Cefadroxil and cephalexin pharmacokinetics and pharmacodynamics in children with musculoskeletal infections.

Cephalexin, a first-generation cephalosporin, is the first-line oral therapy for children with musculoskeletal infections due to methicillin-susceptible Staphylococcus aureus (MSSA). Cefadroxil, a similar first-generation cephalosporin, is an attractive alternative to cephalexin given its longer half-life. In this study, we describe the comparative pharmacokinetics (PK) and pharmacodynamics (PD) of cephalexin and cefadroxil in children with musculoskeletal infections. Children aged 6 months to 18 years with a musculoskeletal infection were enrolled in a prospective, open-label, crossover PK study and given single oral doses of cefadroxil (50-75 mg/kg up to 2,000 mg) and cephalexin (50 mg/kg up to 1,375 mg). Population PK models were developed and used for dosing simulations. Our primary PD target was the achievement of free antibiotic concentrations above the minimum inhibitory concentration (fT >MIC) for 40% of the day for MICs ≤ 4 mg/L. PK of cephalexin (n = 15) and cefadroxil (n = 14) were best described using a one-compartment, first-order absorption model, with a lag time component for cefadroxil. PK parameters were notable for cefadroxil's longer half-life (1.61 h) than cephalexin's (1.10 h). For pediatric weight bands, our primary PD target was achieved by cephalexin 25 mg/kg/dose, maximum 750 mg/dose, administered three times daily and cefadroxil 40 mg/kg/dose, maximum 1,500 mg/dose, administered twice daily. More aggressive dosing was required to achieve higher PD targets. Among children with musculoskeletal infections, oral cephalexin and cefadroxil achieved PD targets for efficacy against MSSA. Given less frequent dosing, twice-daily cefadroxil should be further considered as an alternative to cephalexin for oral step-down therapy for serious infections due to MSSA.

Time for a Change: Considering Vancomycin Alternatives for Pediatric Methicillin-Resistant Staphylococcus aureus Bacteremia.

Vancomycin remains the standard of care for treating methicillin-resistant Staphylococcus aureus (MRSA) bacteremia in pediatrics largely because no alternative antibiotic is definitively superior. Long-standing historical precedent and S. aureus' notable lack of vancomycin resistance are clear benefits, but vancomycin's use remains plagued by nephrotoxicity and the need for therapeutic drug monitoring, with inadequate consensus on how best to dose or monitor vancomycin in pediatrics. Daptomycin, ceftaroline, and linezolid are all promising alternatives, with improved safety relative to vancomycin. However, inadequate and variable efficacy data limit confidence in their use. Despite this, we contend that it is time for clinicians to reconsider vancomycin's place in clinical use. In this review, we summarize the supporting data for using vancomycin versus these other anti-MRSA antibiotics, present a framework for antibiotic decision-making that considers patient-specific factors, and discuss approaches to antibiotic selection for various etiologies of MRSA bacteremia. This review aims to help pediatric clinicians choose among the various treatment options for MRSA bacteremia, acknowledging that the optimal antibiotic choice is sometimes uncertain.

Cefadroxil Comparable to Cephalexin: Minimum Inhibitory Concentrations among Methicillin-Susceptible Staphylococcus aureus Isolates from Pediatric Musculoskeletal Infections.

Cephalexin and cefadroxil are oral first-generation cephalosporins used to treat methicillin-susceptible Staphylococcus aureus (MSSA) infections. Despite its shorter half-life, cephalexin is more frequently prescribed, although cefadroxil is an appealing alternative, given its slower clearance and possibility for less frequent dosing. We report comparative MIC distributions for cefadroxil and cephalexin, as well as for oxacillin, cephalothin, ceftaroline, and cefazolin, for 48 unique clinical MSSA isolates from pediatric patients with musculoskeletal infections. Both cefadroxil and cephalexin had MIC50 values of 2 µg/mL and MIC90 values of 4 µg/mL. MIC50s for oxacillin, cephalothin, and ceftaroline were ≤0.25 µg/mL, and cefazolin's MIC50 was 0.5 µg/mL. While cefadroxil and cephalexin MICs are higher than those for other active agents, the distributions of MICs for cefadroxil and cephalexin are statistically equivalent, suggesting similar in vitro MSSA activities. Cefadroxil should be further considered an alternative agent to cephalexin, although additional work is needed to identify the optimal dose and frequency of these antibiotics for the treatment of serious MSSA infections. IMPORTANCE Cephalexin and cefadroxil are oral antibiotics that are used to treat serious infections due to the bacteria MSSA. While cephalexin is used more commonly, cefadroxil is excreted from the body more slowly; this generally allows patients to take cefadroxil less frequently than cephalexin. In this study, we compared the abilities of cefadroxil, cephalexin, and several other representative intravenous antibiotics to inhibit the growth of MSSA in the laboratory. Bacterial samples were obtained from children with bone, joint, and/or muscle infections caused by MSSA. We found that cefadroxil and cephalexin inhibited the growth of MSSA at similar concentrations, suggesting similar antibacterial potencies. The selected intravenous antistaphylococcal antibiotics generally inhibited bacterial growth with lower antibiotic concentrations. Based on these results, cefadroxil should be further considered an alternative oral antibiotic to cephalexin, although future research is needed to identify the optimal dose and frequency of these antibiotics for serious infections.

Management of an Immunocompromised Pediatric Patient With Multiple Hospitalizations for Symptomatic COVID-19.

Relapse of infection due to SARS-CoV-2 has been rarely described and there is little guidance regarding the management of such cases in immunocompromised hosts. We present a case of an adolescent female with B-cell acute lymphoblastic leukemia hospitalized multiple times for symptomatic SARS-CoV-2 infection who was safely treated with 2 courses of remdesivir (RDV) and has had no additional readmissions to date. Though additional studies are needed to confirm the safety and efficacy of an additional course of RDV in the setting of relapsed or prolonged severe COVID-19, our observations suggest that a second course of RDV may be considered.

Impact of Antimicrobial Stewardship Bundle on Inpatient Use of Highly Bioavailable Antibacterials.

OBJECTIVES: Intravenous (IV) to enteral transition of highly bioavailable antibacterial drugs is associated with improved safety and lower cost. We evaluated the impact of a bundle of stewardship-driven interventions (including in-person stewardship rounding, clinical pathways, and clinical pharmacist-driven enteral transition workflows) on IV versus enteral administration of highly bioavailable antibacterials at a freestanding children's hospital. METHODS: We collected 2010-2018 inpatient usage data for clindamycin, levofloxacin, ciprofloxacin, metronidazole, rifampin, linezolid, and trimethoprim-sulfamethoxazole. We analyzed total use (in days of therapy [DOTs] per 1000 patient-days [PDs]) and the percentage of total use administered enterally, both hospital wide and stratified by unit subgrouping, specifically comparing use 1-year prestewardship implementation with year-5 postimplementation. RESULTS: Across the 8-year study window, clindamycin, fluoroquinolones, and metronidazole, together, accounted for 96% of IV DOTs for highly bioavailable antibacterials. Overall, clindamycin use decreased from 44.4 to 20.2 DOTs per 1000 PDs (P < .001), with the enteral percentage of total use increasing from 23% to 43% (P < .001) hospital wide. Overall, fluoroquinolone use decreased from 33.7 to 19.3 DOTs per 1000 PDs (P < .001), with the enteral percentage increasing from 40.7% to 55.9% (P < .001). Overall, metronidazole use increased, and the enteral percentage decreased (42.0% to 33.7%; P = .007). Low-IV-use antibacterials (rifampin, linezolid, and trimethoprim-sulfamethoxazole) showed no significant changes in total use or the enteral percentage of total use. CONCLUSIONS: Stewardship interventions were associated with decreased overall use and an increased enteral percentage of total use for both clindamycin and fluoroquinolones, although not metronidazole. These data provide an easy-to-collect benchmark for pediatric hospitals to compare IV with enteral use of highly bioavailable antibacterials within the context of overall antibacterial use.

An Immune Recovery-Based Revaccination Protocol for Pediatric Hematopoietic Stem Cell Transplant Recipients: Revaccination Outcomes Following Pediatric HSCT.

Following hematopoietic stem cell transplant (HSCT), patients are at increased risk of vaccine-preventable diseases (VPDs) and experience worse outcomes of VPDs compared to immunocompetent patients. Therefore, patients are routinely vaccinated post-HSCT to restore VPD immunity. Published guidelines recommend revaccination based on time post-HSCT, although optimal revaccination timing and the value of using other clinical and laboratory variables to guide revaccination remain unclear. An institutional immune recovery-based protocol to guide timing of revaccination is used at Children's Hospital Colorado. This protocol incorporates time from transplant, time off immunosuppressive therapy and intravenous immunoglobulin replacement, absence of active graft-versus-host disease (GVHD), and minimum absolute CD4 count, absolute lymphocyte count (ALC), and immunoglobulin G (IgG) levels. The objective of this study is to evaluate the performance of this immune recovery-based revaccination protocol by determining rates of seroprotective vaccine responses achieved and describing demographic, clinical, and laboratory markers associated with protective antibody titers post-revaccination. Rates of seroprotection following revaccination were retrospectively determined for patients who received autologous or allogeneic HSCTs at Children's Hospital Colorado from 2007 to 2017. Percent seropositivity after revaccination was determined for ten VPDs: measles, mumps, rubella, varicella, tetanus, diphtheria, Haemophilus influenzae type B (Hib), poliovirus, hepatitis B virus (HBV), and Streptococcus pneumoniae. The impact of covariates, including post-HSCT vaccine timing, patient demographics, clinical features (diagnosis, donor and conditioning regimen data, GVHD, cytomegalovirus disease), and laboratory parameters (CD4 count, ALC, IgG level), on rates of seroprotection post-revaccination was determined using Wilcoxon rank sum, Fisher's exact, or chi-square tests, as appropriate. One hundred-twelve unique patients among 427 HSCT recipients had available data for both revaccination timing and vaccine titers. Among these, high rates of seroprotection were achieved after revaccination for rubella (100%), diphtheria (100%), tetanus (100%), and Hib (98%). More modest rates of seroprotection were achieved after revaccination with HBV (87%) and pneumococcal conjugate (85%) vaccines. Seroprotection was lower after revaccination with measles (76%), pneumococcal polysaccharide (72%), mumps (67%), and varicella (25%) vaccines. Greater rates of seroprotection were associated with younger age (hepatitis B vaccine, P = .04), lack of prior rituximab treatment (pneumococcal conjugate vaccine, P = .005), lack of total body irradiation (pneumococcal conjugate vaccine, P = .03), and receipt of a non-cord blood transplant (pneumococcal polysaccharide vaccine, P = .04). These results suggest that a revaccination protocol that incorporates both time post-HSCT and patient-specific indicators of immunologic recovery can achieve high rates of seroprotection against most VPDs. Seroprotection rates for HBV and PCV were notably among the highest reported in children post-HSCT, suggesting that an immune recovery-based protocol may improve seroprotection for some VPDs that frequently are associated with lower vaccine responses post-HSCT. Seroprotection rates for other VPDs remained suboptimal after revaccination. Therefore, evaluation of additional strategies, such as the use of novel markers of immune competence and new vaccines, to further optimize protection against VPDs in this population is warranted.