Gentamicin pharmacokinetics and pharmacodynamic correlation in pediatrics—A systematic review

The primary objective of the review is to correlate the pharmacokinetics and pharmacodynamics data of gentamicin. A thorough literature search was carried out using the databases such as Scopus, PubMed, Google Scholar, and Cochrane. The different types of study designs included were observational (5), prospective (7), retrospective (9), cross-sectional (2), retrospective cross-sectional (1), and retrospective cohort (1). The data were extracted from these studies and it was reviewed by the authors. A total of 149 studies were identified through the database; after removing duplicates, 100 articles were screened, 31 articles were excluded from screening, and 69 articles were included. Out of 69 articles, 26 full-text articles were included and 43 full-text articles were excluded. The dosage recommendations under different disease conditions and their minimum inhibitory concentrations were reviewed. For sepsis condition, 5 mg/kg/day is the ideal dose of gentamicin and >2 mg/l shows minimum inhibitory concentration; for urinary tract infection, 4.5–7.5 mg/kg/day dose of gentamicin shows a minimum inhibitory concentration of >2 mg/l toward organism. For severe malnutrition, 7.5 mg/kg/day dose of gentamicin showed an inhibitory concentration of >2 mg/l. Pharmacokinetic and pharmacodynamic correlation model helps to identify the concentration of gentamicin showing sensitivity and resistance toward organisms at a targeted dosage range.


INTRODUCTION
When there is a seasonal change, the prevalence of respiratory infections is high in children. Gentamicin is a narrow therapeutic index drug belonging to the class of aminoglycosides which is effective against Gram-negative organisms such as Escherichia coli, Klebsiella species, Pseudomonas aeruginosa, Klebsiella pneumonia, and Staphylococcus aureus, and resistant against Enterobacteriaceae, Enterococci, and Staphylococci (Krause et al., 2016;Lundergan et al., 1999;MacDougall and Chambers, 2011). It is mainly indicated for the treatment of both upper and lower respiratory tract infections, urinary tract infections (UTI), meningitis, bacterial neonatal sepsis, peritonitis, bacterial septicemia, skin, bone, and soft tissue infections (Pacifici, 2015). The mechanism action of gentamicin involves the inhibition of protein synthesis of bacteria by binding with 30S ribosomal subunits, causing the misreading of the mRNA, and facilitating the premature termination of translation (Hahn and Sarre, 1969;Kushner et al., 2016). The available dosage forms of gentamicin are ointment, injections, and drops (Bloomfield et al., 1978). The preferable route of gentamicin administration includes topical routes, intramuscular (IM), intravenous (IV), intrathecal, auricular, and ophthalmic drops (Bloomfield et al., 1978;Haddad et al., 1986). The recommended dose of gentamicin in pediatrics is 2-7.5 mg/kg every 8 hours; with an initial dose of 2-5 mg/kg/day and the maximum dose is 7.5 mg/kg/day. During maintenance dose therapy, dose adjustment may be required for renal failure patients (Taylor and Keane, 1976). The main adverse effects of gentamicin include nephrotoxicity and ototoxicity, wherein nephrotoxicity is reversible and ototoxicity is irreversible (Saleh et al., 2016). Gentamicin is contraindicated in myasthenia gravis, where neuromuscular transmission may be impaired (Garraghan and Fallon, 2015). Gentamicin interacts with penicillin or cephalosporin, cyclosporin, amphotericin B, and furosemide (Garraghan and Fallon, 2015;Noone and Pattison, 1971). Pharmacokinetic parameters of gentamicin include absorption: poorly absorbed orally; volume of distribution (V d ) in infants (0.4 ± 0.1 l/kg), neonates (0.45 ± 0.1 l/ kg), and children (0.35 ± 0.15 l/kg); protein binding (0%-30%); half-life in neonates: if <1 week for 3-11.5 hours, 1 week to 1 month for 3-6 hour, infants 4 ± 1 hour, children 2 ± 1 hour, peak serum concentration for IM route within 30-90 minutes; and IV route within 30 minutes, which is excreted through the kidneys (Nocton and Gedeit, 2018). Gentamicin has an average trough concentration of <2 µg/ml and an average peak concentration of <12 µg/ml (Garraghan and Fallon, 2015).
Nowadays, all antibiotics are susceptible to bacteria which lead to irrational use of antibiotics. Antibiotic sensitivity testing (AST) being a scientific tool will be helpful to identify the bacteria and will be helpful in rationalizing the antibiotic treatment.
AST is a test that determines the sensitivity of bacteria to an antibiotic. The two methods of AST are dilution method (broth dilution and agar dilution method) and diffusion method (Stokes' disk diffusion and Kirby-Bauer disk diffusion method).
The dilution method is used to find out the growth and identification of bacterial populations. Micro-dilution and macro-dilution are the two types of dilutions, wherein broth and agar are the commonly used media. In broth dilution, consecutive twofold dilutions (1, 2, 4, 8, and 12 µl) of antibiotics are made and in agar dilutions and antibiotics are diluted in agar medium (Khan et al., 2019). The disk diffusion method is the gold standard for confirming the susceptibility of bacteria. In this method, an isolated bacteria colony is selected, suspended into growth media, and standardized through a turbidity test (Graham et al., 1985).
Pharmacokinetics refers to the study of the time course of drug absorption, distribution, metabolism, and excretion. Pharmacodynamics refers to the relationship between drug concentration at the site of action and their effect (Tozer and Rowland, 2006).
The pharmacokinetic-pharmacodynamic modeling links the pharmacokinetics and pharmacodynamics to evaluate doseconcentration-response relationships and describe the effect of time courses resulting from a drug dose (Meibohm and Derendorf, 1997). Hence, this review focuses on the pharmacokineticpharmacodynamics modeling of gentamicin in pediatrics.
The objective of the study is to correlate pharmacokinetic and pharmacodynamic data of gentamicin for the pediatric population for different disease conditions.

Types of participants
It includes pharmacokinetics, pharmacodynamics (sensitivity), and Pharmacokinetic-Pharmacodynamic (PK-PD) correlation of gentamicin studies that were carried out in the pediatric population for different disease conditions.

Types of interventions and outcome
Intervention-comparison of pharmacokinetic and pharmacodynamic data of gentamicin. Outcome-to understand the concentration profile of gentamicin showing sensitivity against bacterial infections.

Electronic searches
A thorough literature search was conducted from the year 1998 to 2020, using the keywords aminoglycosides, gentamicin, population pharmacokinetics, pediatrics, pharmacokinetics and pharmacodynamics correlation, nonlinear mixed effects modeling, therapeutic drug monitoring, and antibiotic sensitivity test in the following database: Cochrane Library, PubMed, Scopus, and Google Scholar.

Data collection and analysis
The collected data was analyzed based on the inclusion and exclusion criteria. The pharmacokinetics and pharmacodynamics studies were categorized, followed by a comparison of the pharmacokinetic and pharmacodynamic profiles of gentamicin.

Data extraction and analysis
Three authors independently extracted all the studies. The following study characteristics were collected: author, study design, country of publication, age range of participants, year of publication, and dose and indication for gentamicin.
A total of 149 articles were identified through searching. 100 articles were screened after removing duplication; 31 articles were excluded from screening; and 69 articles were included. Out of 69 articles, 26 articles were included in the study and 43 articles were excluded. The Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) flow diagram describes the study as shown in Figure 1. All articles included in the review were conducted in pediatrics.

Pharmacokinetic approach in different disease conditions
In Gram-negative bacterial infections, pediatric patients receiving a dose of 7.5 mg/kg/day of gentamicin as the drug of choice. Plasma samples were checked for the targeted trough concentration <2 µg/ml and peak concentration <10 µg/ml. The concentration was found to exceed the therapeutic range. The dose was adjusted to 3 mg/kg/day; their trough and peak concentrations were found to be 1-2 µg/ml and 6 µg/ml, respectively. The adjusted daily dose of gentamicin was 3-5 mg/kg/day which were found to be ideal for Gram-negative bacterial infections (Ismail et al., 1990).
For sepsis, meningitis, and neutropenic fever, neonates received a dose of 5 mg/kg/day of gentamicin every 24 hours as the drug of choice. Blood samples were collected to check for the targeted peak concentration of 8-10 mg/l and trough concentration <2 mg/l. The first dose of gentamicin appears to be more efficient in achieving the target serum concentrations than steady state which would be ideal for sepsis, meningitis, and neutropenic fever (Lim et al., 2020).
For neonatal sepsis and Gram-negative and Grampositive infections, they received a dose of 4 mg/kg of gentamicin as the drug of choice. The trough concentration should not exceed more than 2 mg/l which can lead to toxicity. A dose 4 mg/kg of gentamicin was found to be sufficient to achieve a C max concentration of 5 mg/l with a postnatal age. The dose needs to be increased to 7.5 mg/kg to achieve target peak concentrations of >10 mg/l; trough concentration <2 mg/l in neonates which were effective against sepsis, Gram-negative, and Gram-positive infections (van Donge et al., 2018).
For sepsis, neonates received a dose of 5 mg/kg/day of gentamicin, with a target maximum concentration of 20 mg/l. Low serum levels are achieved with a dosing range of 5-8 mg/ kg/day. A once-daily dose is expected to induce a high C max / Minimal Inhibitory Concentration (MIC) level. Micro-organism activity with MICs was as high as 2 mg/l for gentamicin. A lower maximum concentration is achieved by dividing dose and maximum concentration/minimum inhibitory concentration above 8-10 mg/l would be difficult to reach, particularly for Multi-drug Resistance (MDR) P. aeruginosa (Mareville et al., 2012).
For hypoxic ischemic encephalopathy with hyperthermia, neonates received a dose of 5 mg/kg/day of gentamicin every 24 hours. Blood samples were collected and their targeted trough concentration >2 mg/l and peak concentration <6 mg/l were not obtained among the neonates with 24-hour dosing intervals. At 5 mg/kg/day every 36 hours of dosing intervals, the targeted trough concentration <2 mg/l was obtained in neonates which would be effective against hypoxic-ischemic encephalopathy (Frymoyer et al., 2013). The pharmacokinetic studies' characteristics included in this review are shown in Table 1.

Wound infection
Wound infections are common conditions in pediatrics which occur mainly in the skin for which gentamicin sulfate cream is used as the drug of choice. A wound swab was collected to check for susceptibility. The Gram-negative bacteria such as E. coli (48.3%), Proteus species (74%), K. pneumonia (36%), and P. aeruginosa (86%) show sensitivity toward gentamicin, whereas Gram-positive organism shows resistance against gentamicin (Kibret and Abera, 2011;Mama et al., 2014).

Typhoid fever
Typhoid fever commonly occurs in pediatrics and is caused by contaminated food and water. Gentamicin is effective against Salmonella typhi mainly in pediatrics. The blood samples were collected for sensitivity and S. typhi was identified; it is susceptible to Ceftriaxone (100%), Cefixime, Gentamicin (99.4%), and Ciprofloxacin (98.6%) (Ali and Sultana, 2016). Probiotics are live micro-organisms that help to provide immunity and prevent the infections in neonates. The swab and sputum samples were checked for sensitivity. Bacteria such as Lactobacillus acidophilus was identified and it is sensitive against gentamicin (Zhou et al., 2005).

Severe acute malnutrition (SAM)
SAM is more common in children mainly with pneumonia and UTI conditions. A susceptibility test was carried out with urine and sputum samples. Organisms such as E. coli and nontyphoidal Salmonellae were identified and it shows 100% sensitivity toward gentamicin (Okomo et al., 2011).

Sepsis
Sepsis is more common in neonates; gentamicin is the drug of choice for sepsis. The blood samples were checked for sensitivity and Gram-positive and Gram-negative organisms were identified. Methicillin-resistant S. aureus (MRSA) was sensitive toward gentamicin and Klebsiella and E. coli showed high resistance to Cefotaxime (90.5%), Gentamicin (75%), and Ciprofloxacin (76.2%) (Mokuolu et al., 2002;Pokhrel et al., 2018).
The organisms were identified from different diseases and their percentages of sensitivity toward gentamicin are shown in Table 2 and their respective characteristics for pharmacodynamics are shown in Table 3.

Pharmacokinetic-Pharmacodynamic Correlation
The PK-PD model was developed by using in vitro timekill curve experiments; it is classified into two types: static timekill curve experiments and dynamic time-kill curve experiments.  The correlation was carried out by the semi-mechanistic PK-PD model which describes the time course of the drug concentration and the bacterial growth and killing after antibacterial treatment. For an extremely preterm new-born infant, the highest possible dose is 6 mg/kg for a 36-hour interval, while a dose of 7 mg/kg with a 36-hour interval in the typical term newborn infant. Dosing intervals should longer than 24 hours for extremely preterm infants to reach trough levels of <2 mg/l, unless the dose is reduced to less than 4 mg/kg. To achieve concentrations of <1 mg/l in typical newborn infants, doses of 4 and 5 mg/kg with a 36-hour interval is recommended (Carapetis et al., 2001;Nielsen et al., 2011). In sepsis conditions, 5 mg/kg/day of gentamicin shows a minimum inhibitory concentration of >2 mg/l toward E. coli, P. aeruginosa, Staphylococcus epidermidis, Enterobacter spp., Streptococci, S. aureus, K. pneumoniae, and Citrobacter diversus. For MDR P. aeruginosa, the minimum inhibitory concentration in the range of 8-10 mg/l is not shown (Frymoyer et al., 2013).

CONCLUSION
This review focuses on gentamicin correlating the pharmacokinetics and pharmacodynamics data by using the semimechanistic PK-PD model. This review guides us about how to correlate the pharmacokinetic and pharmacodynamic data. It will help us find out at what concentration gentamicin shows resistance and sensitivity toward bacteria, especially in pediatric population.

ACKNOWLEDGMENT
The authors would like to thank the staff of the Department of Pharmacy Practice, JSS College of Pharmacy, Ooty, for their support.

AUTHORS' CONTRIBUTION
Keerthana Chandrasekar and K. P. Arun formulated the hypothesis. B. Vahini, V. Vijay, and R. Shalini carried out the data collection and analysis. All the authors read and accepted the final manuscript.