Latamoxef is well tolerated after intramuscular or intravenous administration, but it is not absorbed after oral administration. In neonates, the peak serum concentrations are approximately 105 μg/ml after the first dose and 128 μg/ml in steady state after given latamoxef 50 mg/kg, q12h (8). In infants, the peak concentration are 29–75 μg/ml, 68–124 μg/ml, and 200–260 μg/ml at completion of 10–15 min intravenous infusion of 25, 50, and 100 mg/kg, respectively (9). In children, the mean serum levels reach peaks of 96.6 and 76.0 μg/ml in 15 min after intravenous injection of latamoxef 20 mg/kg and 10 mg/kg, respectively (10). The mean serum levels after intravenous drip infusion over a 1-h interval reach peaks of 71.4 and 39.8 μg/ml at the end of the infusion of latamoxef 20 and 10 mg/kg, respectively (10).

The apparent volume of distribution (Vd) is 515–537 ml/kg and 518 ml/kg after administration of a dose of 50 mg/kg in neonates (0–28 day) and infants (1–24 months), respectively (9). In children aged 2 months to 7.5 years, the Vd of latamoxef is 0.4 L/kg (1).

Latamoxef is hardly metabolized in the body. The calculated mean rates of plasma clearance (CL_plasma) are 16–31 ml/min per 1.73 m² in neonates and 137 ml/min per 1.73 m² in infants aged 1–24 months (9). Renal clearance (CL_R) accounts for 63%–74% of total CL_plasma, and a large amount of latamoxef is eliminated through glomerular filtration (11, 12). In pediatrics, elimination half-life values are inversely correlated with gestational and chronological age. The elimination half-life is 6.2 h in neonates less than one week of age, 4.4 h in those one to four weeks and 1.6 h in infants 1–24 months of age (13). In children aged 2 months to 7.5 years, the elimination half-life is 1.8–2 h (14).

Latamoxef has excellent activity against gram-negative aerobic bacteria, particularly the Enterobacteriaceae, such as Escherichia coli (E. coli) and Klebsiella pneumoniae (K. pneumoniae). The minimum inhibitory concentration of latamoxef for 90% (MIC₉₀) of E. coli ranged from 0.125 to 0.5 µg/ml; for K. pneumoniae, 90% of isolates are susceptible to a concentration of 0.5 µg/ml or less (1). Pseudomonas aeruginosa (P. aeruginosa) isolates are moderately sensitive to latamoxef, with 50% being inhibited by 8–32 µg/ml, and concentrations of 64 µg/ml or more are usually required to inhibit 90% of the strains (1). Latamoxef is less active than the cephalosporins against most gram-positive bacteria. The MIC₉₀ of Staphylococcus aureus (S. aureus) strains ranged from 4 to 16 µg/ml. Latamoxef has similar activity against penicillin-resistant and -sensitive strains of S. aureus, but methicillin-resistant S. aureus is resistant to latamoxef (MIC₉₀ > 64 µg/ml) (15–18). The MIC₉₀ of latamoxef for Streptococcus pneumoniae (S. pneumoniae) and Streptococcus pyogenes (S. pyogenes) varies from 1 to 3 μg/ml (18). However, enterococci are resistant to latamoxef (MIC₉₀≥ 64 µg/ml).

Neonates and infants have greatly variable changes in body composition, organ maturity, and development. Hence, special consideration must be given to dosing regimens for both populations.

Population pharmacokinetics (PPK) is a new branch in the field of pharmacokinetic study in recent years. Combining the classical pharmacokinetic model with a population-based statistical model, PPK is used to characterize the pharmacokinetic distribution of a specific population.

Qi et al. found that latamoxef CL in neonates and infants was significantly influenced by current body weight, birth weight, and postnatal age (19). Kou et al. also showed that current body weight and postmenstrual age were identified as significant covariates on latamoxef CL, and current body weight was identified as a significant covariate on latamoxef Vd (20). This change in CL with age can be attributed to renal maturation. In intrauterine life, the glomerular filtration function is established, but it is insignificant. This function begins immediately after birth as the kidneys begin to regulate fluids, water, and electrolytes (21). Newborns have a glomerular filtration rate (GFR) of approximately 40 ml/min/1.73 m², which reaches 66 ml/min/1.73 m² by 2 weeks of age. At approximately 2 years of age, GFR reaches adult levels of 100–125 ml/min/1.73 m² (22). Due to the positive correlation between CL and age, the latamoxef dosing regimen was initially considered only the age factor: 50 mg/kg, q12h in neonates aged 0–1 week, q8h in neonates aged 1–4 weeks, and q6h in infants (1).

However, considering age alone is not sufficient as treatment efficacy is also affected by different bacteria. Hence, dose selection should be based on a combination of pharmacokinetics and pharmacodynamics. As a typical time-dependent antimicrobial agent, the action of latamoxef is largely dependent on the percentage of time when the blood concentration is higher than the minimal inhibit concentration (fT > MIC) during the dose interval (23). Effective dosing regimens for time-dependent antibiotics require that serum drug concentrations exceed the MIC of the causative pathogen for at least 40%–50% of the dosing interval (23). The fT > MIC values for latamoxef are mostly 50%–70% (19, 24, 25).

Monte Carlo simulation combines pharmacokinetic and pharmacodynamic parameters as well as pathogen epidemiology to assess the efficacy of antimicrobial regimens against target strains to optimize empiric antimicrobial therapy (26). Probability of target attainment (PTA) is defined as the percentage of subjects who achieve pharmacokinetics/pharmacodynamics target values. A dosing regimen with a PTA ≥90% is a reasonable choice for empiric antimicrobial therapy.

For the initial dosing regimens in neonatal bacterial infectious diseases, Kou et al. studied 15 dosing regimens under 4 different MIC values (24). The results of PTA of 15 dosing regimens under 4 different MIC values is shown in Table 1. A PTA value ≥90% is reckoned to have a satisfactory effect on the specific MIC. The result also indicates that when 4 μg/ml ≤ MIC ≤ 8 μg/ml, there is a statistically difference between PTA at different administration frequencies at the same dosage (P < 0.05); when MIC ≤ 2 μg/ml, there is no statistically difference between PTA at different administration frequencies at the same dosage (P > 0.05). In neonatal population, the optimal initial dosing regimen for bacterial infectious disease should be followed by a lower dose and less administration frequency, while at the same time achieving bacteriostatic effects. Consequently, Kou et al. recommended 60 mg/kg/day q12h as the desirable initial administration regimen for neonatal infectious diseases.

In other study, Qi et al. pointed out that for neonates and infants, 30 mg/kg q12h is effective against E. coli and K. pneumoniae (MIC ≤ 1 μg/ml). While, a higher dose about 30 mg/kg q8h is required against S. aureus (MIC = 4 μg/ml) (19).

As for the effect of current body weight on CL, Wang et al. also provided a choice that latamoxef dosing regimens could be based on children's body surface area (BSA), since they found that BSA was also a significant covariate to CL and Vd (25). The results of dosing regimens according to BSA under different MIC values are presented in Table 2.

Although there are several dosing regimens options, these regimens are based on simulation results and the efficacy of these regimens needs to be further validated in clinical practice. Yet there is something undeniable about these regimens that provides scientific guidance that contributes to the rational use of latamoxef in pediatrics.

For children, dosage is generally between 40 and 80 mg/kg/day, q6h or q8h, as GFR has reached adult levels. Dosing adjustments based on BSA and MIC values may also be made if necessary (Table 2).

The shortcoming of the current study is that there is no appropriate regimen for children with renal insufficiency. Although renal function plays a crucial role in latamoxef excretion, creatinine clearance (CL_cr) is not well correlated with latamoxef CL. The reason for this may be that the number of samples was limited and most of the participants had normal kidney function. Larger samples are therefore needed for further studies or to use physiologically based pharmacokinetic models to predict dosing regimens in children with renal dysfunction.

Table 3 summarizes the key findings of the pharmacokinetics/pharmacodynamics study of latamoxef in pediatrics.

Latamoxef is generally well tolerated in adults. Local reactions (3%), hypersensitivity (3%), diarrhea (1%), eosinophilia (2.5%), and abnormalities in liver (3%) or renal (2%) function tests are the most commonly reported adverse drug reactions. Other adverse drug reactions such as coagulation disorders, antibiotic-associated colitis, and disulfiram-like reactions have also been reported (1). 3% of patients treated with intravenous or intramuscular latamoxef have reported local reactions such as phlebitis and pain. However, these reactions rarely necessitate discontinuities (27, 28). Hypersensitivity, which manifests in the form of rash and/or drug fever, occurs in about 3% of patients treated with latamoxef. This is the most common reason for stopping treatment. Approximately 4% of patients allergic to penicillin or cephalosporins will have a cross-allergic reaction to latamoxef (18, 29). Patients especially those with a type Ⅰ hypersensitivity reaction to penicillin should use latamoxef with caution. The bleeding risk is thought to be related to the administration of latamoxef. Patients who are seriously ill, debilitated, or malnourished, or with renal impairment, are more likely to develop the condition (30, 31). Abnormalities of liver function manifest as hepatic enzyme abnormalities, such as increased serum glutamic oxaloacetic or pyruvic transaminases or alkaline phosphatase (29). Abnormal results on renal function tests, such as elevated blood urea nitrogen and serum creatinine, as well as hematuria, pyuria, and albuminuria, have been reported in approximately 2% of patients. However, they are rarely thought to be drug-related (29, 32).

Although adverse drug reactions of latamoxef have been less frequently reported in pediatrics, there are still some aspects that need to be addressed.