Incidence, associated factors, and effect on renal function of amoxicillin crystalluria in patients receiving high doses of intravenous amoxicillin (The CRISTAMOX Study): A cohort study

Demotier, Sophie; Limelette, Anne; Charmillon, Alexandre; Baux, Elisabeth; Parent, Xavier; Mestrallet, S.; Pavel, S.; Servettaz, Amélie; Dramé, Moustapha; Muggeo, Anaëlle; Wynckel, Alain; Gozalo, Claire; Taam, Malak Abou; Fillion, Anne; Jaussaud, R.; Trenque, Thierry; Piroth, Lionel; Bani-Sadr, F.; Hentzien, Maxime

doi:10.1016/j.eclinm.2022.101340

Cited by 4 publications

(5 citation statements)

References 24 publications

(31 reference statements)

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“…Crystal nephropathy, which is a result of antimicrobial precipitation and crystallization in the renal tubuli has been documented with high amoxicillin concentrations, but is assumed to be very rare and a specific drug level linked to crystallization has not been defined [ 55 , 56 ].…”

Section: Introducing the ‘Maximum Tolerable Dose’ To Overcome The Abo...mentioning

confidence: 99%

Why We May Need Higher Doses of Beta-Lactam Antibiotics: Introducing the ‘Maximum Tolerable Dose’

2022

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The surge in antimicrobial resistance and the limited availability of new antimicrobial drugs has fueled the interest in optimizing antibiotic dosing. An ideal dosing regimen leads to maximal bacterial cell kill, whilst minimizing the risk of toxicity or antimicrobial resistance. For beta-lactam antibiotics specifically, PK/PD-based considerations have led to the widespread adoption of prolonged infusion. The rationale behind prolonged infusion is increasing the percentage of time the beta-lactam antibiotic concentration remains above the minimal inhibitory concentration (%fT>MIC). The ultimate goal of prolonged infusion of beta-lactam antibiotics is to improve the outcome of infectious diseases. However, merely increasing target attainment (or the %fT>MIC) is unlikely to lead to improved clinical outcome for several reasons. First, the PK/PD index and target are dynamic entities. Changing the PK (as is the case if prolonged instead of intermittent infusion is used) will result in different PK/PD targets and even PK/PD indices necessary to obtain the same level of bacterial cell kill. Second, the minimal inhibitory concentration is not a good denominator to describe either the emergence of resistance or toxicity. Therefore, we believe a different approach to antibiotic dosing is necessary. In this perspective, we introduce the concept of the maximum tolerable dose (MTD). This MTD is the highest dose of an antimicrobial drug deemed safe for the patient. The goal of the MTD is to maximize bacterial cell kill and minimize the risk of antimicrobial resistance and toxicity. Unfortunately, data about what beta-lactam antibiotic levels are associated with toxicity and how beta-lactam antibiotic toxicity should be measured are limited. This perspective is, therefore, a plea to invest in research aimed at deciphering the dose–response relationship between beta-lactam antibiotic drug concentrations and toxicity. In this regard, we provide a theoretical approach of how increasing uremic toxin concentrations could be used as a quantifiable marker of beta-lactam antibiotic toxicity.

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Section: Introducing the ‘Maximum Tolerable Dose’ To Overcome The Abo...mentioning

confidence: 99%

Why We May Need Higher Doses of Beta-Lactam Antibiotics: Introducing the ‘Maximum Tolerable Dose’

2022

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“…First, it is important to acknowledge that our study design is retrospective, which poses inherent limitations. A prospective study, similar to those conducted for Amoxicillin, would provide more robust evidence 38 , 39 . This type of study would involve systematically conducting crystalluria assessments on all hospitalized patients receiving therapeutic doses of SMX, allowing for the observation of positive crystalluria and the early characterization of patients who develop acute kidney injury.…”

Section: Discussionmentioning

confidence: 95%

“…NASM crystals may therefore be observed in urine in the absence of clinically evident kidney lesions. Further prospective studies are required to characterize whether NASM-positive crystalluria is an independent risk factor for AKI, as recently evidenced for amoxicillin 38 , 39 . One may hypothesize that intermittent and sparse crystals may be less toxic for kidney tubule than a huge number of crystals: the number of crystals in urine and the global crystalline volume should be assessed in future studies.…”

Section: Discussionmentioning

confidence: 96%

Sulfamethoxazole-induced crystal nephropathy: characterization and prognosis in a case series

Azencot,

Saint-Jacques,

Haymann

et al. 2024

Sci Rep

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Cotrimoxazole (Trimethoprim/Sulfamethoxazole-SMX) is frequently used in critically ill and immunocompromised patients. SMX is converted to N-acetyl-sulfamethoxazole (NASM) and excreted by the kidneys. NASM may form crystals in urine, especially in acid urine, that may induce a crystalline nephropathy. However, the imputability of crystals in acute kidney injury (AKI) has not been proven. We aimed to assess whether NASM crystals may promote AKI and to investigate risk factors associated with NASM crystalline nephropathy. Patients from Ile-de-France, France who developed AKI under SMX treatment introduced during hospitalization and had a crystalluria positive for NASM crystals were selected. Patients with excessive preanalytical delay for crystalluria or missing data regarding SMX treatment were excluded. We used the Naranjo score to assess the causal relationship between SMX and the development of AKI in patients with positive NASM crystalluria. Fourteen patients were included. SMX was the probable cause of AKI for 11 patients and a possible cause for 3 patients according to Naranjo score. Patients were exposed to high doses of SMX (but within recommended ranges), and most of them had a preexisting chronic kidney disease and were hypoalbuminemic. Urine pH was mildly acid (median 5.9). AKI occured more rapidly than expected after introduction of SMX (median 4 days) and recovered rapidly after drug discontinuation in most, but not all, cases. SMX is a probable cause of crystalline nephropathy. Monitoring of crystalluria in patients exposed to SMX may be of interest to prevent the development of crystalline nephropathy. Approval number of the study: BPD-2018-DIAG-008.

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“…For instance, amoxicillin crystals precipitate frequently in urine when high amounts of amoxicillin are prescribed to patients affected by meningitis, endocarditis or osteitis. Crystals form aggregates of needles with a brush aspect (Figure 7C) [29,30]. Sulfamethoxazole crystals are also frequently observed and may present similar features with dihydrate uric acid crystals, but their polarization profile is more homogeneous and they may also be extremely pleiomorphic (Figure 7D) [31].…”

Section: Drug-induced Crystalsmentioning

confidence: 99%

“…Nevertheless, the rapid recovery of renal function after drug withdrawal suggests that the drug was actually toxic for renal tubules. Moreover, recent studies dedicated to amoxicillin crystalluria evidenced that the presence of crystals predicts prospectively the onset of acute renal failure [29,30].…”

Section: Drug-induced Crystalsmentioning

confidence: 99%

Description of Stone Morphology and Crystalluria Improve Diagnosis and Care of Kidney Stone Formers

2022

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Stone analysis by physical methods is critical to determine their chemical nature and to diagnose the underlying conditions affecting kidney stone formers. This analysis should be completed by a morphologic examination of stone surface and section, leading to the diagnosis of anatomical or metabolic disorders and of specific diseases. Crystalluria study, the analysis of urine crystals, provides complementary information and is extremely useful for both diagnosis and patient follow-up. This review describes briefly how these techniques may be used and in which conditions stone morphology and urine crystal description are particularly relevant for patients medical care.

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Incidence, associated factors, and effect on renal function of amoxicillin crystalluria in patients receiving high doses of intravenous amoxicillin (The CRISTAMOX Study): A cohort study

Cited by 4 publications

References 24 publications

Why We May Need Higher Doses of Beta-Lactam Antibiotics: Introducing the ‘Maximum Tolerable Dose’

Why We May Need Higher Doses of Beta-Lactam Antibiotics: Introducing the ‘Maximum Tolerable Dose’

Sulfamethoxazole-induced crystal nephropathy: characterization and prognosis in a case series

Description of Stone Morphology and Crystalluria Improve Diagnosis and Care of Kidney Stone Formers

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