 received at least one bolus of iodinated contrast media, both products with direct toxicity on renal tubules [START_REF] Brillet | Hospital costs of contrastinduced nephropathy[END_REF][START_REF] Picard | Propensity-based study of aminoglycoside nephrotoxicity in patients with severe sepsis or septic shock[END_REF][START_REF] Cobussen | No increased risk of acute kidney injury after a single dose of gentamicin in patients with sepsis[END_REF], that may increase the tubular toxicity of high-dose cloxacillin. These data have two major clinical implications for the management of patients who require high dose cloxacillin: i) patients with cofactors for AKI, including hemodynamic instability and concomitant use of nephrotoxic agents, should be closely monitored; ii) whenever possible, these cofactors must Several questions arise regarding cloxacillin dose adaptation to avoid trough plasma concentrations >50 µg/mL. We found that, despite patients were prescribed the cloxacillin dose recommended by guidelines, taking into account their eGFR, 57% had trough plasma concentration > 50 µg/mL. This result is consistent with a recent study that reported trough plasma concentration > 50 µg/mL in 83.9% of 62 patients treated by oxacillin or cloxacillin in intensive care unit [START_REF] Neuville | Systematic overdosing of oxa-and cloxacillin in severe infections treated in ICU: risk factors and side effects[END_REF]. Of note, intravenous cloxacillin is mainly bound to plasma proteins (>90%) [START_REF] Rolinson | The binding of antibiotics to serum proteins[END_REF], and the active metabolite is the unbound fraction. In case of hypoalbuminemia (e.g. malnutrition or inflammation), this unbound fraction increases [START_REF] Lindup | Clinical pharmacology: plasma protein binding of drugs[END_REF]. In addition, tubular excretion is a saturable mechanism, with interindividual variations [START_REF] Bins | Saturation of the tubular excretion of beta-lactam antibiotics[END_REF]. Target cloxacillin plasma concentration can be achieved with much lower doses than 12 g/d [START_REF] Visser | Clinical pharmacokinetics of continuous intravenous administration of penicillins[END_REF], which suggests that doses currently recommended are probably too high, especially for the contemporary population of patients with severe staphylococcal infections (i.e. elderly, with comorbidities, and sepsis).

These data suggest that therapeutic drug monitoring of cloxacillin should be developed, as for vancomycin or gentamicin, which would allow early adaptation of daily doses. Individualized treatment is probably necessary for this population of elderly patients with major comorbidities, and multiple comedications. A recent study showed that cloxacillin monitoring was routinely available only in 16.5% of cases in France [START_REF] Charmillon | The ANTIBIOPERF study: a nationwide cross-sectional survey about practices for β-lactam administration and therapeutic drug monitoring among critically ill patients in France[END_REF], although the impact of therapeutic drug monitoring has been demonstrated for this betalactam agent as well as others, when prescribed at high doses [START_REF] Tattevin | Use of high-performance liquid chromatography (HPLC) to monitor beta-lactam plasma concentrations during the treatment of endocarditis[END_REF]. One of the major caveats of therapeutic drug monitoring for cloxacillin is that the therapeutic target has not been validated. In France [START_REF] Neuville | Systematic overdosing of oxa-and cloxacillin in severe infections treated in ICU: risk factors and side effects[END_REF],

we routinely use a target of 20-50 µg/mL for cloxacillin trough plasma concentrations (or steady-state concentrations, in case of continuous administration), for difficult-to-treat MSSA

A C C E P T E D M A N U S C R I P T 14
infections (e.g. cardiovascular or osteoarticular infections), based on the following points: i) the activity of this drug, as for most betalactam agents, is time-dependent, which means that there won't be major gain in terms of efficacy once you reach the MIC; ii) for the main indication of cloxacillin use (i.e. MSSA), MIC90 is at 0.5 µg/mL; iii) tissue diffusion of cloxacillin, although not thoroughly investigated, is probably moderate, at best; and iv) for most betalactam antibiotics, dose-related toxicity is observed above plasma concentrations of 50 µg/mL.

This study has limitations: Firstly, as it was retrospective, investigation of cases was not standardized, hence missing data may have introduced bias. Secondly, no active surveillance of cloxacillin tolerability was in place during the study period. Hence, we had to rely on passive surveillance and voluntary notification, so that cases may have been missed.

Thirdly, only one case underwent kidney biopsy, so that the underlying mechanism of AKI remained unproven in most cases. Lastly, the lack of a control group of patients who received high-dose cloxacillin, but did not develop AKI, precluded identification of risk factors for AKI associated with high-dose cloxacillin. Strengths of this study includes its relatively large sample size, as compared to literature data available to date, and the investigation of each case while patients where still admitted, with the expertise of trained staff from the drug safety monitoring department, and the support of nephrologists and infectious diseases physicians whenever required.

In conclusion, this first case series of 23 patients who developed AKI associated with high dose cloxacillin suggests that direct tubular toxicity and/or tubular precipitation may play a major role. This study advocates for systematic therapeutic drug monitoring when cloxacillin is prescribed at high doses, with a first determination early after introduction (e.g. 48 to 96 hours after cloxacillin start), even when baseline renal function is normal. eGFR must be monitored at least twice a week, and dose of cloxacillin should be reduced as soon as



  We report a case series of 23 patients who developed acute kidney injury (AKI) during treatment with high doses cloxacillin, as recommended for endocarditis or osteomyelitis due to meticillin-susceptible staphylococci  Most cases occurred during the first week of treatment, in elderly patients with cofactors for AKI, including hemodynamic instability, and nephrotoxic agents  Therapeutic drug monitoring of cloxacillin may allow early recognition of trough plasma concentrations >50 ng/mL, and reduce the risk of AKI

7

  Statistical analyses were descriptive. Categorical variables were presented as number and percentages. Continuous variables were presented as medians with first and third quartile (interquartile range, IQR). Statistical analyses were performed using EXCEL 2016 software (Microsoft®, Mountain view, USA). To estimate the incidence of AKI in patients receiving cloxacillin treatment, we extracted data on cloxacillin use in our institution from the pharmacy computerized database (SAP BusinessObjects®, Paris, France). The number of patients who received cloxacillin was estimated by dividing the total amount of intravenous cloxacillin purchased during the study period for the whole institution, by the mean total dose received by each patient (i.e., mean daily dose times mean duration of cloxacillin treatment, in days).

9

  Most patients were receiving drugs with potential immuno-allergic side effects, including proton pump inhibitors(15/23), and non-steroidal anti-inflammatory drugs (NSAID, 2/23), long before cloxacillin was introduced. Hence, the contribution of these drugs is unlikely. In addition, 18 patients were receiving drugs known to reduce renal perfusion and function, mostly diuretics (15/23), angiotensin-converting enzyme (ACE) inhibitors (8/23), and/or angiotensin II receptor blockers (ARB, 6/23). Although they were well tolerated before cloxacillin start, these drugs may have contributed to AKI through their pharmacodynamic properties.Noteworthy, most patients (19/23) were receiving gentamicin in addition to cloxacillin when AKI occurred, either once (n=13), twice (n=4), or thrice (n=2) daily. Of these, only one had documented gentamicin trough plasma concentration >1 µg/mL. Lastly, three patients (13%) underwent CT-scan with iodinated contrast media injection within 48 h before AKI onset, and 9 (39%) presented hemodynamic instability. Overall, only one case of AKI associated with high dose cloxacillin had neither hemodynamic instability, nor concomitant use of gentamicin, or iodinated contrast media injection. patients received intravenous cloxacillin, and one patient received oral cloxacillin. Median duration of cloxacillin treatment when AKI developed was 4 days (IQR, 3-7 days), and median daily dose was 11 g (IQR, 10-12). One patient erroneously received 31.5 g during one day. Cloxacillin plasma concentration was measured before or during AKI onset in 18 patients. The first measure was performed after a median delay of 3.5 days (IQR, 2-4). Thirteen patients (57%) had plasma concentration >50 µg/mL (range 51.4-135.0), including 10 (43% of total), with trough plasma concentration >100 µg/mL. Only 2 patients (9%) had plasma concentrations within the therapeutic target (i.e. 20-50 µg/mL). Among the A C C E P T E D M A N U S C R I P T 10

  e.g. discontinuation of nephrotoxic agents, and early correction of hemodynamic instability).

Fig. 1 :

 1 Fig. 1: Masson's trichrome staining showing acute tubulointerstitial nephritis with

Table 1 . Patients characteristics before cloxacillin start (n = 23)

 1

	Demographics
	Median age, years (interquartile range)	75 (66-80)
	Male/Female, n	16/7
	Comorbidities n (%)
	Cancer	2 (4)
	Diabetes	8 (35)
	Cardiopathy	13 (57)
	High blood pressure	12 (25)
	Kidney function
	Median serum creatinin, µmol/L (IQR)	79 (59-92)
	Median eGFR, mL/min (IQR)	86 (64-110)
	CKD stage ≤ 2, n (%)	20 (87)
	CKD stage 3, n (%)	3 (13)
	CKD stage 4, n (%)	0
	Associated drugs, n (%)
	PPI	15 (65)
	NSAID	2 (9)
	Diuretic	15 (65)
	ACE inhibitor or ARB	14 (61)
	Main indication for cloxacillin, n (%)
	Osteoarthritis infection	9 (39)
	Cardiovascular	7 (30)
	Bacteremia	11 (48)
	Microbiology, n (%)
	MSSA	17 (74)
	Coagulase-negative staphylococci	3 (13)
	Not documented	3 (13)
	eGFR: estimated glomerular filtration rate; CKD: chronic kidney
	disease; PPIs: proton pump inhibitor; NSAID: non-steroidal anti-
	inflammatory drug; ACE: angiotensin-converting enzyme; ARB:
	angiotensin II receptor blocker; MSSA: meticillin-susceptible
	Staphylococcus aureus

This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors.

Funding: This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors Ethical Approval: This study has been approved by the ethical committee of Rennes University hospital (reference number n° 16.99).


archive ouverte pluridisciplinaire HAL, est destinée au dépôt

Telehealth applied to physical activity during cancer treatment: a feasibility, acceptability, and randomized pilot study

Charlène Villaron, François Cury, François Eisinger, Maria-A Cappiello,

Tanguy Marqueste

To cite this version:

Charlène Villaron, François Cury, François Eisinger, Maria-A Cappiello, Tanguy Marqueste. Telehealth applied to physical activity during cancer treatment: a feasibility, acceptability, and randomized pilot study. Supportive Care in Cancer, 2018, 10.1007/s00520-018-4191-4. hal-01781287

L'


T De Rességuier
email: resseguier@ensma.fr

C Roland

G Prudhomme

E Brambrink

J E Franzkowiak

D Loison

E Lescoute

A Sollier

L Berthe

Picosecond Radiography Combined with Other Techniques to Investigate Microjetting from Laser Shock-loaded Grooves

Debris ejection upon shock breakout at a rough surface is a key issue for many applications, including pyrotechnics and inertial confinement fusion. For a few years, we have used laser driven shocks to investigate microjetting in metallic samples with calibrated grooves in their free surface. Fast transverse optical shadowgraphy, time-resolved measurements of both planar surface and jet tip velocities, and post-shock analysis of recovered material have provided data over ranges of small spatial and temporal scales, short loading pulses (ns-order) and extremely high strain rates. The new experiment presented here involves two laser beams in a pump-probe configuration. Picosecond laser irradiation of a thin copper wire generates x-rays which are used to radiograph the microjets expanding from single grooves in tin and copper samples shock-loaded by a longer, nanosecond laser pulse. Such ultrashort radiography can be used to infer the density gradients along the jets as well as inside the samples deep beneath the grooves. Thus, combining this x-ray probe with the other experimental techniques mentioned above provides a more complete insight into the physics of microjetting at very high loading rates and the ballistic properties of the resulting ejecta.

INTRODUCTION

Ejection of high velocity debris and their subsequent impacts are a safety issue for various applications involving shock waves, such as pyrotechnics or inertial confinement fusion. One of the processes governing debris generation from shock-loaded materials, sometimes referred to as microjetting, is the interaction of the shock front with a free surface presenting geometrical defects such as pits, scratches or grooves. It leads to the ejection of small (typically μm-scale) particles of high velocity (a few km/s) ahead of the main surface [e.g. [1][START_REF] Andriot | AIP Conf. Proc[END_REF][START_REF] Zellner | [END_REF][4][5]. In the past few years, we have studied this process under laser-driven shocks, over small spatial (~ μm) and temporal (~ ns) scales, at very high strain rates (~10 7 s -1 ), from straight grooves imprinted in the free surface of laser shock-loaded samples of various metals. To date, our main experimental results include (i) the determination of the mean velocities of both the planar free surface and the tips of the microjets expanding from the grooves, using fast optical shadowgraphy [6][7][START_REF] De Rességuier | AIP Conf. Proc[END_REF] ; (ii) time-resolved measurements of these velocities using Photonic Doppler Velocimetry (PDV, also known as Heterodyne Velocimetry) [6,[START_REF] Roland | [END_REF] ; (iii) some post-shot evidence of the jetting process and the effect of spall fracture, from microscopic examination of recovered samples [6,[START_REF] De Rességuier | AIP Conf. Proc[END_REF] ; (iv) direct observation of the late stage of jet fragmentation into distinct debris, using transverse optical shadowgraphy [START_REF] Roland | [END_REF] ; and (v) an attempt to characterize ejecta size distributions using soft recovery in a gel and x-ray tomography [10]. Yet, the mass distribution in the jets, which is a key issue for the practical applications mentioned above, is still largely unknown in our experiments.

A c c e p t e d M a n u s c r i p t

Besides, some of our post-recovery observations and velocity data have raised questions on wave interactions occurring inside the bulk material and edge effects at the grooves sides [7].

Here, we report the implementation of a new, laser based, ultrafast radiography technique which was recently added to our experimental instrumentation to investigate the mass density along a jet expanding from a single groove of triangular shape, as well as tension inside the bulk sample beneath the groove edges. The application of this same technique to characterize material ejection from periodic grooves of approximately sinusoidal shapes and different shape factors in laser shock-melted tin is described in another contribution [11].

EXPERIMENTAL TECHNIQUE

The experiments were performed in the nano2000 facility of the Laboratoire pour l'Utilisation des Lasers Intenses (LULI, France). Shock loading was driven by a ~ kJ-energy, 5 ns-duration, 1.06 μm-wavelength laser pulse focused on a spot of diameter d (a few mm) in the sample surface, in vacuum to avoid laser breakdown in air. Opposite to this loaded spot, the grooved free surface was monitored with a collimated PDV probe recording both planar surface velocity and jet tip velocity. A second laser pulse of ~10 J-energy and 1.5 ps-duration is focused onto the tip of a freestanding, vertical Cu wire of 20 μm-diameter set a few mm below the sample free surface (Fig. 1). This intense (~2 ×10 18 W/cm 2 ) irradiation creates energetic electrons and generates x-rays through the emission of K-shell radiation, at 8 keV for Cu. Some of these x-rays are transmitted through the sample and the jets to an horizontal Image Plate (IP), which provides in-situ radiography of the ejecta behind the shock-loaded sample at a given instant after shock breakout, accurately controlled by adjusting the time delay between the ns-drive and the psprobe (400 ns in the shots reported here). The duration of the x-ray burst is only slightly longer than the ps laser pulse [12] so that temporal resolution is very good. The use of a thin wire as a backlighter target minimizes the source size to ensure a good spatial resolution too. The IP is set a few tens of cm above the sample, so the radiographs are recorded with a magnification of about 21×. The geometry depicted in Fig. 1, with normal irradiation of the wire by the ps-laser and the IP placed normal to the wire, was demonstrated to be the most relevant for resolution, homogeneity and contrast of the x-ray signal [12]. After each shot, the IP was scanned to measure the photo-stimulated luminescence (PSL), proportional to the x-ray yield. To correlate this PSL value to mass density, step wedges of Cu and Sn with thicknesses ranging from 5 μm to 100 μm were inserted in front of the IP. This onshot calibration removes uncertainties due to shot-to-shot fluctuations [12,13]. It is illustrated in more details in the next section. Finally, the spatial resolution was found to be about 20 μm by performing a static radiography of a 300 lpi-grid located at the sample position (details can be found elsewhere [11]). 1, referred to as "sideways" radiography, along the groove direction. Step wedges of Cu and Sn with different thicknesses are visible at the top right of both images. Such step wedges direct correlation between transmitted x-ray intensity (color scale) and areal mass density. Data analysis is illustrated in Fig. 3, corresponding to the shot in Fig. 2b. It shows the raw radiograph (Fig. 3a), where PSL levels are measured in rectangular zones of interest (blue frames around the jet and the step wedges) and divided by the mean background level measured in their close vicinity (green frames), respectively. This somewhat accounts for the non-uniform background level over the IP, like in Fig. 2b. Then, a correlation between PSL and thickness is inferred from the step wedges, using a Beer-Lambert fit (Fig. 3b). Finally, this fit is used to convert PSL into areal mass density in and near the jet (Fig. 3c). Thus, the resulting estimates of the areal mass ma along the jets are about 10 mg/cm² and 18 mg/cm² in Fig. 2a and2b, respectively. Assuming a uniform particle distribution in the transverse direction, over the width l of the jet supposed to be roughly equal to the diameter d of the loaded spot (see the sketch at the bottom right in Fig. 1), the average mass density in the jet can be evaluated as j = m a / d, about ~ 36 mg/cm 3 in Fig. 2a (Cu) and ~ 60 mg/cm 3 in Fig. 2b (Sn). The radiographs also show very clearly (although more clearly in Cu than in Sn) two lines of low density (pink color in both images) deep inside the bulk sample, between the loaded side (left side) and both edges of the groove. They probably result from local tension due to the interactions of the incident unloading wave with the rarefaction waves reflected from the groove edges [6]. Numerical simulations are under way to understand these effects in more details [START_REF] Roland | [END_REF]10].

Finally, like stated above and depicted in Fig. 1, fast optical shadowgraphy is performed simultaneously along the horizontal direction. As detailed elsewhere [6,7], it provides mean velocities of the free surface (1.49 km/s in the shot on Cu, 1.51 km/s in that on Sn), and of the jet tip (4.6 km/s in the shot on Cu, 4.0 km/s in that on Sn), consistent with the radiographs and with velocity data obtained previously [6,[START_REF] Roland | [END_REF].

"IN-PLANE" RADIOGRAPHY

Fig. 4a shows another example of radiograph of a Sn sample where the groove direction is normal to the wire, unlike in Fig. 1. In this "in-plane" configuration, the mass density can be evaluated without integrating along the jet width, while the optical shadowgraphs show jetting "from the side" (Fig. 4b). Based on the transmission through the step wedges, a gradient of areal mass density along the expanding jet can be roughly inferred, from about 30 at the bottom to 10 mg/cm² at the tip. In this high intensity shot, focused on a 1.5 mm-diameter spot, measured velocities of the planar free surface and of the jet tip are 2.9 km/s and 5.7 km/s, respectively. Shock breakout pressure is 50 GPa, well above the pressure range over which Sn is expected to melt on release [START_REF] Mabire | AIP Conf. Proc[END_REF][START_REF] Buttler | [END_REF]. Thus, the free surface is actually the contour of an expanding cloud of tiny droplets (so-called microspall [16]), with a more blurry aspect than in Fig. 2b where Sn remained solid beneath the free surface. From the shadowgraphs in Fig. 4b, jet thickness is evaluated to about 70 μm. Hence, like in the previous section, the mean density in the jet j can be estimated as 1.4 g/cm 3 (using the ~ 10 mg/cm 2 areal mass measured near the jet tip). This is about 20 times higher than in the lower pressure shot in Fig. 2b. Such increase is consistent with the effect of melting which was shown to sharply enhance the amount of shock-produced ejecta [START_REF] Zellner | [END_REF].

CONCLUSION

A short-pulse laser-generated K x-ray source was used to radiograph the jets expanding from single grooves of triangular shape in the free surface of laser shock-loaded Cu and Sn samples. High quality radiographs with good spatial and temporal resolution were obtained. Step wedges were introduced at each shot to correlate x-ray transmission with areal mass densities. Further work is under way to improve this calibration. Nevertheless, direct estimations of the ejecta mass distributions along the jets could be provided, as well as some new insight into the tension induced deep inside the bulk samples, below the jets, from both sides of the grooves. Thus, this ultrafast radiography technique, fully compatible with PDV measurements and optical shadowgraphy, performed simultaneously in other directions (see Fig. 1), offers a means for a complete characterization of the ballistic properties (i.e. mass and velocity distributions) of the ejecta, to be understood and anticipated to efficiently protect nearby equipment against their impacts.

FIGURE 1 .Fig. 2

 12 FIGURE 1. Schematic of the experimental setup.The irradiation of a freestanding Cu wire by a psduration laser pulse generates an x-ray burst which is used to radiograph the jet expanding from a groove in the free surface of a sample subjected to a ns-laser driven shock. PDV measurement and optical shadowgraphy are performed simultaneously along other directions. In this configuration referred to as "sideways" in this paper, radiography is performed along the groove direction.

FIGURE 2 .

 2 FIGURE 2. Typical radiographs recorded behind Cu and Sn samples subjected to laser shock loading (onto their left surface, not shown), showing jetting from a straight groove in their free surface. (a) : Cu sample, 250 μm-thick, groove of 20° half-angle, loaded spot of 2.8 mm-diameter, shock breakout pressure 34 GPa ; (b) : Sn sample, 260 μm-thick, groove of 30° half-angle, loaded spot of 3.0 mm-diameter, shock breakout pressure 20 GPa. The time delay between the ns-drive (laser shock) and the psprobe (x-ray burst) is 400 ns in both shots.

FIGURE 3 .

 3 FIGURE 3. Illustration of radiography analysis for the record shown in Fig. 2b : raw radiograph (a), PSL-thickness correlation (b), and areal mass density in and near the jet (c).

FIGURE 4 .

 4 FIGURE 4. Microjetting behind a 260 μm-thick Sn sample with a groove of 30° half-angle under a laser shock applied on a 1.5 mm-diameter spot, leading to a shock breakout pressure of 50 GPa. (a) : radiograph recorded 400 ns after the ns-laser shot, in the "in-plane" radiography configuration (i.e. normal to the groove direction) ; (b) : shadowgraphs recorded simultaneously in the other direction (i.e. along the groove direction) with 5 ns-exposure times, at successive instants after the ns-laser shot.

ACKNOWLEDGMENTS

The access to the LULI facility was attributed via the Institut Laser Plasma (ILP, FR 2707). We thank all the nano2000 staff for their kind help.