Company-Albir et al. reported the safe and effective use of intraperitoneal vancomycin in a Neonatal Intensive Care Unit (NICU) full-term patient with PD-related peritonitis (on continuous PD). Vancomycin was administered at a dose of 25 mg/L, without a loading dose. Serum levels at 2 and 5 days from treatment start were 8.4 and 7.4 mg/L, respectively, with clinical cure, even without reaching the recommended serum levels (22).

A study by Sridharan et al. reported serum vancomycin concentrations from nine Pediatric Intensive Care Unit (PICU) children with kidney dysfunction receiving vancomycin at standard dosing. These patients had a significantly reduced drug clearance, a prolonged elimination half-life and area under the time – concentration curve during the dosing interval extrapolated to infinity. The recommended area under the time – concentration curve over 24 h (AUC₀₋₂₄) of > 400 was achieved by 62.5% of the patients of this subgroup (25). This study demonstrated a good correlation between the trough concentration and the AUC₀₋₂₄.

Abid et al. reported the safe and effective intraperitoneal vancomycin use to treat MRSA osteomyelitis in a 2-year-old girl on continuous PD (CPD) for kidney failure and with scarce peripheral IV access options (26). Vancomycin MIC was favorable. Vancomycin was administered intraperitoneally at a concentration of 20 mg/L for 14 h per day for 2 weeks. Serum levels on days 6 and 8 were adequate. The calculated vancomycin AUC/MIC ratio was adequate and exceeded the recommended ratio of 400. In the presence of peritonitis, 90% of intraperitoneal vancomycin is absorbed, compared to 50% in the absence of peritonitis. The International Society for Peritoneal Dialysis (ISPD) guidelines recommend a dose of intraperitoneal vancomycin of 1 g/L for initial treatment, followed by 25 mg/L for maintenance in children on CPD, or 30 mg/kg as a loading dose, followed by 15 mg/kg every 3–5 days in case of intermittent therapy with one daily exchange (63). Nevertheless, published data on children are sparse, with very little information on dosing in neonates.

Indeed, IV access unfeasibility is not unusual in infants and children, especially when the vessels need to be preserved for HD fistulae or when the risks of placing an IV access outweigh the benefits. In these cases, drug dosing and monitoring require special attention. When vancomycin is administered by continuous infusion, the AUC is calculated by multiplying the steady-state serum concentration by a factor of 24 (h). The same approach was used in the case reported by Abid et al. Intraperitoneal vancomycin exposure was considered comparable to IV administration, given that no vancomycin was eliminated over the remaining 10 h per day without PD, in a patient with kidney failure since birth and with no residual kidney function. This approach may be considered in exceptional cases, bearing in mind the tendency of a prolonged time to steady-state in dialysis patients.

Smit et al. provided a dosing adaptation guideline for IV vancomycin in a wide population of 1,892 children and adolescents, including overweight, obese individuals with an impaired renal function (patients on KRT were excluded), with available vancomycin concentrations after at least two IV administrations (27). From these data, they developed a two-compartment model with inter-individual variability on clearance and peripheral volume of distribution, with a final proposed dosing guideline for intermittent IV administration, according to both kidney function (measured with bedside Schwartz formula) and body weight (doses and administration intervals are fully reported in Table 1). The aim was reaching an AUC₂₀ of 400–700 mg/h/L at day 3 after treatment start. Already in the first 24 h, target AUCs were reached in all individuals with impaired renal function. Overlapping results were obtained, adapting the dosing guideline to a continuous infusion regimen (15 mg/kg as a loading dose, followed after 3 h by the proposed daily dose as 24-h infusion).

In their retrospective cohort, Fitzgerald et al. reported the therapeutic drug monitoring of IV vancomycin in 16/43 pediatric patients with AKI after cardiac arrest. The median initial vancomycin dose was 10 (IQR 10–15) mg/Kg, administered at a median interval of 8 (IQR 6–12) h. The range of initial dosing intervals was wide in patients with AKI. All children underwent vancomycin concentration measurement within 3 days from the first dose, with higher first drug concentrations in patients with AKI, indifferently below or over 1 year of age (median 16 vs 7 mg/L, P=0.003). The initial eGFR was a significant predictor of AKI on day five (23). In this special population, decreased drug clearance was evident early. However, early concentration monitoring was not performed on all patients with a low initial eGFR, indicating the need for an earlier therapeutic drug monitoring in high-risk populations with renal impairment (23).

Special consideration should be made to the recent study by Smit et al. (27). PK studies on vancomycin in the pediatric obese population are limited, especially in children and adolescents with impaired renal function. The authors demonstrated that drug clearance was well predicted by combining total body weight and renal function calculated with bedside Schwartz equation, which is normalized for body surface area, and suggested dose adjustments not on trough concentrations alone, but with Bayesian forecasting, based on PK models, such as the proposed one. These data indicate that obese children may present some hyperfiltration, though without translating into increased vancomycin clearance. With the proposed dosing, effective and safe exposures at day 3 (AUC_day3 of 400–700 mg/h/L) and in the first 24 h are expected throughout the pediatric population over 1 year of age. The current suggested doses [IDSA and British National Formulary for children (64)], as compared to the proposed dosing regimen, resulted instead in higher exposures (AUC_day3 >700 mg/h/L) in obese pediatric patients with reduced renal function.

Cies et al. described the use of continuous infusion vancomycin in the dialysate fluid in 11 ICU patients requiring CKRT (21). The median administered dose was 25 mg/L, with a mean plateau level of 22.8 ± 3.3 mg/L. All children were administered a loading dose before the CKRT started. When vancomycin was started after CKRT, a single loading dose of 15–20 mg/kg was given intravenously over 60 min and afterwards added continuously into the CKRT solution, dialysate and/or replacement fluid depending on hemodialysis modality. Serum levels were monitored. If the first plateau level was within range, daily plateau levels were obtained for the duration that the vancomycin was mixed in the CKRT solution(s). If the first vancomycin plateau level was out of range, the concentration in the CKRT solution(s) was adjusted. Ten out of 11 patients reached therapeutic levels within 8 h. A serum plateau level higher than 15 mg/L was reached in all patients (target 15–30 mg/L), regardless of CKRT modality, dose and flow rate. No adverse events were reported.

Data about vancomycin use in CKRT are scarce and not specific for the pediatric population. Adult data have identified factors influencing PK, such as inotropes/vasopressors, extrarenal drug clearance, CKRT intensity and circuitry, as well as albumin concentration (60, 61). Studies demonstrated an increase of drug clearance by at least 30% in changing from hemofiltration to hemodiafiltration and that ultrafiltration rates are a limiting factor for drug concentrations (62). The study by Cies et al. pushes forward the already reported practice of adding antibiotics to dialysate solutions, common in PD. Regarding its application to the pediatric population, adding vancomycin to CKRT solution has the advantage of minimizing the chance of high serum concentrations and potential toxicities, ensuring drug delivery only while receiving CKRT. Moreover, the vancomycin serum plateau level should correspond to the drug concentration in CKRT solution(s), regardless of the membrane, dialysis modality or intensity. This may also result in a lower drug consumption per day and eventually cost saving (21).

Sridharan et al. published a retrospective study on the use of empirical IV vancomycin in 13 PICU patients with renal dysfunction due to AKI, receiving standard doses (Table 1) (24). Vancomycin was dosed and resulted in the recommended range only in 22% of patients with renal dysfunction (median concentration of 7.4 mg/l). Moreover, concomitant use of other potentially nephrotoxic medicines, such as meropenem, gentamicin, piperacillin, and furosemide, was significantly more common amongst children with AKI than others. Ten patients survived and three died.

Recommended vancomycin dosing regimens may prove ineffective in reaching therapeutic trough levels in critically-ill children with renal dysfunction. This is because sub-therapeutic levels imply underdosing, while drug accumulation during AKI may lead to toxicity, with a consequent higher risk of mortality. Moreover, in ICU settings, the concomitant use of other nephrotoxic anti-infective agents or different medicines is not uncommon. The authors mention the possibility of estimating AUC₂₄ and titrating vancomycin levels by a Bayesian approach using validated softwares from population-specific pharmacokinetic parameters, but with the limitation of a lack of supporting cost-effectiveness studies.

Cies et al. described a case of a full-term newborn that presented complications after adenovirus infection, with multi-organ failure, disseminated intravascular coagulation and eventually P. aeruginosa sepsis/septic shock (30). She required CKTT with hemodiafiltration and then ECMO and was treated with meropenem, first 40 mg/kg in a single bolus, followed by continuous infusion at a dose of 10 mg/kg/h (meropenem MIC=0.25 mg/L.) After 3 days, a meropenem serum concentration of 21 mg/L was obtained (clearance of 7.9 mL/kg/min), with a 100% f T>MIC. This regimen provided a 100% target attainment for serum concentrations above the MIC for ≥40% of the dosing interval and cultures sterilization (30). Indeed therapeutic drug monitoring is critical, and individualized, PK-based regimens may help reach optimal efficacy in these patients.

Alqaqaa et al. reported the case of a 4-year-old boy with a recent diagnosis of leukemia in status post-induction chemotherapy who presented septic shock due to E. coli, requiring extracorporeal membrane oxygenation (ECMO) and CKRT (29). Meropenem was at first administered at a dose of 40 mg/kg intravenously every 8 h, together with amikacin and vancomycin. The patient presented progressive renal failure and eventually required CVVHD, so meropenem was shifted to continuous infusion at a dose of 10 mg/kg/h. Serum drug concentrations were monitored daily, registering a rise from 718 mg/L on day three (before continuous infusion) to 3,553 mg/L on the seventh day. The continuous infusion was stopped for supratherapeutic levels, and intermittent administration (20 mg/kg every 12 h) was started 12 h later, with subsequent falling trough levels. The reported volume of distribution (Vd) was 0.026 L/kg with a clearance of 0.051 mL/kg/min.

Goldstein et al. and colleagues studied meropenem dosing in children with ESKD. They reported easy clearance by hemodialysis, in line with studies on adults (28). Also, the median drug half-life between dialytic sessions was similar to what was reported for adults with ESKD (73). A single dose of 20 mg/kg (maximum 500 mg) was administered before and after two separate hemodialysis (HD) treatments in seven children and adolescents (six male and one female) with P. aeruginosa central-line infections (28). The drug was well tolerated without adverse effects. Meropenem reduction percentage was well correlated with increasing urea reduction percentage (average increase in meropenem clearance of 295%). The median drug half-life was 7.3 h off dialysis. The 20 mg/kg dose was insufficient to ensure an acceptable interdialytic pharmacodynamics profile of 70% duration with a drug concentration > 4 mg/L (the MIC₉₀ for P. aeruginosa) in four of the seven patients. Simulated doses able to guarantee an acceptable pharmacodynamics profile, achieving suitable peak concentrations, were 25 mg/kg/day or an alternate daily dose of 40 mg/kg.

The chosen single dose of 20 mg/kg followed data from the literature reporting no dose-dependent effects on PK in children receiving doses from 10 to 40 mg/kg. However, such a dose was inadequate to maintain bactericidal concentrations between dialysis sessions. According to the model of dosing simulation, a dose of 40 mg/kg every other day could ensure concentrations above 4 mg/L in children with ESKD, by administering the drug after every dialytic session. Therefore, the suggested regimen for children on dialysis in an ICU setting would be 25 mg/kg/day after dialysis treatment, hypothesizing daily sessions (28).

Rapp and colleagues developed a PK model for meropenem, confirming that CKRT is an influential parameter on clearance for easy drug diffusion through the dialysate membrane. They described the development of a meropenem PK model in 40 critically-ill PICU children, of which 14 with renal impairment and 11 on CKRT (31). Data were fitted with a two-compartment model with first-order elimination (PK parameters: individual clearance-CL, central volume of distribution, individual inter-compartment clearance-Q and peripheral volume). As eGFR had a significant effect on individual clearance, a final CL covariate submodel for children with CRTT was developed. Monte Carlo simulations were used to determine the most suitable dosing regimen for patients with severe kidney failure with CKRT or without CKRT, defined as the probability of target attainment as 50% of the time that free drug remains above the MIC over a 24-h period (fT>MIC) and 100% fT> MIC, at steady state. Meropenem dosing regimens are listed in Table 2. For each dosing regimen, thethreshold for nephrotoxicity (44 ml/L) was crossed for patients with severe renal failure for doses of 120 mg/kg/day. The suggested regimen for children with renal failure, regardless of the need of CKRT, was intermittent infusion 60 mg/kg/day for MIC < 2 mg/L or continuous infusion 60 mg/kg/day for MIC > 4 mg/L.

The suggested dose of 60 mg/kg/day, either by intermittent or continuous administration, is consistent with pediatric recommendations. However, further studies on children on CKRT only, focusing on the effects of dialysate/filtration flow rate on elimination, are needed. For bacteria with a high MIC of > 4 mg/L, continuous infusion appeared to be the best regimen to achieve 50% or 100% f T>_MIC in children on CKRT, as well as for those with normal or augmented renal clearance. For germs with lower MIC, intermittent administration was appropriate in children with renal failure, on CKRT and with normal renal function alike, but not for children with an augmented renal clearance. Therapeutic drug monitoring is especially necessary for these vulnerable populations, considering that doses of 120 mg/kg/day, either on intermittent or continuous infusion, may lead to accumulation and possible toxicity.

One of the included studies focused on panipenem/betamipron (PAPM), a carbapenem active against Gram-negative and Gram-positive, aerobic and anaerobic bacteria, mainly eliminated by the kidneys (32). It is administered with beta-mipron (BP), an organic anion tubular transport inhibitor inhibiting the active transport of panipenem in the renal cortex and thus reducing its nephrotoxic potential. For panipenem, it is desirable to maintain a concentration above the MIC through the dosing interval. The recommended dose for adults with no renal impairment is 0.5 g every 12 h, increasing to 1 g every 12 h, with no reported data on children. Dialysate and ultrafiltrate flow on CKRT are expected to influence its PK (74–76).

Hayakawa et al. provided data on the PK and most suitable dosing regimen of PAPM in four critically ill patients on CKRT, of which one 16-year-old female (32). They developed an in vitro model to estimate PK, offering a predictive formula to determine the appropriate regimens during CKRT, calculating panipenem total clearance as the sum of clearance dependent on the body together with CKRT. Most importantly, the influence of CKRT-dependent clearance on total clearance increases when the high-volume replacement CKRT is done in case of severe AKI. In PK simulation, the doses and intervals for administration were adjusted to maintain the breakpoint MIC of 4 mg/L throughout the dosing intervals. Total drug clearance during CKRT was estimated based on dialysate flows, ultrafiltrate flows and renal function of patients. PK values of the drug were measured in the four patients. The adolescent patient had a 24-h creatinine clearance (CrCL) of 32 ml/min and received 1 g x3/day of PAPM. Reported PK values during CKRT were: AUC 124 mg/h/ml, half-life 4.6 h, steady-state volume 0.84 l/kg, total clearance 135 ml/min and clearance by CKRT 33.8 ml/min, with almost equal predictive clearance values. The appropriate dosing regimens to maintain an adequate plasma concentration level throughout the dosing intervals were established through predictive formulas applied to various renal functions during CKRT.

Last, it is worth reporting the experience of Ye and colleagues in establishing an ex-vivo, physiologically-based PK (PBPK) simulation model for prediction of the PK of ertapenem in pediatric patients with renal impairment and PD evaluation after validation of adult data (76). Ertapenem concentrations were simulated in children with kidney impairment after an intravenous administration of 15 mg/kg, chosen for healthy individuals with a target of achieving 40%T>MIC. Despite no significant changes in maximum/peak serum concentration (C_max), the AUC value was 1.42-fold higher in mild kidney impairment, 1.84-fold higher in moderate renal impairment and 3.52-fold higher in ESRD than in healthy children. Based on these changes, the dose was adjusted to 13 mg/kg bis-in-die (bid) in mild renal impairment, 9 mg/kg bid in moderate renal impairment, 6 mg/kg bid in severe renal impairment, and 5 mg/kg bid in ESRD. %T> MIC was evaluated, with a probability of reaching 40%T>MIC (MIC ≤ 4 mg/L) of nearly 100%. As there is no data on ertapenem for pediatric patients with renal impairment, a PBPK model represents an important tool for incorporating changes in this special population.

In the study by Sirinavin et al. on the use of IV gentamicin, data on 23 infants and children with various degrees of kidney failure indicated that gentamicin half-life could be estimated by multiplying the serum creatinine concentration by a factor of four (37). All participants received from 2 to 2.5 mg/kg as a first dose, with a dosing schedule over the first 24–48 h that followed adult guidelines and subsequent doses and administration intervals that followed PK calculations instead. The suggested schedule was one-half of the usual dose every half-life, three-quarters of the dose every two half-lives, or a full dose every three half-lives, and the choice of a regimen depends on the entity of renal impairment to avoid prolonged periods of sub-therapeutic concentrations. Administration schedules with dosing intervals longer than 24 h ensure a maximal bactericidal activity while reducing adverse effects. There was a statistically significant correlation between gentamicin half-life and serum creatinine concentration. (37).

Lanao et al. described the PK of amikacin in their prospective study on children with both normal and impaired renal function (38). Ten of the 18 included patients had various degrees of kidney impairment. All children received 7.5 mg/kg/dose in single bolus; then blood samples were withdrawn at 0, 0.5, 2.0, 4.0, 8.0, 12.0, and 16.0 h to determine blood levels. There was a linear correlation between the deterioration of renal function and a progressive decrease in the drug elimination rate. The study reported a decrease of the distribution constants, the overall elimination rate constant and serum clearance, with an increase of the distribution volume at steady state. The serum half-life, which was 1 h in children with normal kidney function, reached values of 14 h in children with severe renal impairment. The main modification in the PK of amikacin in children with kidney impairment was the decrease in the elimination rate, determining significant increases in the serum half-life. Thus, serum drug concentrations should be monitored systematically, together with renal function.

Gentamicin administration at improper intervals may lead to either sub-therapeutic or potentially toxic serum concentrations. Yoshioka and colleagues reported the use of intramuscular gentamicin in 15 children and adolescents aged from 8 to 17, weighing 23 to 60 kg, with impaired kidney function. Peak levels and the change in blood levels up to the fourth dose were measured (36). A decline of serum concentrations appeared to be delayed in decreased kidney function, proportionally to the degree of renal damage. In particular, the half-life value increased sharply when CrCL values fell below 20 ml/min/1.73 m². They also produced a diagram, plotting the half-life values against CrCL values, and calculated an equation of fitted regression line to predict the half-life for a known CrCL to adjust the dosing interval. Three patients were treated with the adjusted dosing schedule (administration intervals of 2.2, 3.5 and 3.7 times the estimated half-life, respectively). Peak blood levels, measured for repeated dose, remained within therapeutic levels, with no accumulation.

In the study by Butragueño-Laiseca and colleagues, data on dosing regimens of ceftolozane-tazobactam in three critically-ill children, of which two had kidney impairment, were reported (42). Patient B, of 19 months of age with hypoplastic left heart syndrome at Glenn stage, had pneumonia due to MDR P. aeruginosa and stage II KDIGO AKI with eGFR of 22 mL/min/1.73 m²; he received an adjusted dose of 36 mg/kg every 8 h. Patient C, of 9 months and on CKRT after heart transplantation, had pneumonia due to MDR P. aeruginosa and ESBL E. coli bacteremia, for which he received 30 mg/kg every 8 h. CKRT settings were blood flow 30 mL/min, substitution flow 160 mL/h, dialysis flow 250 mL/h, extraction 60 mL/h, and total effluent flow 470 mL/h. Drug PK was defined through patients' parameters by Bayesian estimation based on a population PK model. Dosing regimens were decided by the treating physicians, according to available data in the literature and each child's conditions. As a maximum exposure bound, the first PK criterion for dose selection was the 95th percentile of adult ceftolozane exposure (AUC₀₋₈ = 628 (mg h/L) and C_max = 151 mg/L). Patient B exceeded it, with an AUC₀₋₈ = 1,481 (mg h/L) and a C_max = 220 mg/L. As a potential efficacy bound, the second criterion was a minimum blood plasma concentration (C_min) = 16 for ceftolozane. This was met by all patients (C_min ≥ 16). Drug blood concentrations were measured and were always above the ceftolozane MIC. The terminal half-life of ceftolozane in patient B was double that of the patient without renal impairment because of a lower volume of distribution at steady state. For the hemodialyzed patient, the total estimated ceftolozane clearance rate during CVVHDF (0.39 L/h) was about half of that for the patient with a normal renal function. For both patients B and C, the predicted individual PK profiles were within the 90% predicted intervals computed from a model with the same individual characteristics.

The PK of this drug had previously been reported for healthy adults or adults with renal impairment (91–93). In this population, the dose requires adjustment for CrCL ≤ 50 ml/min. A 2.5-fold increase in the AUC for ceftolozane was found in subjects with moderate kidney impairment, while for subjects with severe kidney impairment, the AUC for ceftolozane increased by 4.4-fold. Data on PK for children and adolescents are limited (94–98), finding that exposures estimated through a non-compartmental analysis were similar to those reported for adults but with no data regarding children with renal impairment or on dialysis. Results for the patient with AKI suggested that patients with moderate to severe renal impairment should require a decrease in the dose or a lower frequency of administration. As regards CKRT, an ex-vivo experiment did not report significant differences in the sieving coefficient between hemofilter types, ultrafiltrate flow rates or KRT modality (97). Increases in effluent flow and dialysis flow directly increase trans-membrane clearance, especially in children using moderate and high effluent flows (99). The extraction ratios and sieving coefficients found in this study were similar to previous adult findings. Moreover, the total estimated ceftolozane clearance rate during CVVHDF was half of the child with a normal renal function. However, dosing recommendations for CKRT do not apply to intermittent hemodialysis for PK differences. All patients reached a high AUC at steady-state and a % f T>_MIC of 30% of an 8-h dosing interval for a MIC ≤ 4 mg/L. A dose of 10 mg/kg every 8 h may be sufficient in patients with AKI, with a dose reduction in line with the one proposed for adults with AKI, while a dose of 30 mg/kg every 8 h can be considered for children on CKRT and a high effluent rate.

The retrospective study by Stitt et al. reported PK data on four critically ill children (three male and one female, aged 0.5–5 years) admitted to PICU, on continuous venovenous hemodiafiltration (CVVHDF) for AKI, fluid overload and to aid in ammonia clearance, treated with intravenous cefepime, empirically (three cases) or targeting K. pneumoniae pneumonia (one case) (41). Cefepime doses ranged from 48 to 64 mg/kg every 6–12 h. Drug peak, mid-interval and trough concentrations were measured at steady state. All children had a low or absent urine output during therapeutic drug monitoring, thus minimizing the effect of intrinsic renal clearance on cefepime PK. The minimum starting clearance dose of KRT was 2,000 ml/1.73 m²/h with 50% diffusive and 50% convective clearance. Optimal free trough concentrations were reached in three patients (100% f T>1_XMIC, with desirable free trough concentrations ranging from one to four times the MIC for cefepime), with one of them, with the lowest CVVDHF clearance and blood flow rates, reaching 100% f T>4_XMIC. One patient achieved 98.3%100% f T>1_XMIC. There were no reported adverse effects directly linked to the drug. Their retrospective study provides the first data on cefepime PK in children on CKRT, suggesting that the standard doses of 50 mg/kg every 12 h may not allow reaching easily aggressive pharmacodynamics targets of 100% f T>_1−4XMIC in this special population. Despite the limit of only four included patients, their data suggest the wide use of therapeutic drug monitoring as a valuable tool to reach more aggressive pharmacodynamics targets, especially in case of higher prescribed clearance. The calculated volume of distribution and drug half-life in these patients were similar to values for patients without renal impairment, but it is not possible to assume any more definitive link between delivered CVVHDF clearance and cefepime clearance due to data being limited.

Morris et al. reported the case of an 8-year-old 17-kg girl with congenital heart disease multiorgan failure with AKI, requiring continuous peritoneal dialysis, that presented S. epidermidis bacteremia, successfully treated with IV daptomycin (44). The chosen dose was 8 mg/kg/dose every 48 h (for concerns for resistance) for 19 days in total, and PD scheme had 10 ml/kg cycle volumes and hourly cycles. The MIC for daptomycin was 0.125 mg/L. There was a good, rapid clinical and microbiological response, with a good safety profile. Drug concentrations were measured using a validated high-performance liquid chromatography assay. Peak and trough serum concentrations were 68 mg/L and 14.6 mg/L, respectively (target trough <20 mg/L). They demonstrated in their study that an IV dosage of 8 mg/kg every 48 h during continuous PD achieved peak concentrations similar to those achieved at steady state in adults with CrCL of more than 30 mL/min treated with 6 mg/kg every 24 h. Moreover, exposure on the second day after dosage was in line with the IV suggested dose of 6 mg/kg every 48 h for adults on continuous peritoneal dialysis. There is a correlation between toxicity and trough levels, with a chance that CPK elevation will be significantly higher with a trough serum concentration ≥ 24.3 mg/L. According to the elimination half-life, the authors suggested that serum trough concentration should be performed before the third dose in pediatric patients on continuous PD when steady state is likely to have been achieved with doses every 48 h, with a recommended trough concentration of <20 mg/L. Moreover, they recommended serum peak concentration measurement and AUC/MIC calculation only in case of concern about clinical efficacy or reduced probability of pharmacodynamic target attainment for MICs higher than 0.5 mg/L (44).

Chan et al. described a case of peritonitis and bacteremia in a 5-year-old girl that underwent a liver transplant and developed renal failure, requiring hemodialysis (43). She was first empirically treated with vancomycin and piperacillin-tazobactam (doses not specified but adapted for kidney function). Vancomycin-resistant E. faecium (VRE) was found in peritoneal fluid culture, and the therapy was first shifted to meropenem and linezolid (dose not specified), with subsequent resolution of fever. A second culture was found positive for linezolid-resistant VRE, so current therapy was discontinued and daptomycin was initiated and continued for 113 days at a dose of 6 mg/kg every 48 h, then empirically increased to 8 mg/kg for dialytic treatment and persisting positivity of cultures, for concern for reduced potency against E. faecium as compared to S. aureus. Drug concentrations were measured before HD after dose increase. After 45 min since the end of infusion, the serum concentration would approximate the MIC at steady state of adult patients with S. aureus bacteremia and a normal renal function receiving 6 mg/kg. The drug was well tolerated with normal creatine phosphokinase (CPK) levels. Clinical cure was achieved, and the patient eventually underwent combined liver and kidney transplant.

Dumangin et al. described the safe and effective use of temocillin after dosage adjustment in a 7-month-old ex-preterm infant with ESRD to treat a urinary tract infection (UTI) due to a susceptible ESBL-producing Enterobacter cloacae (MIC = 6 mg/L). Temocillin was administered in this patient with a loading dose of 3.5 mg/kg, followed by a maintenance dose of 10 mg/kg/day through continuous infusion. The loading dose was empirical and corresponded to one-third of the maintenance dose. The latter was 5-fold lower than the usual pediatric recommended dose, as described in the summary of product characteristics for infections by ESBL-producing Enterobacteriaceae. Treatment duration was 10 days, with clinical cure. Urinary and plasmatic concentrations of drugs were monitored. The estimated urinary concentration at the end of therapy was 38.7 mg/L. 100% f T_>MIC was achieved in urine since temocillin elimination in urine is predominant (52% to 92%) and delayed in kidney dysfunction. The accumulation rate in urine was similar to adults with severe kidney insufficiency. Plasma levels were 47.0 and 61.8 mg/L after 6 and 10 days of treatment, respectively, with an estimated free concentration of 7.0 and 9.2 mg/L. Free plasma concentrations were estimated to be above the MIC during the last 4 days of treatment, with a minimum of 40% f T_>MIC (47). Temocillin dosing was adjusted with a reduction by 0.6-, 0.3-and 0.1-fold for a CrCL of 60, 30 and 10 mL/min/1.73 m², respectively, according to the available data from the literature, as reported above. Other authors proposed increasing the dosing interval maintaining the same dose as in normal patients (103). Larger clinical and PK studies on temocillin are required in order to determine the optimal regimens for infants and children with kidney impairment.

Healy and colleagues provided valuable colistin PK information in their 2011 report on an adolescent with extensive burn injury by MDR A. baumannii with septic shock and on CVVHDF, receiving a standard dose for moderate renal impairment (2.5 mg/kg/day). C_max, Cmin, AUC0–24 h, total body clearance, and elimination half-lives (t _1/2) of colistin were 3.6 ±1.0 mg/L, 0.9 ± 0.5 mg/L, 47.1 ±14.4 mg/hr/L, 5.2 ±1.7 ml/min, and 12.3 ±9.4 h (mean ±SD), respectively (48).The elimination half-life of colistin during CVVHD was prolonged (13.4 ±5.1 h) while corresponding values on dialysis were 9.4 ±4.6 h. Serum concentrations were at or above the MIC for >90% of treatment. The average peak to MIC ratio was adequate, with a dose of 2.5 mg/kg every 24 h. Despite adequate serum levels and repeat negative cultures, the patient eventually died after developing acidosis, coagulopathy and vasopressor-dependence (48).

Recent evidence from the adult population suggested both peak/MIC and (AUC)/MIC ratios as important parameters for bacterial eradication (104–106). Therefore, dosing should be adjusted to the organism MIC, even though the product literature does not provide such recommendations. Moreover, to avoid underdosing in the early phases of treatment, dosing should follow the actual body weight when adequate drug concentrations are critical. In the report, doses according to an ideal patient weight would have led to underdosing without achievement of adequate peak/MIC and (AUC)/MIC ratios. The principal means of excretions of colistin is thought to be extra-renal, with significantly reduced clearance in critically ill patients (107, 108). Data from this study are in line with the literature on adults also in reporting some degree of drug removal by dialysis (107). The kidney function appears not to alter the individual dose size, but it is advisable, according to these preliminary data, to use it to guide the frequency of administration, to avoid accumulation and nephrotoxicity risk. Therefore, the suggested minimum dose to achieve adequate peak/MIC and (AUC)/MIC ratios for organisms with low MICs is 2.5 mg/kg, while a dose of 5 mg/kg may be more appropriate for higher MICs (1–2 mg/L). In case of decreased kidney function, the administration intervals should be lengthened, but not longer than once every 24 h. Studies on colistin use in younger patients or even neonates are lacking and therefore needed.

Schaefer et al. led a large RCT for evaluation of efficacy, safety and acceptance of combined intraperitoneal treatment with vancomycin/teicoplanin and ceftazidime, administered either intermittently or continuously in 90 pediatric patients with continuous peritoneal dialysis (CPD)-related peritonitis (195 episodes in total), proving the equivalence of continuous and intermittent treatment (39). Children randomized to continuous treatment received an intraperitoneal loading dose of glycopeptide and ceftazidime (Table 8), followed by maintenance doses added to each dialysate bag. In the intermittent administration groups, the glycopeptide was administered in two loading doses seven days apart and ceftazidime during one dialysis cycle per day (Table 8). Treatment response was evaluated after 60 h and after seven days of treatment by changing Disease Severity Score (DSS) and clinical decision. In case of satisfactory response at the initial (60 h) treatment, ceftazidime was discontinued in a gram-positive infection and the glycopeptides in case of a gram-negative infection. If clinical improvement was considered insufficient, the antibiotic therapy was tailored individually. Twenty-seven relapses were reported within 4 weeks after the end of therapy. Clinical cure rates by treatment group are reported in Table 8. In Gram-positive infections, there were no differences between continuous (RR 1.17; 95% CI, 0.51–2.67) and intermittent administration (RR 0.83; 95% CI, 0.30–2.27) and between vancomycin (RR 1.41; 95% CI, 0.58–3.45) and teicoplanin (RR 0.70; 95% CI, 0.28–1.76) as regards the relative risk for primary treatment failure according to DSS. Unresponsive cases to initial treatment were due to S. aureus. In Gram-negative peritonitis, germs with in vitro resistance to ceftazidime were cultured in nearly all cases of lack of response by DSS.

Eradication of the causative germ from the dialysate was observed significantly more often in the continuous than in the intermittent treatment groups both after 60 h (94 vs. 67%, P < 0.001) and after seven days (99 vs. 90%, P = 0.03). In four patients from the continuous administration group, elevated plasmatic levels of glycopeptides were found, while in two intermittently treated children underdosing was observed (but with adequate clinical treatment and not increased relapse rates). Plasmatic levels of intermittently administered vancomycin were inversely correlated with residual GFR but with no relation between blood levels and GRF for intermittent teicoplanin. There was a significant decrease in residual GFR during peritonitis (p = 0.005), showing no differences in relation to the type of glycopeptide or administration. The Authors demonstrated the validity of intermittent glycopeptide administration in children with ESRD, as all patients showed acceptable and safe blood levels during the first 60 h of treatment. Moreover, there were no secondary treatment failures due to inadequate tissue levels.

The nephrotoxic action of glycopeptides remains a concern even in the case of dialysis because of residual kidney function contributing to total solute and water clearance. In this study, residual kidney function deteriorated, but it was not possible to recognize glycopeptide therapy or peritonitis itself as the leading cause. Teicoplanin levels, because of a higher plasma protein binding, were not affected by residual kidney function on the third day of treatment and were more stable after many days after the administration on the loading dose, unlike vancomycin levels. The routine use of glycopeptides for the treatment of CPD-related infections should be in any way discouraged for the increasing prevalence of VRE after their widespread use. As for ceftazidime in combination therapy, it was used for its broad coverage against Gram-negative organisms, including Pseudomonas, avoiding the toxicity of aminoglycosides. It was also chosen for its outstanding bidirectional transperitoneal diffusion and prolonged half-life in ESKD, so once-daily intraperitoneal administration appears an appropriate administration regimen. In this study, it was administered during one prolonged dwell period or over continuous administration. The treatment response was judged discrepantly by clinical decision and DSS, but the delayed bacterial elimination in patients receiving intermittent treatment did not affect the final treatment outcome or the risk of relapse.

The other retrieved study was a case report by Shetty et al. on the use of empirical intraperitoneal combined therapy to treat PD-related peritonitis by N. mucosa in a 17-year-old male adolescent with ESKD (40). There are few reported cases in adults with ESKD, and there is no specific guideline for the optimal treatment in children with kidney dysfunction. The patient was first treated empirically with intraperitoneal cefazolin (500 mg/L) and gentamicin (8 mg/L) as a loading dose, followed by a maintenance dose of 125 mg/L and 4 mg/L, respectively. Prompt clinical response was evident after 48 h. Before discharge, after 6 days of therapy, he was shifted to intraperitoneal ceftriaxone (125 mg/L) for 2 weeks as targeted therapy. Clinical and biochemical cures were confirmed at one-month evaluation.

Acyclovir is the first choice treatment for severe HSV infections in newborns. The drug is mainly eliminated through the kidney with a combination of glomerular filtration and tubular secretion (112). The molecule is small, water-soluble, with a low protein binding, making it readily eliminated by all kinds of dialysis. Acyclovir has a time-dependent killing, correlating efficacy and time above the MIC of serum concentration. For this reason, a continuous infusion is a valuable option. Concentrations in the CSF correspond to 30–50% of plasma concentrations. Dosing should aim at maintaining plasma levels of 3 mg/L or above to ensure CSF concentrations of at least 1 mg/L for optimal outcomes, below 50–70 mg/L, to avoid neurotoxicity (112). Continuous infusion administration is a safe and effective option in case of failure of intermittent administration (113). Nevertheless, there are no data in the literature regarding the use and PK of acyclovir during CKRT. Standard dosing recommendations are at risk of therapeutic failure.

Cies et al. reported data on the use of acyclovir to treat disseminated HSV-1 infection in a 14-day-old neonate with fulminant kidney failure requiring CKRT (34). Acyclovir was already administered intravenously at the standard dose of 20 mg/kg/dose every 8 h, but after conversion to ECLS and CKRT, the dose was increased to 30 mg/kg/dose every 8 h. Because of persistently high viral loads, the continuous infusion was started, with acyclovir being added to the dialysate solution for CKRT (5.5 mg/L), in order to maintain plasma concentrations of at least 3 mg/L and thus at least 1 mg/L in the cerebrospinal fluid (CSF). Serum concentrations at 24 and 72 h after continuous infusion start were adequate for this purpose.

In this article, the existing literature on acyclovir use for adults on CKRT was used as a model. The practice of adding anti-infective medicines to the dialysate solution is not new, usually common in peritoneal dialysis, but not as well-represented in hemodialysis. Modern dialysis filters, circuits and machines may make standard adult dosing recommendations not appropriate to date (34). The Authors chose the intra-dialytic administration route to minimize fluctuations from dialysis clearance based on flow rates. This strategy was successful and confirmed by serum concentrations measurements at 24 and 72 h. Drug PK may be affected by sequestration in the circuit, increased volume of distribution and increased clearance during CKRT, with all available data being derived from adult studies. Ex-vivo models/circuits may indeed be helpful for the improvement of dosing regimens and CKRT patient outcomes.

Peramivir has been experimentally considered an alternative for oseltamivir-resistant strains, but there are no further data on the use of this drug in children.

Shetty et al. reported the case of a 10-year-old male renal transplant recipient that developed renal failure requiring ECMO and CKRT for oseltamivir-resistant 2009 H1N1 pneumonia (33). He was successfully treated with IV peramivir for 2 weeks at an initial dose of 2.2 mg/kg/day. Over the first 72 h of therapy, peak and trough drug levels were assessed, with a subsequent dose increase to 5.4 mg/kg/day to reach a target trough concentration of >1,500 ng/mL. There were no reported adverse effects, with clinical cure and kidney failure improvement by day 13 of treatment. It was administered through an Emergency New Drug Application; the dosage was adapted from adult dose and adjusted in order to achieve adequate target trough concentrations, according to peak and trough levels at 72 h. In addition, the patient's recovery and viral clearance may have been helped because immunosuppressive therapy for renal transplant was discontinued when CKRT was started to sustain kidney function, even facing the risk of graft rejection (33).

Favipiravir is a nucleotide analog inhibiting RNA polymerase approved against influenza in China and Japan. The molecule is hydrophilic, with a protein-bound fraction of 50% and a distribution volume of 15–20 L. It is administered orally for its excellent bioavailability (100%) and is quickly absorbed with a t_max from 30 to 60 min (114). It is mainly eliminated through the kidney, and it has a time- and dose-dependent PK. Serum concentrations may significantly be affected by an impaired kidney function, but there is a lack of studies on drug metabolism in the literature, and there are no existing recommendations for its safe use in children with kidney dysfunction.

Favipiravir was used with no dose adjustment and no measurement of plasma levels by Ozsurekci and colleagues in two out of 11 critically ill children diagnosed with the multisystem inflammatory syndrome in children (MIS-C) after Covid-19 infection, on CKRT, with eGFR <30 ml/min/1.73 m² (35). Doses followed weight as per the recommendations for Ebola (Table 9), without any dose adjustment for kidney dysfunction. Favipiravir use was safe and effective in this category of patients. Other studies in adults recommended dose adjustment in case of kidney impairment (115) due to the accumulation in reduced eGFR of an inactive metabolite, which might be related to toxicity. However, there is a lack of data on the optimal dose and adjusted dose to eGFR for both adults and children (116). In the latter especially, the drug is used off-label. As reported by Ozsurekci, there are no suggestions from the literature about skipping the loading dose in patients with GFRs from 30 to 50 m/min/1.73 m², as the expected increase of two- to three-fold in plasma concentrations is considered safe (117). Larger studies are needed to clarify this aspect.

Linder et al. enrolled 56 NICU patients (of which 36 ELBW neonates) with Candida bloodstream infection in a prospective study comparing the effectiveness and tolerability of three different amphotericin B preparations (45). Thirty-four neonates had serum CrCL of < 1.2 mg/dl and received amphotericin B at a dose of 1 mg/kg/day; patients with serum CrCl ≥ 1.2 mg/dl received either liposomal amphotericin B at a dose of 5 mg/kg/day (6 patients) or amphotericin B colloidal dispersion at a dose of 3 mg/kg/day on the first day, then 5 mg/kg/day (16 patients). There were no significant differences in mortality and no deterioration of kidney function. In case of positive urine cultures or fungus ball, a second antifungal agent was added directly, or introduced for persistent infection for more than 10 days, clinical signs and/or persistent thrombocytopenia. After 14 days from the last positive blood culture, therapy was discontinued in uncomplicated cases. Sterilization of the blood was reported in 67.6% of patients treated with amphotericin B, in 83.3% of patients treated with liposomal amphotericin B in 57.1% of those treated with amphotericin B colloidal dispersion when used as monotherapy. After adding a second antifungal agent, success rates were 100%, 83.3%, and 92.8% in the three groups. Liposomal amphotericin B and amphotericin B colloidal dispersion were safe and effective in premature infants with kidney dysfunction, as effective as conventional amphotericin B for eradicating invasive Candida infections. Therefore, the lipid formulation of amphotericin B is among the drugs of choice for invasive Candida infections in infants with kidney failure.

Cheng et al. reported the successful use of a combination of antifungal agents to treat C. parapsilosis peritonitis in a full-term neonate, requiring PD for kidney failure after E. coli sepsis, treated with broad-spectrum antibiotics. IV amphotericin B lipid formulation was started at a dose of 4 mg/kg/day, together with intraperitoneal fluconazole at 0.1 mg/mL to enhance peritoneal penetration, but without success. (46). The dialysis tube was removed after isolation of C. parapsilosis from blood and peritoneal dialysate; CVVHF was started. Oral 5-flucytosine (50 mg/kg/day) that is usually administered with amphotericin B or fluconazole for fungal peritonitis was also added, and its dose was adjusted to glomerular filtration rate (10–50 mL/min/1.73 m²), increasing the interval of administration from 12 to 24 h. Serum levels were maintained under 100 mg/L (118). IV caspofungin (25 mg/m²/day, then increased to 40 mg/m²/day) was started for concerns about drug resistance and its low nephrotoxicity. The optimal and safe dose for caspofungin in neonates with kidney impairment is yet to be established. IV fluconazole at a dose of 10 mg/kg/day was added because of persistent elevation of CRP levels. Reported MICs at 48 h for C. parapsilosis were 0.5 mg/L for 5-flucytosine, 2 mg/L for fluconazole, 0.125 mg/L for voriconazole and 1.5 mg/L for amphotericin B. Resolution of the episode, with the improvement of clinical conditions and urine output was reported after 10 days of treatment, and medications were gradually discontinued and followed by a two-week oral course of fluconazole (10 mg/kg/day). C. parapsilosis peritonitis is known to be more aggressive, with higher complication rates as compared to other Candida species.

Oualha et al. described fluconazole PK reporting the case of a 17-year-old patient requiring CVVHD and receiving IV fluconazole for C. parapsilosis cholecystits, with sensitivity to fluconazole (MIC 0.5 mg/L) (49). The administered dose was 10 mg/kg/day, that were continued until day 63, when the patient developed biliary fungal peritonitis and septic shock, leading to death. Drug concentrations were measured in plasma and dialysis effluent through a high-performance liquid chromatography assay with ultraviolet detection. An individual PK model was developed to calculate the cumulated drug amount recovered in the dialysis effluent, using the effluent flow rate (4,090 ml/h) and volumes at each time sampling. The estimated PK parameters (Table 10) were used to plot the plasma time profile of fluconazole concentrations, the plasma AUC curve and plasma trough concentrations. Fluconazole bile concentrations were estimated to be similar to those in plasma, suggesting an adequate bile excretion. Fluconazole elimination was high in bile and dialysis route, and higher than in healthy individuals, due to an absent tubular reabsorption in an anuric patient. The Authors failed to integrate also bile concentrations in the model, due to uncertain bile volumes and flows. The concentrations fell below the 10 mg/L target 10 h after the first dose. A loading dose of 900 mg with a maintenance dose of 600 mg twice daily were identified as the best regimen to reach optimal peak and trough concentrations.

As discussed by the Authors, higher loading doses and daily maintenance doses in 2 daily administrations may be suggested in individuals on CVVHD with candidiasis, especially in Candida spp with an MIC >2 mg/L. Due to the notable inter-individual and intra-individual variabilities, repeated therapeutic drug monitoring is a valuable option, especially in the infection site.