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Regioisomerization Strategy in Iridium(III) Complexes Achieving Enhanced Type I Photosensitization and Tumor Photoimmunotherapy
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
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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.
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