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Review and Acid-Base Disorders Triggered by Aminoglycoside or Colistin Therapy: A Systematic Review

Martin Scoglio 1,* , Gabriel Bronz 1, Pietro O. Rinoldi 1,2, Pietro B. Faré 3,Céline Betti 1,2, Mario G. Bianchetti 1, Giacomo D. Simonetti 1,2, Viola Gennaro 1, Samuele Renzi 4, Sebastiano A. G. Lava 5 and Gregorio P. Milani 2,6,7

1 Faculty of Biomedicine, Università della Svizzera Italiana, 6900 Lugano, Switzerland; [email protected] (G.B.); [email protected] (P.O.R.); [email protected] (C.B.); [email protected] (M.G.B.); [email protected] (G.D.S.); [email protected] (V.G.) 2 Department of Pediatrics, Pediatric Institute of Southern Switzerland, Ospedale San Giovanni, Ente Ospedaliero Cantonale, 6500 Bellinzona, Switzerland; [email protected] 3 Department of Internal , Ospedale La Carità, Ente Ospedaliero Cantonale, 6600 Locarno, Switzerland; [email protected] 4 Division of Hematology and Oncology, The Hospital for Sick Children, Toronto, ON M5G 1X8, Canada; [email protected] 5 Pediatric Unit, Department of Pediatrics, Centre Hospitalier Universitaire Vaudois, and University of Lausanne, 1011 Lausanne, Switzerland; [email protected] 6 Pediatric Unit, Fondazione IRCCS Ca’ Granda Ospedale Maggiore Policlinico, 20122 Milan, Italy 7 Department of Clinical Sciences and Community Health, Università degli Studi di Milano, 20122 Milan, Italy  * Correspondence: [email protected] 

Citation: Scoglio, M.; Bronz, G.; Abstract: Aminoglycoside or colistin therapy may alter the renal tubular function without decreasing Rinoldi, P.O.; Faré, P.B.; Betti, C.; the glomerular filtration rate. This association has never been extensively investigated. We conducted Bianchetti, M.G.; Simonetti, G.D.; a systematic review of the literature following the Preferred Reporting Items for Systematic Reviews Gennaro, V.; Renzi, S.; Lava, S.A.G.; and Meta-Analyses recommendations. Databases searched included United States National Library et al. Electrolyte and Acid-Base of Medicine, Excerpta Medica, and Web of Science. For the final analysis, we evaluated 46 reports, Disorders Triggered by published after 1960, describing 82 cases. A total of 286 electrolyte and acid-base disorders were Aminoglycoside or Colistin Therapy: reported. Hypomagnesemia, , and were reported in more than three A Systematic Review. Antibiotics 2021, 10, 140. https://doi.org/10.3390/ quarter of cases. Further disorders were, in decreasing order of frequency, metabolic , antibiotics10020140 , , hypouricemia, , and . Six electrolyte and acid-base disorders were reported in seven cases, five in 12 cases, four in 16 cases, Academic Editors: three in 31 cases, two in 11 cases, and one in five cases. Laboratory features consistent with a loop Patricia Agudelo-Romero and of Henle/distal tubular dysfunction were noted in 56 (68%), with a proximal tubular dysfunction Jose Caparros-Martin in three (3.7%), and with a mixed dysfunction in five (6.1%) cases. The laboratory abnormality was Received: 30 December 2020 unclassified in the remaining 18 (22%) cases. Treatment with aminoglycosides or colistin may trigger Accepted: 27 January 2021 a proximal tubular or, more frequently, a loop of Henle/distal tubular dysfunction. Published: 1 February 2021 Keywords: dyselectrolytemia; aminoglycosides; colistin; hypomagnesemia; hypokalemia; hypocalcemia Publisher’s Note: MDPI stays neutral with regard to jurisdictional claims in published maps and institutional affil- iations. 1. Introduction Parenteral aminoglycoside antimicrobials are often prescribed for the treatment of infections caused by mycobacteria, Neisseria gonorrhoeae, and protozoa [1,2]. However, the most common application of these antimicrobials is for infections caused by aerobic Copyright: © 2021 by the authors. Gram-negative bacteria [1]. Since many patients affected by cystic fibrosis have chronic Licensee MDPI, Basel, Switzerland. pulmonary infection with Pseudomonas aeruginosa, many cystic fibrosis patients receive This article is an open access article frequent and prolonged courses of these antimicrobials [2]. distributed under the terms and ≥ conditions of the Creative Commons A mild renal impairment that is almost always reversible occurs in 10% of subjects re- Attribution (CC BY) license (https:// ceiving an aminoglycoside for a prolonged period [1]. On the other hand, the glycopeptide creativecommons.org/licenses/by/ antibiotic colistin, which is used parenterally for infections caused by multi-drug resistant 4.0/). Gram-negative bacteria, possesses a nephrotoxicity similar to that of aminoglycosides [3].

Antibiotics 2021, 10, 140. https://doi.org/10.3390/antibiotics10020140 https://www.mdpi.com/journal/antibiotics Antibiotics 2021, 10, x FOR PEER REVIEW 2 of 9

A mild renal impairment that is almost always reversible occurs in ≥10% of subjects receiving an aminoglycoside for a prolonged period [1]. On the other hand, the glycopep- tide antibiotic colistin, which is used parenterally for infections caused by multi-drug re- Antibiotics 2021, 10, 140 2 of 9 sistant Gram-negative bacteria, possesses a nephrotoxicity similar to that of aminoglyco- sides [3]. It has been known for about 70 years that aminoglycoside therapy may sporadically alter theIt renal has been tubular known function for about without 70 years decreasing that aminoglycoside the glomerular therapy filtration may rate sporadically [4]. Since thisalter association the renal has tubular never function been extensively without decreasing investigated, the glomerular we performed filtration a systematic rate [4]. Sincere- viewthis of association the published has never literature. been extensivelyThe purpose investigated, of this review we is performed to document a systematic the pattern review of electrolyteof the published and acid-base literature. disorder The and purpose the time of of this resolution review isfollowing to document aminoglycoside the pattern or of colistinelectrolyte therapy. and acid-base disorder and the time of resolution following aminoglycoside or colistin therapy. 2. Results 2. Results 2.1. Search Results—Completeness of Reporting 2.1. Search Results—Completeness of Reporting The literature search process is summarized in Figure 1. For the final analysis, we The literature search process is summarized in Figure1. For the final analysis, we evaluated 46 reports [5–50] published between 1961 and 2020 in English (N = 45) and evaluated 46 reports [5–50] published between 1961 and 2020 in English (N = 45) and Spanish (N = 1). They had been reported from the following countries: United States of Spanish (N = 1). They had been reported from the following countries: United States of AmericaAmerica (N (N = 12), = 12), India India (N (N = 8), = 8), United United Kingdo Kingdomm (N (N = 7), = 7), Turkey Turkey (N (N = 4), = 4), Ireland Ireland (N (N = 3), = 3), Greece,Greece, Israel, Israel, Taiwan Taiwan (N (N = =2), 2), Australia, Australia, Be Belgium,lgium, Canada, Canada, Croatia, Croatia, Paraguay, Paraguay, and and Spain Spain (N(N = 1). = 1). A total A total of of82 82cases cases were were identified identified am amongong the the articles articles reviewed, reviewed, including including 15 15 cystic cystic fibrosisfibrosis patients patients (nine (nine females females and and six six males males 15 15 toto 30 30 years years of ofage). age). Reporting Reporting completeness completeness waswas high high in in31 31 (38%), (38%), moderate moderate in in 37 37 (45%), (45%), and and low low in in the the remaining remaining 14 14 (17%) (17%) cases. cases.

Records identified Records identified Records identified throughsearchin the through search in the through search in National Library Excerpta Medica the Web of Science Database Database Database (N = 651 ) (N = 3234 ) (N = 219 )

Records screened after duplicates removed (N = 3871)

Records excluded (N = 3746) - No original articles (N = 2423) - Not including humans (N = 902) - Abstracts (N = 223) - Not pertaining (N = 198)

Full-text assessed in detail for eligibility (N = 125)

Records excluded (N = 81) - No orginal cases (N = 41) - Not pertaining (N = 20) - Animal studies (N = 7) - With kidney injury (N = 13)

Secondary references (N = 1) Personal files (N = 1)

Full-text articles included (N = 46)

Figure 1. Flowchart of the literature search process.

Figure2.2. Findings1. Flowchart of the literature search process. The baseline characteristics of the patients are listed in Table1. Fifty-eight (71%) patients were ≥20 years of age, 19 (23%) were 3 to 19 years of age, three (3.7%) were 4 weeks to 2 years of age, and two (2.4%) < 4 weeks of age. Approximately half of the cases were non-tuberculous or tuberculous respiratory infections. The other common infections included abdominal, urinary, and drug-induced neutropenia; Aminoglycosides Antibiotics 2021, 10, x FOR PEER REVIEW 3 of 9 Antibiotics 2021, 10, x FOR PEER REVIEW 3 of 9

Antibiotics 2021, 10, x FOR PEER REVIEW 3 of 9

2.2. Findings 2.2. Findings The baseline characteristics of the patients are listed in Table 1. Fifty-eight (71%) pa- The baseline characteristics of the patients are listed in Table 1. Fifty-eight (71%) pa- tients2.2. Findings were ≥ 20 years of age, 19 (23%) were 3 to 19 years of age, three (3.7%) were 4 weeks tients were ≥ 20 years of age, 19 (23%) were 3 to 19 years of age, three (3.7%) were 4 weeks to 2 years of age, and two (2.4%) < 4 weeks of age. Approximately half of the cases were to 2 yearsThe baseline of age, characteristicsand two (2.4%) of < the4 weeks patients of age. are listedApproximately in Table 1. half Fifty-eight of the cases (71%) were pa- non-tuberculous or tuberculous respiratory infections. The other common infections in- tientsnon-tuberculous were ≥ 20 years or tuberculous of age, 19 (23%) respiratory were 3 infections.to 19 years Theof age, other three common (3.7%) wereinfections 4 weeks in- cluded abdominal, urinary, and drug-induced neutropenia; Aminoglycosides were pre- tocluded 2 years abdominal, of age, and urinary, two (2.4%) and drug-induced< 4 weeks of age. neutropenia; Approximately Aminoglycosides half of the cases were were pre- Antibiotics 2021, 10, 140scribed in the vast majority of the 82 patients (most frequently and tobramy- 3 of 9 non-tuberculousscribed in the vast or majority tuberculous of the respiratory 82 patients infections. (most frequently The other gentamicin common andinfections tobramy- in- cin). The authors of the aforementioned reports never associated the observed electrolyte cludedcin). The abdominal, authors of urinary, the aforementioned and drug-induced reports neutropenia; never associated Aminoglycosides the observed electrolytewere pre- and acid-base disorders to an excessive aminoglycoside or colistin dosage. Thirty percent scribedand acid-base in the vastdisorders majority to an of excessive the 82 patients aminog (mostlycoside frequently or colistin gentamicin dosage. Thirtyand tobramy- percent of the patients had at least one prior course of aminoglycoside treatment. Electrolyte and cin).of the The patients authorswere had of prescribed atthe least aforementioned on ine prior the vast course report majority of saminoglycosi never of the associated 82 patientsde treatment. the (most observed Electrolyte frequently electrolyte and gentamicin and acid-base disorders were mostly (65%) reported ≤ 4 weeks after starting the antimicrobial andacid-base acid-base disorderstobramycin). disorders were to mostly Thean excessive authors (65%) reported ofaminog the aforementionedlycoside ≤ 4 weeks or colistinafter reports starting dosage. never the Thirty antimicrobial associated percent the observed treatment. Electrolyte and acid-base disorder was not clinically symptomatic in one third oftreatment. the patients Electrolyteelectrolyte had at least and and acid-baseon acid-basee prior coursedisorder disorders of was aminoglycosi to not an clinically excessivede treatment. symptomatic aminoglycoside Electrolyte in one or third and colistin dosage. of the cases. Neuromuscular or muscle were observed in the remain- acid-baseof the cases. disorders ThirtyNeuromuscular percentwere mostly of irritability the (65%) patients reported or muscle had at ≤ leastweakness4 weeks one after prior were starting course observed the of aminoglycoside inantimicrobial the remain- treatment. ing patients. treatment.ing patients. ElectrolyteElectrolyte and and acid-base acid-base disorder disorders was were not mostly clinically (65%) symptomatic reported ≤ 4in weeks one third after starting the of the cases. Neuromuscularantimicrobial treatment. irritability Electrolyte or muscle and weakness acid-base were disorder observed was in not the clinically remain- symptomatic Table 1. Baseline characteristics of patients with electrolyte and acid-base disorder. ingTable patients. 1. Baseline in one characteristics third of the of cases. patients Neuromuscular with electrolyte irritabilityand acid-base or muscledisorder. weakness were observed in the remainingCharacteristics patients. N (%) Table 1. Baseline characteristicsCharacteristics of patients wi th electrolyte and acid-base disorder.N (%) Gender Gender Table 1. BaselineCharacteristicsFemale characteristics of patients with electrolyte and51 acid-baseN disorder.(62)(%) Female 51 (62) GenderMale 31 (38) CharacteristicsMale N31 (38) (%) UnderlyingFemale infection 51 (62) UnderlyingGender infection Non-tuberculous Malerespiratory infection * 2331 (28)(38) Non-tuberculous respiratoryFemale infection * 5123 (28) (62) UnderlyingTuberculosis infection 17 (21) TuberculosisMale 3117 (21) (38) Non-tuberculousAbdominalUnderlying respiratory infection infection infection * 1323 (16)(28) Abdominal infection 13 (16) Non-tuberculousUrinaryTuberculosis tract respiratory infection infection * 23 1117 (13)(21) (28) UrinaryTuberculosis tract infection 17 11 (13) (21) Infection Abdominalassociated with infection neutropenia ☩ 135 (6.1) (16) Infection associatedAbdominal with infection neutropenia ☩ 135 (6.1) (16) Urinary Othertract infection 13 11 (16) (13) UrinaryOther tract infection 1113 (16) (13) InfectionInfection Antimicrobialassociated associated with with agent neutropenia neutropenia ☩ 55 (6.1) (6.1) Antimicrobial agent GentamicinOtherOther 133713 (45)(16) (16) Gentamicin 37 (45) AntimicrobialAntimicrobialTobramycin agent agent 11 (13) TobramycinGentamicin 3711 (13) (45) CapreomycinGentamicin 378 (9.8)(45) CapreomycinTobramycin 118 (9.8) (13) TobramycinKanamycin 114 (4.9)(13) KanamycinCapreomycin 84 (4.9) (9.8) CapreomycinViomycinKanamycin 428 (2.4)(9.8) (4.9) Viomycin 2 (2.4) KanamycinColistinViomycin 2 24 (2.4)(4.9) (2.4) ColistinColistin ◆ 2 2 (2.4) (2.4) UnspecifiedViomycin aminoglycoside ◆ 122 (2.4)(15) UnspecifiedUnspecified aminoglycoside aminoglycoside 1212 (15) (15) ColistinOtherOther 66 2 (7.3) (2.4) (7.3) Other ◆ 6 (7.3) PreviousPreviousUnspecified antimicrobial antimicrobial aminoglycoside therapy therapy courses courses 242412 (29)(15) (29) Previous antimicrobial therapy courses✙ 24 (29) DurationDuration of antimicrobial of antimicrobialOther therapy therapy ✙ 6 (7.3) Duration of antimicrobial therapy Previous antimicrobial≤1≤ week1 week therapy courses 11 1124 (15)(29) (15) ≤12–4 week weeks 37 11 (15) (50) Duration of antimicrobial2–4 weeks therapy ✙ 37 (50) 2–42–6 weeks months 17 37 (50) (23) 2–6≤1 months week 1711 (23)(15) 2–6>6 months months 9 17 (23) (12) >62–4Main months weeks findings 37 9 (12)(50) >6 months 9 (12) NeuromuscularMain2–6 monthsfindings irritability 42 17 (23) (52) MainMuscle findings weakness 2 (2.4) Neuromuscular>6 months irritability 42 9 (52)(12) NeuromuscularIrritability and irritability weakness 11 42 (52) (13) MuscleMain findingsweakness 2 (2.4) Data are presentedMuscle as medianweakness (with interquartile range) or as frequency 2 (with percentage) (2.4) * 15 patients were NeuromuscularIrritability and weaknessirritability 1142 (13)(52) affected byIrritability cystic fibrosis; and weaknessinduced by anticancer therapy; reference 11 #24; information (13) not available in Data are presented8 cases. as medianMuscle (with weakness interquartile range) or as frequency (with 2percentage) (2.4)* 15 Data are presented as median (with interquartile range) or as frequency (with◆ percentage) ✙* 15 patients were affected by cystic fibrosis; ☩ induced by anticancer therapy; reference #24; infor- patients were affectedIrritability by cystic fibrosis; and weakness ☩ induced by anticancer therapy; ◆ reference 11 #24; (13)✙ infor- mation not availableA in total 8 cases. of 286 electrolyte and acid-base disorders were reported in the 82 patients Datamation are not presented available(Table as2 in ).median 8 Hypomagnesemia,cases. (with interquartile hypokalemia, range) or as frequency and hypocalcemia (with percentage) were * 15 reported in more patients were affected by cystic fibrosis; ☩ induced by anticancer therapy; ◆ reference #24; ✙ infor- A total thanof 286 three electrolyte quarter and of cases. acid-base Proteinuria, disorders glucosuria, were reported and aminoaciduria in the 82 patients were reported in mationA nottotal available of 286 in electrolyte 8 cases. and acid-base disorders were reported in the 82 patients (Table 2). Hypomagnesemia,<10% of cases. The hypokalemia, urinary magnesium and hypocalcemia excretion, were assessed reported in justin more over than half of patients (Table 2). Hypomagnesemia,with hypomagnesemia, hypokalemia, was always and hypocalcemia inappropriately were high. reported Similarly, in more the than urinary chloride A total of 286 electrolyte and acid-base disorders were reported in the 82 patients excretion was inappropriately high in 21 cases with hypokalemic . (Table 2). Hypomagnesemia, hypokalemia, and hypocalcemia were reported in more than Antibiotics 2021, 10, 140 4 of 9

Table 2. Prevalence of electrolyte, acid-base disorder, and abnormal urinary findings.

Abnormal Finding N (%) Electrolyte and acid-base disorders Hypomagnesemia 70 (85) Hypokalemia 69 (84) Hypocalcemia 64 (78) Metabolic alkalosis 35 (43) Hyponatremia 22 (27) Hypophosphatemia 18 (22) Hypouricemia 5 (6.1) Hypernatremia 2 (2.4) Metabolic acidosis 1 (1.2) Relevant urinary findings Pathological proteinuria 6 (7.3) Normoglycemic glucosuria 4 (4.9) Generalized aminoaciduria 3 (3.7) Inappropriately high electrolyte excretion * 37 (45) Chloride ** 21 (26) Data are presented as frequency (with percentage). * patients presenting with hypomagnesemia (24-h magnesium excretion ≥ 500 µmol or a fractional magnesium clearance ≥ 2.0 × 10−2); ** patients presenting with hypokalemia and metabolic alkalosis (24-h chloride excretion ≥ 20 mmol or fractional chloride clearance ≥ 0.5 × 10−2).

Using the criteria suggested in the section, Materials and Methods, the patients were classified as shown in Table3. Three quarters of the cases presented with a loop of Henle/distal tubular dysfunction (isolated or, more rarely, associated with a proximal tubular dysfunction) or with a proximal tubular dysfunction.

Table 3. Classification of electrolyte and acid-base disorders.

Disorder N (%) Females/Males Age Loop of Henle/Distal 56 (68) 36/20 29 [19–57] Tubular Dysfunction * Proximal Tubular 3 (3.7) 0/3 35, 71, 73 Dysfunction ** Mixed Dysfunction 5 (6.1) 3/2 41, 43, 49, 53, 64 Unclassified 18 (22) 12/6 25 [19–28] Abnormality Data are presented as frequency, as median and interquartile range (≥6 cases), or as individual values (<6 cases). Patients with an unclassified electrolyte and acid-base disorder were significantly (p < 0.02) younger than patients with either and a mixed or a proximal tubular dysfunction. * hypomagnesemia, hypocalcemia, hypokalemia, or metabolic alkalosis; ** hypophosphatemia, hypouricemia, metabolic acidosis, proteinuria, glucosuria, or generalized aminoaciduria.

The time to resolution was ≤ 1 week in 10 (19%) cases, 2 to 4 weeks in 22 (41%) cases and > 4 weeks in 22 (41%) cases. This information was not available for 28 cases.

3. Discussion The potential of aminoglycosides and colistin to induce renal tubular dysfunction has not been systematically addressed so far. This analysis demonstrates that treatment with aminoglycosides or colistin may transiently alter the renal tubular function, without any concomitant relevant decrease in glomerular filtration. We observed (1) a proximal tubular, (2) a loop of Henle/distal tubular, and (3) a mixed tubular dysfunction. However, we were not able to classify a minority of cases as proximal tubular, loop of Henle/distal tubular, or mixed tubular dysfunction. The clinical picture associated with the altered electrolyte and acid-base balance may include or neuromuscular irritability. Antibiotics 2021, 10, 140 5 of 9

In this analysis, renal magnesium wasting was the most common electrolyte disor- der. This observation is supported by the results of a well-designed study of patients treated with , where after two weeks, the only electrolyte abnormality noted was magnesium [51]. The mechanisms by which aminoglycosides may alter the renal tubular function remain speculative. Available data suggest that the proximal tubular diseases (and the ) might result from a mitochondrial dysfunction. On the other hand, the loop of Henle/distal tubular injury might result from an activation of the -sensing receptor [52–55]. Several factors may modulate the potential of aminoglycosides to induce acute kidney injury including pre-existing reduced renal function, prolonged treatment, liver dysfunc- tion, , reduced effective blood volume, and combined therapy with other nephrotoxic drugs [1,2]. Finally, it is assumed that gentamicin has the greatest nephrotoxic potential, followed by tobramycin, amikacin, and netilmicin [1,2]. The results of the present analysis do not allow us to confirm if the information available for acute kidney injury may be extrapolated to renal tubular dysfunction. In cystic fibrosis patients, hyponatremia, hypokalemia, and metabolic alkalosis may result either from a tubular disturbance or from excessive loss in sweat. Infants with cystic fibrosis are primarily at risk for this non-renal disturbance due to the poor salt content of infant formula and or breast milk. Likewise, in older cystic fibrosis patients, this biochemical abnormality may develop under heat . In contrast with renal tubular dysfunction, urinary chloride excretion is low in this setting [56,57]. A major strength of our systematic review validated that electrolyte and acid-base disorders can be triggered by aminoglycoside and colistin therapy. However, the current available information does not allow documenting the prevalence of such disorders associ- ated with these antimicrobials. Second, the reporting completeness was high in <40% of cases. Future work is necessary to address this. In conclusion, many classes of antimicrobials may cause electrolyte and acid-base disorders [58]. The present review supports the association of aminoglycosides and col- istin therapy with either a proximal tubular or, more frequently, a loop of Henle/distal tubular dysfunction. In these patients, the glomerular filtration is normal or no more than marginally impaired.

4. Materials and Methods 4.1. Search Strategy This review was accomplished following the Preferred Reporting Items for Systematic Reviews and Meta-Analyses recommendations [59]. Searches were run in the databases of the United States National Library of Medicine, Excerpta Medica, and Web of Science on July 10, 2020 and repeated on November 10, 2020. Original reports published after 1960, with no language limits considered. The search strategy incorporated the terms (acidosis OR alkalosis OR electrolyte disturbances OR hypercalcemia OR OR hyper- magnesemia OR hypernatremia OR hypocalcemia OR hypokalemia OR hypomagnesemia OR hyponatremia) AND (aminoglycoside OR amikacin OR capreomycin OR colistin OR dibekacin OR gentamicin OR isepamicin OR kanamycin OR neomycin OR netilmicin OR paromomycin OR plazomicin OR sisomicin OR spectinomycin OR [dihydro]streptomycin OR tobramycin OR viomycine). References listed within bibliographies of the retrieved records and pertinent personal files of the authors were also considered for inclusion. Two authors independently screened all identified titles and abstracts in a nonblinded fashion. Upon retrieval of relevant reports, full-text publications were reviewed for eligibility.

4.2. Eligibility Criteria We included original articles and letters that reported individual humans on parenteral aminoglycoside or colistin therapy presenting with otherwise unexplained electrolyte (total calcium ≥ 2.80 mmol/L; ionized calcium ≥ 1.40 mmol/L; total calcium ≤ 2.20 mmol/L; Antibiotics 2021, 10, 140 6 of 9

ionized calcium ≤ 1.10 mmol/L; total magnesium ≥ 1.20 mmol/L; total magnesium ≤ 0.70 mmol/L; ≥ 146 mmol/L; sodium ≤ 134 mmol/L; ≥ 5.1 mmol/L; potassium ≤ 3.4 mmol/L; inorganic ≥ 2.00 mmol/L; inorganic phosphate ≤ 1.00 mmol/L) or metabolic acid-base disorders (acidosis: ≤ 18 mmol/L and pH ≤ 7.38; alkalosis: bicarbonate ≥ 27 mmol/L and pH ≥ 7.42). Since children and adults importantly differ with respect to , age- and gender-dependent reference values were used for the definition of hyper- and hypouricemia [60]. Patients with preexisting conditions (alcohol use, diabetes, ), condi- tions predisposing to electrolyte and acid-base disorder (i.e., , ), concur- rent agents with potential nephrotoxic activity (i.e., , , , etc.), and finally those with a diagnosis of acute kidney injury (rise in circulating level to ≥1.5 times baseline or increase by ≥27 µmol/L above the upper limit of normal for age) were excluded [61]. Cystic fibrosis individuals with electrolyte abnormalities such as hyponatremia, hypokalemia, and metabolic alkalosis associated with low urinary chloride excretion were also excluded [56,57].

4.3. Data Extraction Data were extracted using a piloted form and transcribed into a predefined spread- sheet. The data extracted from each case meeting inclusion criteria were demographics, diagnosis, clinical findings possibly associated with the electrolyte and acid-base disor- der including neuromuscular irritability (such as perioral numbness, of the hands and feet, muscle , carpopedal , laryngospasm, , Lust sign, Trousseau sign, or ), muscle weakness or acidotic Kussmaul breathing, in- formation on aminoglycoside (or colistin) therapy before onset of electrolyte or acid-base disorders, laboratory values, and time to resolution after withdrawing the antimicrobial therapy. Effort was made to retrieve following laboratory values: acid-base balance, levels of calcium, inorganic phosphate, magnesium, potassium, sodium or uric acid in blood, and renal parameters. Available information on glucosuria, aminoaciduria, and urinary excretion of magnesium or chloride was also recorded. If needed, attempts were also made to contact original authors to obtain missing data. The accuracy in describing diagnosis and clinical presentation, drug treatment, laboratory data, and time to recovery of electrolyte and acid-base imbalance was used to grade completeness of reporting as high, moderate, or low.

4.4. Analysis-Classification-Statistics It has been hypothesized that electrolyte and acid-base disorders triggered by amino- glycoside therapy may result either from a proximal tubular or from an apparent loop of Henle/distal tubular dysfunction [58]. Hence, we tentatively made the diagnosis of proximal tubular dysfunction in patients presenting with at least three of the following: hy- pophosphatemia, hypouricemia, metabolic acidosis, proteinuria, glucosuria, or generalized aminoaciduria. On the other hand, we made the diagnosis of loop of Henle/distal tubular dysfunction in cases with at least three of the following: hypocalcemia, hypomagnesemia, hypokalemia, or metabolic alkalosis. The diagnosis of mixed tubular dysfunction was made in cases presenting with features consistent both with a proximal tubular and a loop of Henle/distal tubular dysfunction. The evaluation of urinary magnesium or chloride excretion was made as recommended in the literature [56]. The remaining cases were considered unclassified. Missing data were managed by pairwise deletion. Categorical data are presented as frequency and were analyzed using the Fisher’s exact test. Continuous data are presented as median and interquartile range (≥6 cases) or as individual values (<6 cases) and were analyzed using the Kruskal–Wallis test and the Dunn posttest. Significance was assumed at p < 0.05.

Author Contributions: S.A.G.L. and G.P.M. conceptualized the study design and supervised the writing of the manuscript. M.S. and G.B. performed the literature search and the study selection. Antibiotics 2021, 10, 140 7 of 9

M.G.B. and P.O.R. performed the data analysis. S.A.G.L. and G.P.M. supervised the data analysis. M.S., P.B.F. and S.R. wrote the first version of the manuscript. P.B.F., C.B., G.D.S., V.G. and S.R. gave a significant contribution in the interpretation of results. M.S. formatted the manuscript according to journal guidelines and acted as the corresponding author. All authors have read and agreed to the published version of the manuscript. Funding: This research received no external funding. Conflicts of Interest: The authors declare no conflict of interest.

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