Antibiotics and chronic kidney disease: Dose adjustment update for infectious disease clinical practice

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Antibiotics and chronic kidney disease: Dose adjustment update for infectious disease clinical practice夽 Antibiotiques chez le patient insuffisant rénal : actualisation des adaptations posologiques à la pratique clinique en infectiologie B. Aloy a , V. Launay-Vacher a , A. Bleibtreu b , P. Bortolotti c , E. Faure c , A. Filali c , R. Gauzit d , M. Gilbert e , P. Lesprit f , R. Mahieu g , V. Meyssonnier h , M. Ogielska i , J. Romaru j , D. Salmon k , S. Alfandari l , A. Lemaignen m,∗ a

Service ICAR, service de néphrologie, hôpitaux universitaires Pitié-Salpêtrière–Charles-Foix, AP–HP, 75013 Paris, France Service de maladies infectieuses et tropicales, hôpitaux universitaires Pitié-Salpêtrière–Charles-Foix, AP–HP, 75013 Paris, France c Unité des maladies infectieuses, CHRU de Lille, 59000 Lille, France d Réanimation Ollier et équipe mobile d’infectiologie, CHU Cochin, AP–HP, 75014 Paris, France e Service de néphrologie et transplantation rénale, CHRU de Lille, 59000 Lille, France f Service de biologie clinique, hôpital Foch, 92150 Suresnes, France g Service de maladies infectieuses et tropicales, CHU d’Angers, 49100 Angers, France h Service de médecine interne, hôpital de la Croix Saint-Simon, 75020 Paris, France i Service de médecine, pôle santé Léonard-de-Vinci, 37170 Chambray-lès-Tours, France j Service de médecine interne, maladies infectieuses et immunologie clinique, hôpital Robert-Debré, 51100 Reims, France k Unité de maladies infectieuses et d’immunologie, hôpitaux universitaires Paris Centre, université Paris-Descartes, AP–HP, 75004 Paris, France l Service de réanimation et maladies infectieuses, centre hospitalier Dron, 59200 Tourcoing, France m Service de médecine interne et maladies infectieuses, université de Tours, CHRU Bretonneau, 37044 Tours, France b

a r t i c l e

i n f o

Article history: Received 21 February 2018 Received in revised form 10 April 2018 Accepted 24 June 2019 Available online xxx Keywords: Antibiotics Pharmacokinetics Renal failure

a b s t r a c t Antibiotic prescription in chronic kidney disease patients poses a twofold problem. The appropriate use of antibacterial agents is essential to ensure efficacy and to prevent the emergence of resistance, and dosages should be adapted to the renal function to prevent adverse effects. SiteGPR is a French website for health professionals to help with prescriptions to chronic kidney disease patients. A working group of infectious disease specialists and nephrology pharmacists reviewed the indications, dosing regimens, administration modalities, and dose adjustments of antibiotics marketed in France for patients with renal failure. Data available on the SiteGPR website and detailed in the present article aims to provide an evidence-based update of infectious disease recommendations to health professionals managing patients with chronic kidney disease. © 2019 Elsevier Masson SAS. All rights reserved.

r é s u m é Mots clés : Antibiotiques Insuffisance rénale Pharmacocinétique

La prescription d’antibiotiques chez le patient insuffisant rénal chronique pose un double problème d’optimisation des posologies. Elle doit prendre en compte les posologies des recommandations, afin de garantir l’efficacité et de prévenir l’apparition de résistances, et les adapter à la fonction rénale, pour prévenir la survenue d’effets secondaires indésirables. Un groupe de travail composé d’infectiologues et de pharmaciens en néphrologie a revu les indications, les posologies, les modes d’administration et les adaptations posologiques, chez le patient insuffisant rénal, des antibiotiques à usage systémique présentés sur SiteGPR (outil d’aide à la prescription chez le patient insuffisant rénal). La mise à jour disponible

夽 Part of this work was presented at the Séminaires Universitaires de Néphrologie in February 2018 by BA and MO. ∗ Corresponding author. Service de médecine interne et maladies infectieuses, CHRU Bretonneau, 2, boulevard Tonnellé, 37044 Tours cedex 9, France. E-mail address: [email protected] (A. Lemaignen). https://doi.org/10.1016/j.medmal.2019.06.010 0399-077X/© 2019 Elsevier Masson SAS. All rights reserved.

Please cite this article in press as: Aloy B, et al. Antibiotics and chronic kidney disease: Dose adjustment update for infectious disease clinical practice. Med Mal Infect (2019), https://doi.org/10.1016/j.medmal.2019.06.010

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sur SiteGPR et présentée ici a pour but de fournir une actualisation des recommandations de posologies des antibiotiques aux professionnels de santé en charge des patients insuffisants rénaux, sur la base des ressources bibliographiques disponibles. ´ ´ es. © 2019 Elsevier Masson SAS. Tous droits reserv

1. Introduction Chronic kidney disease (CKD) is a common comorbidity as 8.2% to 13.7% of the French population has a glomerular filtration rate (GFR) < 60 mL/min/1.73 m2 [1,2]. Patients presenting with CKD are particularly vulnerable to infections as the quality of their humoral and cellular immune response is impaired [3]. Infectious diseases are the second leading cause of death in end-stage CKD patients [4]. Thus, antibiotic treatment is common in these patients, and requires special attention. Impairment of renal elimination, absorption, distribution, and metabolism of antibiotic drugs may be observed because of the pathophysiology changes due to renal failure [3]. These changes in the drug pharmacokinetics may lead to their accumulation and toxicity if doses are not adjusted to the renal function, such as neurotoxicity of beta-lactams, renal and otological toxicity of aminoglycosides and glycopeptides, etc. [5,6]. Dosage adaptation can be performed in various ways: • according to the dosing method, i.e. reducing unit doses without changing the administration interval. This method is preferred for “time-dependent” antibiotics to maintain as long as possible the concentrations above the minimum inhibitory concentration (MIC) over 24 hours, depending on the infection severity; • according to the interval method, i.e. maintenance of unit doses and spacing of administrations. This method is preferred for “concentration-dependent” antibiotics, as the maximum concentration (Cmax ) is the main pharmacokinetic parameter correlated with efficacy; • according to a mixed method, i.e. when the dosing method does not achieve sufficient concentrations or when the interval method does not lead to sufficient therapeutic coverage between two administrations. The main objective is to obtain a concentration of antibiotics within the therapeutic range (i.e., effective and non-toxic). This adaptation is all the more necessary as therapeutic drug monitoring is often not easily available in most hospitals, except for aminoglycosides and vancomycin. In routine clinical practice the assessment of renal function should be performed with the CKD-EPI formula for dosing adjustment [7,8]. GFR is obtained in mL/min/1.73 m2 and should be reported to the actual body surface area of the patient and expressed as mL/min. This formula cannot always be used, especially when the body mass index (BMI) is below 18.5 kg/m2 or in patients presenting with acute kidney injury. The less accurate Cockcroft–Gault formula should not be used as it has not been evaluated using current creatinine assay techniques and is not validated in elderly patients or in patients with a BMI lower than 18.5 or higher than 30 kg/m2 . Overall, its use in dosing adjustment is not strongly evidence-based. Empirical dosing adjustment should not be performed, because of a high risk of overdosing or ineffectiveness. Thus, referring to studies specifically performed in CKD patients should be systematic. Information available in the summary of product characteristics (SPC) (EU equivalent of the US Physicians’ Desk Reference) mostly comes from old studies, often based on outdated

doses of antibiotics that are no longer recommended. SiteGPR is a website for health professionals, dealing with medication management in patients presenting with CKD. The proposed dosing adjustments are based on an analysis of recent data available in the literature on pharmacokinetics, drug efficacy and in patients with chronic renal failure. To optimize antibiotic stewardship in these patients, a multidisciplinary working group updated dosing adjustments for antibiotic treatments based on recent literature data and current guidelines in infectious diseases, between September 2016 and May 2017.

2. Methods A request for an update of dosing recommendations for antibiotics on SiteGPR was sent to the French Infectious Disease Society (French acronym SPILF) in September 2016. A working group made of infectious disease specialists was set up and tasked with suggesting an update of indications, administration modalities and dosing regimens for antibiotics presented on SiteGPR. The experts were divided into seven pairs, each responsible for a group of antibiotics. For each drug, French and English guidelines were reviewed. Additional literature analysis by molecule was performed on PubMed for specific indications not considered in the guidelines, particularly with respect to dose adjustment in intensive care settings. The set of proposals was then reviewed by and discussed with the whole working group until a consensus was reached. Antibiotics no longer commercialized in France were notified and no data was added. The recommendations of the working group were then inte® grated by the GPR team (Guide de Prescription et Rein), made of nephrology pharmacists, for each antibiotic. Based on the updates proposed by the working group, the team reviewed dosing adjustment in CKD patients. Preferred literature sources were pharmacokinetic, efficacy, and tolerability multiple dose studies. Selected dosages were those obtained from CKD patients not on dialysis for whom a reliable estimate of GFR was available, and those obtained from chronic dialysis patients whose dosing regimen corresponded to those mentioned in the infectious disease guidelines. SPC and literature reviews were used in the absence of other available sources.

3. Results A total of 101 antibiotics were reviewed by the working group. Specific recommendations, modifications, or additions to legally mandated information were made for 57 molecules (Table 1). The modifications focused on indications, administration modalities, and usual dosing for patients with normal renal function. No update was made for 15 drugs as no recent data was available; the molecules being no longer marketed in France (Table 2). No changes were made to 29 drugs for which recommendations from the SPC were consistent (Table 3). The modifications were posted on the SiteGPR website in May 2017.

Please cite this article in press as: Aloy B, et al. Antibiotics and chronic kidney disease: Dose adjustment update for infectious disease clinical practice. Med Mal Infect (2019), https://doi.org/10.1016/j.medmal.2019.06.010

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Table 1 List of drugs for which recommendations were made by the working group and consequences on dosing adjustment. Liste des médicaments pour lesquels le groupe de travail a émis des recommandations et conséquences sur l’adaptation posologique des médicaments. Antibiotics (INN) Aminoglycosides Amikacin

Gentamicin Tobramycin Cephalosporins Cefaclor

Cefalexin Cefadroxil

Cefamandole Cefazolin

Cefepime

Cefixime

Cefotaxime

Cefoxitin

Cefradine Ceftazidime ± avibactam

Ceftobiprole

Ceftolozane + tazobactam

Recommendations

Dosing adjustment in CKD patients

Depending on clinical severity: 20 to 30 mg/kg as a 30-minute infusion [22–24]

There is no established regimen that ensures both the good efficacy and tolerability of aminoglycosides in case of renal failure. When the prescription of aminoglycosides is clinically required, the unit dosage should not be decreased as aminoglycosides are concentration-dependent antibiotics. A single infusion is most often sufficient. If several infusions are needed, the residual concentration should be monitored and dose administration should be spaced accordingly [25]

Gram-positive cocci infections: 3 to 5 mg/kg Gram-negative bacilli infections: 5 to 8 mg/kg [23] Gram-positive cocci infections: 3 to 5 mg/kg Gram-negative bacilli infections: 5 to 8 mg/kg [23] Indications are limited to tonsillitis due to Streptococcus pyogenes and lower urinary tract infections. Little PK/PD data is available; thus, this oral cephalosporin cannot be recommended for use in other indications [26,27] The use of cefalexin should be avoided because its PK/PD profile is not compatible with oral administration Indications are limited to tonsillitis due to Streptococcus pyogenes and lower urinary tract infections. Cefadroxil is not mentioned in the recent guidelines for urinary tract or upper respiratory tract infections [26,27] Curative treatment: in the absence of recent data, available data on the efficacy of a 3 g/day dosage is limited Mild infections: 60–80 mg/kg as 4 to 6 SIIs or CIVIP after an SII loading dose (one-quarter or one-third of the daily dose) Severe infections: 80 to 100 mg/kg/day as 3 daily infusions or CIVIP after a loading dose of 30 mg/kg over one hour Surgical antibiotic prophylaxis: unit dose (except for obese patients): 2 g [30–34] Mild infections: 4 g/day as 2 infusions Severe infections: 6 g/day as 3 infusions. Prolonged or continuous infusion is associated with a better PK/PD profile [35,36] Effective concentrations cannot be obtained in indications other than urinary tract infections because of the PK/PD profile of cefixime Standard doses: 1–2 g every 8 hours High doses: 100 to 150 mg/kg/day (bone and joint infections) or 200 to 300 mg/kg/day (central nervous system infections) divided into 4 to 6 infusions Continuous infusion is possible in case of severe infections [34,39] Mild infections: 3 to 6 g/day Severe infections or/and MIC > 8 mg/L: 8 g/24 h as a continuous infusion [41] Cefradine is not mentioned in the recent guidelines for urinary tract and respiratory tract infections [26,27,43] Standard doses: 2 g of ceftazidime (± 0.5 g of avibactam) every 8 hours as 2-hour IV infusions Continuous infusion: 6 g/day after a 2-g loading dose High doses: higher doses may be proposed for severe infections, infectious sites with difficult diffusion of antibiotics, or with borderline MICs. In these cases, it is advisable to monitor the drug concentration [44,45] Standard doses: 500 mg as 2-hour IV infusions every 8 hours High doses: 1 g/8 h as prolonged infusions over 4 hours The main pharmacodynamic parameter of efficacy is the amount of time when the concentration is greater than the MIC. In case of infections due to pathogens with a MIC > 4 mg/L, or even in case of a substantial increase in the distribution volume, and/or pneumonia, standard doses may not allow sufficient duration of efficacy A small-scale study showed that higher doses (1 g/12 h or 1 g/8 h) as prolonged infusions over 4 hours are well-tolerated and possibly more effective [47] Standard doses: 1 g ceftolozane/0.5 g tazobactam every 8 hours as a 1-hour infusion High doses: twice higher doses may be proposed for severe infections, in case of borderline MICs, or infectious sites with difficult diffusion of antibiotics. Good stability as prolonged infusions over 4 hours was reported in a case report [49,50]

Dosing adjustment if GFR < 30 mL/min [28]

Dosing adjustment if GFR < 60 mL/min [28] Dosing adjustment if GFR < 40 mL/min [29]

Dosing adjustment if GFR < 50 mL/min, unless prophylactic treatment as a single dose Dosing adjustment if GFR < 60 mL/min, unless prophylactic treatment as a single dose A loading dose should be administered to patients with CKD or on dialysis Tolerability should be monitored (risk of metabolic encephalopathy at high doses and increased risk of digestive bleeding) [10] Dosing adjustment if GFR < 50 mL/min Neurological tolerability should be monitored [37] Dosing adjustment if GFR < 20 mL/min [38]

Dosing adjustment if GFR < 60 mL/min [28]. Limited experience with high doses in CKD patients Neurological tolerability should be closely monitored [40]

Dosing adjustment if GFR < 50 mL/min [42] Limited experience with high doses in CKD patients Dosing adjustment if GFR < 30 mL/min [28] Dosing adjustment if GFR < 50 mL/min, keeping the 4/1 ratio of ceftazidime/avibactam when avibactam is prescribed [46]

Dosing adjustment if GFR < 50 mL/min [48]

Dosing adjustment if GFR < 50 mL/min, maintaining the 2/1 ratio of ceftolozane/tazobactam [51]

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4 Table 1 (Continued) Antibiotics (INN) Cefuroxime

Ceftriaxone

Recommendations

Dosing adjustment in CKD patients

IV or intramuscular: 2 to 6 g/day depending on the infection severity Cefuroxime is not mentioned in the guidelines for urinary tract or ENT infections Standard doses: 1 to 2 g/day as 1 daily infusion. Can be used by the SC and IM routes in case of vascular access difficulty High doses: 75–100 mg/kg/day as 1 or 2 infusions for central nervous system infections [39]

Dosing adjustment if GFR < 30 mL/min [28]

MLS (macrolides/lincosamides/synergistin drugs) Lincomycin This molecule is no longer mentioned in the recent French guidelines. Clindamycin should be preferred [52,53] Clindamycin Curative treatment: 600 mg 3 to 4 times a day [32,54] Clarithromycin Prophylaxis: 500 mg/24 hours Standard curative doses: 500 mg twice daily High curative doses: 1000 mg twice daily Clarithromycin is a CYP3A4 inhibitor. Potential interactions should be taken into account Erythromycin Oral route: 1 g every 8 to 12 hours, before meals IV: 1 g every 8 to 12 hours Erythromycin is a potent CYP3A4 inhibitor. Because of potential interactions with many drugs, of potentially severe adverse effects, the use of other macrolides is preferred, except in patients presenting with gastroparesis Oral combination: 1.5 MIU of spiramycin and 125 mg of metronidazole Spi3 times a day ramycin + metronidazole Telithromycin Because of potentially severe adverse effects and potential interactions with many drugs, the use of other macrolides is preferred Pristinamycin Standard doses: 1 g 3 times a day High doses: 4 g per day as 4 intakes Quinolones Indications are limited to acute or recurrent uncomplicated cystitis in Pipemidic acid the summary of product characteristics. However, it is no longer mentioned in the recent guidelines for urinary tract infections [27,55] Ciprofloxacin Single oral dose: 500 mg, only in the 3rd line treatment of uncomplicated acute cystitis Multiple oral doses: depending on the indication: 500 mg every 8 to 12 hours or 750 mg every 8 to 12 hours IV treatment: 400 mg every 8 to 12 hours Pefloxacin Pefloxacin is rarely used. It is no longer mentioned in the recent guidelines for urinary tract infections [27] Single oral dose: 400 mg as a single dose. Only in the 3rd line Ofloxacin treatment of uncomplicated acute cystitis Multiple oral doses: 200 mg every 8 to 12 hours or 400 mg every 12 hours [57] Oxazolidinones Standard doses: 600 mg/12 hours Linezolid High doses: 600 mg every 8 hours, used in case of severe infections in the intensive care unit [58] Imidazoles Standard doses: 500 mg 3 times a day, IV or oral route Metronidazole High doses: 750 mg 3 times daily, IV C. difficile infections: 250 mg 4 times daily, oral route Cyclines Standard doses: 100 mg as a loading dose, and then 50 mg/12 h as a Tigecycline 1-hour IV infusion High doses: 200 mg as a loading dose, and then 100 mg/12 h as a 1-hour IV infusion Tigecycline should be kept for multidrug-resistant infections in the absence of alternatives Risk of resistance acquisition: the drug should be used as part of a combination therapy [60–64] Glycopeptides Standard doses: 6 mg/kg/12 hours as 3 infusions, and then 6 mg/kg Teicoplanin once daily High doses: 12 mg/kg/12 hours as 3 to 5 infusions, and then 12 mg/kg once daily Concentration target: ≥ 20 to 30 mg/L Vancomycin Surgical prophylaxis: single dose of 15 mg/kg as a one-hour IV infusion Curative treatment: CIVIP should be preferred: loading dose of 30 mg/kg as a 2-hour infusion, and then 20 to 30 mg/kg/day for mild infections or 30 to 40 mg/kg/day for severe infections Doses should be adapted to the MIC of the microorganism and residual concentrations [30,66,67]

Significantly increased half-life when GFR < 30 mL/min but risk of ineffectiveness with adapted doses [28] Good tolerability data has been reported in patients with CKD and/or on hemodialysis following administration of 2 g every 12 hours for Enterococcus faecalis endocarditis [19] Tolerability of higher doses is not documented in CKD patients Neurological toxicity should be closely monitored Dosing adjustment if GFR < 60 mL/min [28] No need for dosing adjustment [28] Dosing adjustment if GFR < 30 mL/min [28]

Dosing adjustment if GFR < 15 mL/min [28]

Metronidazole: dosing adjustment if GFR < 15 mL/min; spiramycin: no need for dosing adjustment [28] Dosing adjustment if GFR < 30 mL/min [28] PK, efficacy, and tolerability data is not available in CKD patients No need for dosing adjustment [28]

Single dose: no need for dosing adjustment Multiple doses: dosing adjustment if GFR < 60 mL/min by spacing out the administration interval [56]

Single dose: no need for dosing adjustment Multiple doses: discordant data in CKD patients Single dose: no need for dosing adjustment Multiple doses: dosing adjustment if GFR < 50 mL/min by spacing out the administration interval

Dosing adjustment if GFR < 30 mL/min More frequent and more severe thrombocytopenia cases have been reported in patients with stage 4 and 5 renal failure [59] Dosing adjustment if GFR < 15 mL/min [28]

No need for dosing adjustment [65]

Loading dose, and then dosing adjustment if GFR < 60 mL/min depending on steady state plasma concentrations [28]

Loading dose, and then dosing adjustment depending on steady state plasma concentrations [68]

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B. Aloy et al. / Médecine et maladies infectieuses xxx (2019) xxx–xxx Table 1 (Continued) Antibiotics (INN) Penicillins Cloxacillin

Amoxicillin

Recommendations

Dosing adjustment in CKD patients

Oral route: 50 mg/kg/day as 3 intakes, without exceeding 4 g/day The limitation at 4 g/day results from the saturation of the absorption mechanism of the molecule. Only mild infections may be treated with this low dosage IV route: 100 to 200 mg/kg/day depending on the infection severity, divided into 4 to 6 60-minute IV infusions, or continuous infusion [34,69]

Conflicting data. Pharmacokinetic studies indicate that it is not necessary to adjust the dosage of cloxacillin, irrespective of the level of renal function, because of extra-renal elimination mechanisms (mainly fecal) that compensate for the decreased urine elimination in CKD patients. However, recommendations from the ANSM are based on pharmacovigilance data; they recommend reducing the cloxacillin dosage by 50% in patients with creatinine clearance < 30 mL/min [70] Dosing adjustment if GFR < 30 mL/min. A loading dose should be administered [28]

Benzylpenicillin (penicillin G)

Depending on the indications: 1 g every 8 to 12 hours; 2 g every 8 hours; 100 mg/kg/day as 4 infusions; 200 mg/kg/day as 4 to 6 infusions [39,71–73] A risk of crystalluria is associated with doses > 8 g/24 h. This risk could be limited with a continuous administration or with fractionating doses into 5 or 6 intakes and appropriate hydration Standard doses: 1 or 2 g every 8 hours, oral or IV routes (in grams of amoxicillin) If higher doses of amoxicillin are needed, the additional administration of amoxicillin alone can be performed. As a reminder, the maximum acceptable doses of clavulanic acid are 200 mg/infusion and 1200 mg/day IM route: no recent data IV route: 3 g every 6 to 8 hours (in grams of ampicillin) This molecule is not extensively used in France, and it is kept for severe infections due to Acinetobacter spp. Ampicillin alone is no longer marketed in France. Doses similar to those of amoxicillin may be used [74] Standard doses: 12 to 24 MIU/day divided into 6 infusions per day or by continuous IV infusion [75,76]

Phenoxymethylpenicillin (penicillin V) Benzathine benzylpenicillin Oxacillin

Prophylaxis: 1 MIU every 8 hours Exclusive prophylactic indication This molecule should no longer be used as a curative treatment Prophylaxis: 1.2 MIU/month or every 3 weeks Curative treatment: 2.4 MIU/week [75,76] 100 to 200 mg/kg/day divided into 4 to 6 infusions [39,71–73]

Amoxicillin + clavulanic acid

Ampicillin ± sulbactam

Pivmecillinam

400 mg 2 or 3 times daily

Standard doses: 4 g every 6 to 8 hours (in grams of piperacillin) Piperacillin ± tazobactam High doses: higher doses may be suggested for severe infections, infectious sites with difficult diffusion of antibiotics, or when the MIC is borderline. In these cases, prolonged or continuous infusions should be preferred Standard doses: 250 mg/kg/day of ticarcillin divided into 3 to 6 Ticarcillin ± clavulanic infusions acid High doses: doses ranging from 15 to 20 g and as high as 25 g per day can be administered depending on the infection severity As a reminder, the maximum acceptable doses of clavulanic acid are 200 mg/infusion and 1200 mg/day Carbapenems Standard doses: 1 g per day Ertapenem High doses: doses of 1 g twice daily should be suggested for patients presenting with severe or difficult-to-treat infections [79,80] Meropenem Standard doses: 1 or 2 g three times daily depending on the weight and the type of infection High doses: doses  6 g/day may be considered for the most severe infections, infectious sites with difficult diffusion of antibiotics, or to adapt to high MICs. In these cases, drug concentrations should be monitored [80] Other drugs Standard doses: 3 to 6 g/day 3 times daily after a loading dose of 2 g Aztreonam High doses: in case of severe infections, Enterobacteriaceae infections with MICs > 4 mg/L, or Pseudomonas aeruginosa infections: 8 g/day as 4 infusions or continuous infusion Trimethoprim Curative treatment: cystitis: 300 mg once daily Prophylaxis: recurrent cystitis: 100 mg/day [27] Antibacterial activity: 800/160 mg 2 or 3 times daily, IV or oral Trimethoprim + Sulfamethoxazole Antiparasitic activity: IV, 4 to 15 ampoules (400/80 mg)/day or up to 80–100 mg/kg/day divided into 3 or 4 intakes (based on sulfamethoxazole doses) Prophylaxis: 400/80 mg/day or 800/160 mg 3 times a week [27,84]

Dosing adjustment based on amoxicillin only if GFR < 30 mL/min A loading dose should be administered [28]

Dosing adjustment based on ampicillin only if GFR < 30 mL/min A loading dose should be administered [28]

Dosing adjustment if GFR < 50 mL/min As for the administration of a high dose of benzylpenicillin in CKD patients undergoing hemodialysis, a daily dose  10 MIU is not recommended because of the risk of seizures [77] No need for dosing adjustment if GFR > 15 mL/min No data available if GFR < 15 mL/min [28] Dosing adjustment if GFR < 50 mL/min [10] No need for dosing adjustment but neurological tolerability should be monitored [70] Dosing adjustment if GFR < 30 mL/min A loading dose should be administered [10] Dosing adjustment if GFR < 40 mL/min [78]

Dosing adjustment on the basis of ticarcillin if GFR < 60 mL/min [28] Limited experience of high doses in CKD patients

Dosing adjustment if GFR < 30 mL/min. Risk of neurological toxicity (seizures), even with adapted doses [81] Dosing adjustment if GFR < 50 mL/min [82]

Dosing adjustment if GFR < 30 mL/min, maintaining the administration interval (“dosing method”). A loading dose should be administered irrespective of the renal function [83] Dosing adjustment if GFR < 30 mL/min except for a single dose treatment Dosing adjustment if GFR < 30 mL/min, unless single dose treatment Urinary tract infections: risk of ineffectiveness if GFR < 50 mL/min (sulfamethoxazole urine concentrations too low) [9,28]

Please cite this article in press as: Aloy B, et al. Antibiotics and chronic kidney disease: Dose adjustment update for infectious disease clinical practice. Med Mal Infect (2019), https://doi.org/10.1016/j.medmal.2019.06.010

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6 Table 1 (Continued) Antibiotics (INN) Daptomycin

Fosfomycintrometamol

Sulfamethizole

Recommendations

Dosing adjustment in CKD patients

Mild infections: 6 to 8 mg/kg/24 h Severe infections: 10 to 12 mg/kg/24 h The choice of the dose/kg depends on the MIC of the microorganism (≤ 0.25 mg/L vs. unknown or > 0.25 mg/L) and on the infection severity [11–13] Standard doses: 3 g as a single intake In the absence of alternatives, 3 administrations 2–3 days apart may be used for infections at risk of complication [27]

Dosing adjustment if GFR < 30 mL/min [85]

Indications in the Summary of product characteristics are limited to female uncomplicated acute cystitis due to susceptible Escherichia coli. However, the molecule is not mentioned in the recent guidelines for urinary tract infections [27]

Single dose: no need for dosing adjustment Multiple doses: accumulation risk Risk of ineffectiveness if GFR < 15 mL/min (poor excretion of the drug in the urine) Lack of PK, efficacy, or tolerability data in CKD patients Risk of ineffectiveness if GFR < 30 mL/min (poor excretion of the drug in the urine)

Recommendations: modification or addition compared with the summary of product characteristics, dosing regimens in patients with normal renal function; INN: International nonproprietary name; CKD: chronic kidney disease; GFR: glomerular filtration rate; PK/PD: pharmacokinetics/pharmacodynamics; SII: slow intravenous infusion; CIVIP: continuous intravenous infusion by pump; MIU: millions of international units; ANSM: French Agency for the Safety of Health Products.

Table 2 Drugs no longer marketed in France, for which no recommendations could be drafted in the absence of recent data available (n = 15). Médicaments n’étant plus commercialisés en France et n’ayant pu faire l’objet de recommandations en l’absence de données récentes disponibles (n = 15). Nalidixic acid, bacampicillin, biclinocillin, cefalotin, cefapirin, cefatrizin, cefpirome, cefsulodine, dirithromycin, enoxacin, isepamicin, mezlocillin, netilmicin, quinupristin-dalfopristin, spectinomycin

Table 3 Drugs without any updates made to the recommendations of the summary of product characteristics (n = 29). Médicaments n’ayant pas entraîné de recommandations différentes de celles présentes dans les résumés des caractéristiques du produit (n = 29). Fusidic acid, azithromycin, cefotiam, cefpodoxime, ceftaroline, colistin, doxycycline, flumequine, fosfomycin, imipenem + cilastatin, josamycin, lomefloxacin, levofloxacin, lymecycline, metacycline, midecamycin, minocycline, moxifloxacin, nitrofurantoin, norfloxacin, ornidazole, roxithromycin, spiramycin, streptomycin, sulfadiazine, tedizolid, temocillin, thiamphenicol, tinidazole

4. Discussion The clinical use of a medication does not always reflect its marketing authorization application. This is particularly true for anti-infective agents, for which multiple considerations must be taken into account: the accessibility of the infected site (tonsil in tonsillitis versus vegetation in infective endocarditis or spinal fluid in meningitis, etc.), the infection severity, and the evolution of microbial resistance and epidemiology. The SPCs advise health professionals to refer to official guidelines for the appropriate use of antibacterial drugs, and dosages usually prescribed for severe infections are often higher than those mentioned in the marketing authorization. The application of infectious disease recommendations in patients with CKD is limited by the lack and poor quality of available data. It is best to refer to studies conducted under prescribing conditions corresponding to infectious disease guidelines (dosage, indication, mode and route of administration), with pharmacokinetic parameters, efficacy, and tolerability observed in patients with varying degrees of renal function. Most antibiotics have been marketed for many years. Studies in patients with CKD are therefore often old and have not been carried out with current prescribing regimens. The indication and the choice of molecule, according to each disease, can be applied to CKD patients. However, renal failure may modify the activity of some antibiotic drugs, especially when

treating urinary tract infections. Indeed, their treatment requires adequate concentrations of antibiotics in kidneys and urine, which can decrease and become insufficient with the reduction of GFR. Sulfamethoxazole or nitrofurantoin monotherapy should for instance be avoided for the treatment of urinary tract infections in case of CKD, as their concentration in urine is too low [9]. When the dosing regimen is changed in patients with normal kidney function, adjusting these recommendations to CKD patients is more complex. Most often, doses are increased compared with those mentioned in the SPC. For instance, doses proposed in the SPC for daptomycin for patients with normal renal function range from 4 to 6 mg/kg/day with 50% reduction of doses when the GFR lowers below 30 mL/min [10]. However, these doses are known to be largely inadequate regardless of the infection severity. Dosing regimen ranging from 6–8 mg/kg/day to 10–12 mg/kg/day are currently recommended in most guidelines [11–13]. In CKD patients a simple rule of three could theoretically be applied, i.e. reducing these higher doses by 50% when the GFR is < 30 mL/min. However in practice, only clinical data obtained from these specific patients can ensure a safe and effective use. Indeed, the pharmacokinetics of drugs is not linear. Saturable mechanisms (transport, metabolism) are involved. For a same level of renal function, an effective and well-tolerated antibiotic at a reduced dosage in a given indication may become toxic and/or ineffective at a higher dosage in another indication, although using the same dose-reduction coefficient. Studies of daptomycin in CKD and dialysis patients have shown that administering the drug at a dose of 10 mg/kg every 48 hours was a good choice in these patients [14,15]. Some antibiotics such as tedizolid do not require dose adjustment in CKD patients as no significant pharmacokinetic changes have been observed in these patients [16]. For other molecules, such as doxycycline, the decreased renal clearance observed in CKD patients is offset by an increase in extra-renal clearance [17]. Other antibiotics, such as ceftriaxone, are used in CKD patients without adjusting the dosage, at doses up to 4 g/day. Despite the observed pharmacokinetic changes in CKD patients, the benefit/risk ratio remains favorable to overdosing. Dosing adjustment to the renal function carries a high risk of ineffectiveness, although overdosing is relatively well-tolerated [18,19]. However, if no adjustment is necessary at a given dosage, it may be necessary to do so for higher dosage, otherwise overdosing may occur. For ceftriaxone, dosage of 75 to 100 mg/kg/day as 1 or 2 infusions are recommended for central nervous system infections, but no data is available in renal disease patients at such dosages. Given the severity of the infection and in the absence of a therapeutic alternative, empirical full-dose administration should be considered in those patients, closely monitoring the occurrence of adverse

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effects related to overdosing. Several cases of neurological toxicity have been reported after ceftriaxone administration in patients with CKD and dialysis at doses ranging from 1 to 4 grams per day [20,21]. CKD requires pharmacological therapeutic follow-up. Measurement of plasma levels is justified for all antibiotics, and particularly for those with a narrow therapeutic index, to assess their effectiveness (peak concentration for concentration-dependent antibiotics, residual concentration for time-dependent ones) and their toxicity (residual concentration). Although rapidly developing in large healthcare facilities, therapeutic drug monitoring remains elsewhere insufficient and usually only focuses on a few molecules (glycopeptides, aminoglycosides, ceftazidime, etc.). Non-nephrotoxic antibiotics without any dose adjustment required should be favored in CKD patients. The infection site and severity, bacteriological documentation, and ecological impact of the antibiotic should also be taken into consideration. Failing this, either an antibiotic with a known dose adjustment, which efficacy and safety have been evaluated in appropriate studies, or an antibiotic with a broad therapeutic index and an easy-to-perform monitoring of pharmacokinetic and pharmacodynamic parameters, should be selected. Empirical prescriptions should be avoided as much as possible to avoid the potentially serious consequences of under- or overdosing. These recommendations should be considered as a basis for prescription. They should be adapted according to the clinical presentation of the patient, taking into consideration any other comorbidities (particularly obesity). In all cases, effective antibiotic therapy should be reevaluated within 48 to 72 hours depending on clinical and laboratory findings, and tolerability should be closely monitored. Disclosure of interest The authors declare that they have no competing interest. Funding No funding was received for this article written with the help of the French infectious disease society (French acronym SPILF) and the SiteGPR group (http://sitegpr.com/fr/qui-sommes-nous/). Contribution of authors SA coordinated the working group. BA and AL wrote the first draft of the article. BA, VLV, AB, PB, EF, AF, RG, MG, PL, RM, VM, MO, JR, DS, SA, and AL contributed to the literature analysis, the update of antibiotic prescription criteria, the revision of the article, and the approval of the final version. The modifications were posted on the SiteGPR website in May 2017. References [1] Bongard V, Dallongeville J, Arveiler D, Ruidavets J-B, Cottel D, Wagner A, et al. [Assessment and characteristics of chronic renal insufficiency in France]. Ann Cardiol Angeiol 2012;61(4):239–44. [2] Breton G, Froissart M, Janus N, Launay-Vacher V, Berr C, Tzourio C, et al. Inappropriate drug use and mortality in community-dwelling elderly with impaired kidney function – the Three-City population-based study. Nephrol Dial Transplant 2011;26(9):2852–9. [3] Johnson DW, Fleming SJ. The use of vaccines in renal failure. Clin Pharmacokinet 1992;22(6):434–46. [4] Agence de la biomédecine. Rapport REIN; 2015 [Accessed on October 25, 2017] https://www.agence-biomedecine.fr/IMG/pdf/rapport rein 2015.pdf. [5] Deshayes S, Coquerel A, Verdon R. Neurological adverse effects attributable to ␤-lactam antibiotics: a literature review. Drug Saf 2017;40(12):1171–98. [6] Manian FA, Stone WJ, Alford RH. Adverse antibiotic effects associated with renal insufficiency. Rev Infect Dis 1990;12(2):236–49.

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