Development of a Highly In Vivo Efficacious Dual Antitumor and Antiangiogenic Organoiridium Complex as a Potential Anti-Lung Cancer Agent.

Nephro-Urol Mon. 2018 March; 10(2):e58580. doi: 10.5812/numonthly.58580. Published online 2018 March 10. Research Article Nephrotoxic Effect of Gentamicin and Amikacin in Neonates with Infection Saeed Alinejad,1 Parsa Yousefichaijan,2 Masoud Rezagholizamenjany,3,* Yosef Rafie,3 Manijeh Kahbazi,4 and Ali Arjmand1 1 Department of Pediatric, Assistant Professor of Pediatric, Arak University of Medical Sciences, Arak, Iran Amir Kabir Hospital, Department of Pediatric Nephrology, Associate Professor of Pediatric Nephrology, Arak University of Medical Sciences, Arak, Iran 3 School of Medicine, Arak University of Medical Sciences, Arak, Iran 4 Department of Pediatric, Associate Professor of Pediatric, Arak University of Medical Sciences, Arak, Iran 2 * Corresponding author: Mr. Masoud Rezagholizamenjany, School of Medicine, Arak University of Medical Sciences, Arak, Iran. Tel: +98-9184374727, E-mail: masoudrezagholi074@gmail.com Received 2017 July 23; Accepted 2018 February 03. Abstract Background: Infection and its treatment as a common problem in children may induce different complications. Ampicillin and aminoglycosides, as choice drugs for this condition, may have many important side effects, such as nephrotoxic side effects. Therefore, the aim of this study was to evaluate the nephrotoxic effect of gentamicin and amikacin in neonates with infection. Methods: This clinical trial and double blind study was conducted on 80 children with aminoglycosides addministration. Initially, during hospital admission, serum and urine samples were collected for diagnosis of infection. Children based on their treatment were divided to 2 groups, 40 children were treated by ampicillin and amikacin and 40 children were treated by ampicillin and gentamicin, during a 7-day period. At the end of the treatment period, serum and urine samples were taken for measurment of laboratory variables, and GFR, for evaluation of kidney function. Results: Blood Urea Nitrogen (BUN), creatinine and GFR before and after treatment in the two groups did not have statistically significant differences (P > 0.05). In addition age, gender, birth age, infection type, occupation, and education of parents and milk type were equal in the 2 groups. Conclusions: Based on the present study, there were no significant differences between nephrotoxic effect of gentamicin and amikacin in the two groups. Keywords: Nephrotoxic Effect, Gentamicin, Amikacin, Infection 1. Background Infectious diseases in the neonatal population and their treatment is a common problem in pediatrics (1). Since combination of ampicillin and aminoglycosides as an approved treatment of choice has been used in infections, yet they all have many important side effects and studies have not evaluated these effects (2, 3). Due to high concentration of aminoglycosides in the renal cortex, this drug may have side effects on the kidneys, such as nephrotoxic effect, indicated by an increase of serum creatinine, from its baseline, in range of 0.5 or more than 0.5 milligrams per deciliter. In contrary to the therapeutic effects of aminoglycoside, this toxicity is not dose-dependent (4). Therefore, high or low concentration of aminoglycosides in the cortex of the kidney induces nephrotoxic effects as a common and important side effect (5). Also, increasing duration of treatment with aminoglycosides increases the risk of nephrotoxic effect, so that more than 14 days of treatment increases the risk of nephrotoxic effect to 50% (6, 7). Aminoglycosides induce damage of proximal convoluted tubule, and rarely induce dysfunction of glomeruli. Furthermore, acute tubular necrosis and reduced GFR and anuria can occur at the end, as a life threatening complication and in most cases, the induced nephrotoxic effect by these drugs is irreversible (8). Based on this context, this research found infectious diseases in the neonatal population and its treatment as a common problem. Therefore, the aim of this study was to evaluate the nephrotoxic effects of gentamicin and amikacin in the neonatal population to make better use of medications for infection, with lower nephrotoxic effects. 2. Methods 2.1. Study Settings This was a double blind clinical trial study, which was hospital-based, conducted in the pediatric clinic of AmirKabir and Taleghani hospital of Arak city. 2.2. Study Population In total, 80 children with complete gestational age, different source of infection, and indication for treatment Copyright © 2018, Nephro-Urology Monthly. This is an open-access article distributed under the terms of the Creative Commons Attribution-NonCommercial 4.0 International License (http://creativecommons.org/licenses/by-nc/4.0/) which permits copy and redistribute the material just in noncommercial usages, provided the original work is properly cited. Alinejad S et al. with aminoglycosides, were evaluated in this study. Based on synchronization the cases were divided to 2 groups. During the study, parents of patients, who wished to discontinue their participation or were not available to complete the study, were assigned by patients with similar clinical and demographic factors. 2.3. Measurements After selection of children, basic information, including age (day) and gender (male or female) was recorded in the question list and first serum and urine samples were taken from the patients. Children were divided to 2 groups and treated during 7 days by ampicillin or gentamicin; 40 children by ampicillin and amikacin and 40 children by ampicillin and gentamicin. Antibiotics were injected intravenously by micro infusion set and within a 30minute period. Ampicillin was used for Listeria and group B of Streptococcus, and aminoglycosides were used for enteric gram negatives. Registeration of laboratory variables was done by secondary serum and urine samples. Studied variables included bicarbonate, BUN, creatinine, sodium, potassium, calcium, U/A, and GFR, and nephrotoxic effect was defined as an increase of serum creatinine, from its baseline, in the range of 0.5 or more than 0.5 milligrams per deciliter. 2.4. Antibiotics Doses Antibiotic doses of the 2 groups were used based on gestational age and weight, as mentioned in Table 1. 2.5. Inclusion and Exclusion Criteria Infants with indication of treatment with aminoglycoside, whose parents had provided an informed consent, were included in the study. In addition, the exclusion criteria were underlying congenital renal and urinary tract disorders, such as Bartter, RTA and any proximal tubular dysfunction, recent history of nephrotoxic medications use, especially gentamicin and amikacin, ABG acid-base disorders, and disrupted tests before the start of treatment. 2.6. Ethical Considerations Ethical issues (including plagiarism, data fabrication, and double publication) ware completely taken into consideration by the authors. In addition, the ethical committee of Arak University of Medical Sciences approved the study protocol. 2 2.7. Statistical Analysis Data analysis was conducted by frequency, mean, standard deviation, and standard error, for quantitative variables in the SPSS program. In addition, covariance analysis, chi-square test, independent T-test, or equivalent nonparametric tests were used to compare the mean parameters in groups, and after these tests significant differences (P < 0.05) were considered. 3. Results A statistically significant difference was found between evaluated factors, thus nephrotoxic effect of Gentamicin and Amikacin were equal in the current study. Based on Table 2, demographic information in the 2 groups were equal. In total, 80 children were evaluated, 45 male and 35 female (P = 0.652). Mean age of children was 3.51 ± 2.76 in the Gentamicin group, 3.22 ± 2.50 in the Amikacin group, and 3.36 ± 2.63 in total (P = 1). Also, other evaluated factors including father’s educational status (P = 0.864), mother’s educational status (P = 0.407), father’s occupation status (P = 0.338), mother’s occupation status (P = 0.603), and living area (P = 1) were equal in the 2 groups. Based on Table 3, that indicated renal function tests criteria, these 2 drugs did not have different nephrotoxic effects on children. Furthermore, BUN before treatment with antibiotics in the gentamicin group was 29.85 ± 14.38 and in the amikacin group was 29.81 ± 16.33 (P = 0.670) and after treatment with antibiotics in the gentamicin group, BUN was 23.45 ± 14.53 and in the amikacin group, it was 24.87 ± 15.25 (P = 0.992). Glomerular Filtration Rate before treatment with antibiotics in the gentamicin group was 26.73 ± 7.47 and in the amikacin group was 29.11 ± 16.24 (P = 0.402), and after treatment with antibiotics, in the gentamicin group, it was 41.81 ± 18.28 and in the amikacin group, 38.21 ± 13.85 (P = 0.324). Before treatment with antibiotics in the gentamicin group Cr was 0.85 ± 0.21 and in the amikacin group, it was 0.84 ± 0.26 (P = 0.896) and after treatment with antibiotics in the gentamicin group, this was 0.56 ± 0.16 and in the amikacin group, it was 0.60 ± 0.16 (P =0.340). Calcium in the gentamicin group was 8.68 ± 0.7 and in the amikacin group was 9.11 ± 1.2 (P = 0.813). Sodium in the gentamicin group was 138.87 ± 5.71 and in the amikacin group was 139.98 ± 6.8 (P = 0.431). Potassium in the gentamicin group was 4.42 ± 0.62 and in the amikacin group was 4.61 ± 0.54 (P = 0.158). Bicarbonate in the gentamicin group was 17.74 ± 2.39 and in the amikacin group, this was 18.13 ± 3.47 (P = 0.558). As shown in Table 4, there were no differences between the 2 groups regarding delivery status of children. In this section, gestational age, birth weight, infection source, birth height, head circumference at birth, Nephro-Urol Mon. 2018; 10(2):e58580. Alinejad S et al. Table 1. Doses of Administered Antibiotics Antibioticsa Postnatal Age ≤ Seven Days 1200 to 2000, g > Seven Days > 2000, g 1200 to 2000, g > 2000, g Amikacin 7.5 (Per 12 - 18 hr) 10 (Per 12 hr) 7.5 (Per 8 - 12 hr) 10 (Per 8 hr) Gentamicin 2.5 (Per 12 - 18 hr) 2.5 (Per 12 hr) 2.5 (Per 8 - 12 hr) 2.5 (Per 8 hr) Ampicillinb , c 50 (Per 24 hr) 75 (Per 24 hr) 75 (Per 24 hr) 100 (Per 24 hr) a mg/kg/hr, IM or IV. b In meningitis dose of Antibiotics will doubled. c Doses of Ampicillin were equal in two groups. Table 2. Demographic Status of Children in the Gentamicin and Amikacin Groups Variables Groups Total Gentamicin Amikacin Male 21 (52.5) 24 (60) 45 (56.2) Female 19 (47.5) 16 (40) 35 (43.8) P Value 0.652 Gender 1 Age, y Mean ± SD 3.51 ± 2.76 3.22 ± 2.50 3.36 ± 2.63 Under diploma 20 (50) 21 (52.5) 41 (51.3) Diploma and associate 17 (42.5) 15 (37.5) 32 (40) Bachelor and higher 3 (7.5) 4 (10) 7 (8.7) 0.864 Fathers education level 0.407 Mothers education level Under diploma 24 (60) 19 (47.5) 43 (53.8) Diploma and associate 14 (35) 15 (37.5) 29 (36.2) Bachelor and higher 2 (5) 6 (15) 8 (10) 0.338 Fathers occupation Self-employed 20 (50) 26 (65) 46 (57.5) Employer 16 (40) 10 (25) 26 (32.5) Employee 4 (10) 4 (10) 8 (10) Housewife 39 (97.5) 38 (95) 77 (96.3) Employer 1 (2.5) 1 (2.5) 2 (2.5) Employee 0 (0) 1 (2.5) 1 (1.2) 0.603 Mothers occupation 1 Living area Urban 25 (62.5) 24 (60) 49 (61.3) Rural 15 (37.5) 16 (40) 31 (38.7) type of consumed milk and maternal diseases during pregnancy were evaluated; all of these studied variables were equal in the 2 groups of gentamicin and amikacin (P < 0.05). Nephro-Urol Mon. 2018; 10(2):e58580. 4. Discussion The current study compared nephrotoxic effect of gentamicin and amikacin. It was concluded that based on the 3 Alinejad S et al. Table 3. Kidney Function Tests and Electrolytes in Gentamicin and Amikacin Groups Variables Groups Gentamicin Total 0.558 Bicarbonate Mean ± SD 17.74 ± 2.39 18.13 ± 3.47 17.94 ± 2.84 0.992 BUN before treatment, mg/dL Mean ± SD 29.85 ± 14.38 29.81 ± 16.33 29.83 ± 15.35 0.670 BUN after treatment, mg/dL Mean ± SD 23.45 ± 14.53 24.87 ± 15.25 0.402 GFR before treatment, mL/min Mean ± SD 26.73 ± 7.47 29.11 ± 16.24 28.41 ± 11.85 41.81 ± 18.28 38.21 ± 13.85 40.01 ± 16.05 0.85 ± 0.21 0.84 ± 0.26 0.85 ± 0.23 0.324 GFR after treatment, mL/min Mean ± SD 0.896 Cr before treatment, mg/dL Mean ± SD 0.340 Cr after treatment, mg/dL Mean ± SD 0.56 ± 0.16 0.60 ± 0.16 0.58 ± 0.16 0.813 Calcium, mg/dL Mean ± SD 8.68 ± 0.7 9.11 ± 1.2 8.89 ± .0.95 0.431 Sodium, mEq/L Mean ± SD 138.87 ± 5.71 139.98 ± 6.8 139.58 ± 6.25 4.42 ± 0.62 4.61 ± 0.54 4.51 ± 0.58 0.158 Potassium, mEq/L Mean ± SD current study, the nephrotoxic effect of gentamicin and amikacin were equal and there were not aesthetic preferences for these drugs. Bajracharya et al. in a study compared nephrotoxic effect of amikacin and gentamicin throughout creatinine clearance test, in post-operative patients with normal renal function. They found that although the dose of administered gentamicin is much lower than amikacin, gentamicin has a greater nephrotoxic effect (9), but this study found that nephrotoxic effect of these drugs were equal in the 2 groups. Sweileh et al. in their study investigated the nephrotoxic effect of gentamicin and amikacin. They evaluate 94 children in 2 groups of gentamicin (45 children) and amikacin (49 children). They found that amikacin was significantly less nephrotoxic than gentamicin and that multiple dosing of gentamicin was more nephrotoxic than single dosing, yet the nephrotoxic effect of amikacin was not significantly dependent on frequency of dosing (10); the current study did not confirm these results. Also, Dayan et al. in a study found that nephrotoxic effect were reduced by reduction in frequency of aminoglycosides consumption (11); this factor was not 4 P Value Amikacin evaluated in the current study. Sassen et al. in a study, evaluated the effect of gentamicin on dysregulation of renal sodium transporters in rats. They found that the fraction excretion of electrolytes was significantly increased in 7 days of treatment with gentamicin (12). Takamoto et al. in a study on the effect of antibiotics on glucose absorption in the kidneys, found that glucose absorption in proximal tubule of kidneys were reduced in children with consumption of gentamicin (13). Akbari et al. in a study investigated the effect of anti-biotherapy on renal function. They evaluated 142 patients and found that GFR contributed to renal function and it was reduced in children treated by antibiotics (14), which is similar to the current findings. Also, Wolf et al. in their study found that impaired renal function was higher in infections of diabetic foot (15). Pannell et al. in a study evaluated nephrotoxic effect of gentamicin and found that gentamicin had some complications on kidneys (16). Roger et al. in a study evaluated the impact of amikacin and gentamicin on the serum concentrations. They conducted this on 63 ICU patients with severe sepsis. Also, these drugs increased peak serum concentra- Nephro-Urol Mon. 2018; 10(2):e58580. Alinejad S et al. Table 4. Delivery and Medical Status of Children in the Gentamicin and Amikacin Groups Variables Groups Gentamicin Total 1 Gestational age, week Mean ± SD 35.4 ± 3.08 35.4 ± 5.39 35.4 ± 4.23 0.965 Birth weight, g Mean ± SD 2477.25 ± 624.55 2470.37 ± 780.19 2473.31 ± 702.35 0.619 Infection source Sepsis 33 (82.5) 35 (87.5) 68 (85) Pneumonia 5 (12.5) 4 (10) 9 (11.3) UTI 2 (5) 1 (2.5) 3 (3.7) 47.52 ± 2.59 46.71 ± 3.44 47.11 ± 3.01 33.3 ± 2.08 32.77 ± 3.02 33.03 ± 2.49 0.237 Birth height, cm Mean ± SD 0.652 Birth head circumference, cm Mean ± SD 0.346 Type of milk Formulas 0 (0) 1 (2.5) 1 (1.2) Breast milk 39 (97.5) 36 (90) 75 (93.8) Both 1 (2.5) 3 (7.5) 4 (5) 0.317 Multiple pregnancies Singleton 34 (85) Twins 4 (10) 4 (10) 8 (10) Triplets 2 (5) 1 (2.5) 3 (3.7) 35 (87.5) 69 (86.3) Yes 5 (12.5) 5 (12.5) 10 (12.5) No 35 (87.5) 35 (87.5) 70 (87.5) 1 Gestational diabetes 0.009 Number of pregnancy 1 13 (32.5) 23 (57.5) 36 (45) 2 12 (30) 14 (35) 26 (32.5) 3 12 (30) 1 (2.5) 13 (16.3) >3 3 (7.5) 2 (5) 5 (6.2) 1 Gestational HTN Yes 1 (2.5) 1 (2.5) 2 (2.5) No 39 (97.5) 39 (97.5) 78 (97.5) 0.235 Delivery maternal age, y Mean ± SD 30.30 ± 5.74 tions in 59% of patients (17). Sonia et al. conducted a study on neonates and evaluated fractional excretion of Magnesium, as a marker of nephrotoxicity induced by aminoglycoside, and found that FE of Mg could be considered as a biomarker of tubular damage and nephrotoxicity effect of aminoglycoside therapy could be detected by this marker Nephro-Urol Mon. 2018; 10(2):e58580. P Value Amikacin 28.77 ± 5.65 29.5 ± 5.70 (18). Therefore, all of the mentioned studies found the nephrotoxicity effect of gentamicin and amikacin and the difference of their complications, yet the current study did not find this difference in nephrotoxicity effect of drugs. The limitation of this study was the lack of cooperation of parents in the study, however after the importance of 5 Alinejad S et al. antibiotherapy on renal function was explained to them, they were convinced. Based on a few clinical studies that have been carried out regarding the nephrotoxic effect of aminoglycoside in children, further studies are required with greater number of cases for evaluation of antibiotic side effects. 4.1. Conclusion Based on the current study, there are no differences between gentamicin and amikacin regarding nephrotoxic effects. Therefore, there are no aesthetic preferences regarding side effects, between gentamicin and amikacin for use in the pediatrics population. Acknowledgments This work was performed in partial fulfillment of the requirements for Dr. Yosef Rafie, School of Medicine, Arak University of Medical Sciences, Arak, Iran. Footnote Conflicts of Interest: The authors declared no competing interests. References 1. Gallardo-Godoy A, Muldoon C, Becker B, Elliott AG, Lash LH, Huang JX, et al. Activity and Predicted Nephrotoxicity of Synthetic Antibiotics Based on Polymyxin B. J Med Chem. 2016;59(3):1068–77. doi: 10.1021/acs.jmedchem.5b01593. 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