Identifying Effective Durations of Antibiotic Therapy for the Treatment of Carbapenem-resistant Enterobacterales Bloodstream Infections: A Multicenter Observational Study.

In a propensity-score-weighted cohort of 183 adults with carbapenem-resistant Enterobacterales bacteremia at 24 US hospitals, patients receiving short courses of active therapy (7-10 days, median 9 days) experienced similar odds of recurrent bacteremia or death within 30 days as those receiving prolonged courses of active therapy (14-21 days, median 14 days).

Challenges in the Treatment of Invasive Aspergillosis in Immunocompromised Children.

Invasive aspergillosis (IA) is associated with significant morbidity and mortality. Voriconazole remains the drug of choice for the treatment of IA in children; however, the complex kinetics of voriconazole in children make dosing challenging and therapeutic drug monitoring (TDM) essential for treatment success. The overarching goal of this review is to discuss the role of voriconazole, posaconazole, isavuconazole, liposomal amphotericin B, echinocandins, and combination antifungal therapy for the treatment of IA in children. We also provide a detailed discussion of antifungal TDM in children.

Challenges with Utilizing the 1,3-Beta-d-Glucan and Galactomannan Assays To Diagnose Invasive Mold Infections in Immunocompromised Children.

Establishing the diagnosis of invasive mold infections (IMI) in immunocompromised children is challenging due to nonspecific clinical presentations and the limited sensitivity of traditional culture-based methods. Rapid non-culture-based diagnostics such as the 1,3-beta-d-glucan and galactomannan assays have emerged as promising adjuncts to conventional diagnostic tests in adults. Available data suggest that 1,3-beta-d-glucan has limited accuracy in the pediatric population and is not recommended to be used for the diagnosis of IMI in children. On the other hand, the diagnostic performance of the serum and bronchoalveolar lavage galactomannan in immunocompromised children is comparable to results observed in adults and can be used as a screening tool in children at high risk of developing invasive aspergillosis (IA) who are not receiving mold-active antifungal prophylaxis and as a diagnostic tool in symptomatic children suspected of having IA. Herein, we summarize the available evidence for the use of these rapid non-culture-based diagnostics in immunocompromised children. We also summarize potential causes of false positivity for the 1,3-beta-d-glucan and galactomannan assays.

Successful Treatment of Persistent Burkholderia cepacia Complex Bacteremia with Ceftazidime-Avibactam.

We report our clinical experience treating a 2-month-old infant with congenital diaphragmatic hernia who experienced prolonged bacteremia with Burkholderia cepacia complex (Bcc) despite conventional antibiotic therapy and appropriate source control measures. The infection resolved after initiation of ceftazidime-avibactam. Whole-genome sequencing revealed that the isolate most closely resembled B. contaminans and identified the mechanism of resistance that likely contributed to clinical cure with this agent. Ceftazidime-avibactam should be considered salvage therapy for Bcc infections if other treatment options have been exhausted.

Low-dose Gentamicin for Uncomplicated Enterococcus faecalis Bacteremia May be Nephrotoxic in Children.

BACKGROUND: Uncertainty exists regarding the role of synergistic gentamicin for uncomplicated Enterococcus faecalis bacteremia in children. METHODS: We conducted a retrospective, observational study comparing clinical outcomes of children with E. faecalis bacteremia without endocarditis receiving ampicillin monotherapy with those receiving ampicillin along with low-dose gentamicin therapy. To account for nonrandom assignment of combination therapy, propensity score weighting was combined with multivariable regression to estimate the effect of combination therapy on duration of bacteremia, bacteremic relapse, and acute kidney injury (AKI). RESULTS: One hundred sixty-three (52%) patients received ampicillin with low-dose gentamicin, and 150 (48%) patients received ampicillin monotherapy. Incorporating propensity-score weighting with additional adjustment for source control measures, patients receiving combination therapy experienced bacterial clearance 10 hours faster than children receiving ampicillin monotherapy (adjusted mean difference 0.42; confidence interval (CI), .02 to .82; P = .04). Bacteremic relapse was similar between the two groups (17% vs 18%); adjusted hazards ratio (aHR) 1.12; 95% CI, .65 to 1.92. Children receiving low-dose gentamicin had approximately twice the risk of developing AKI compared to children not receiving this agent, adjusting for the receipt of additional nephrotoxins (aHR 1.94; 95% CI, 1.48-2.97). CONCLUSIONS: Our study suggests that for children with uncomplicated E. faecalis bacteremia, the addition of low-dose gentamicin may decrease the time to bacterial clearance by 10 hours but without any impact on recurrent bacteremia. However, with this potential benefit comes the increased likelihood of AKI. Low-dose gentamicin for the treatment of uncomplicated enterococcal bacteremia may pose harm to children with limited benefit.

Carbapenem therapy is associated with improved survival compared with piperacillin-tazobactam for patients with extended-spectrum ß-lactamase bacteremia.

BACKGROUND: The effectiveness of piperacillin-tazobactam (PTZ) for the treatment of extended-spectrum ß-lactamase (ESBL) bacteremia is controversial. We compared 14-day mortality of PTZ vs carbapenems as empiric therapy in a cohort of patients with ESBL bacteremia who all received definitive therapy with a carbapenem. METHODS: Patients hospitalized between January 2007 and April 2014 with monomicrobial ESBL bacteremia were included. A decrease of >3 doubling dilutions in the minimum inhibitory concentration for third-generation cephalosporins tested in combination with 4 µg/mL of clavulanic acid was used to confirm ESBL status. The primary exposure was empiric therapy, defined as antibiotic therapy administered to a patient before ESBL status was known. Patients were excluded if they did not receive a carbapenem after ESBL production was identified. The primary outcome was time to death from the first day of bacteremia. Propensity scores using inverse probability of exposure weighting (IPW) were used to estimate the probability that a patient would receive PTZ vs carbapenems empirically. We calculated overall hazard ratios for mortality censored at 14 days using Cox proportional hazards models on an IPW-adjusted cohort. RESULTS: A total of 331 unique patients with ESBL bacteremia were identified. One hundred three (48%) patients received PTZ empirically and 110 (52%) received carbapenems empirically. The adjusted risk of death was 1.92 times higher for patients receiving empiric PTZ compared with empiric carbapenem therapy (95% confidence interval, 1.07-3.45). CONCLUSIONS: PTZ appears inferior to carbapenems for the treatment of ESBL bacteremia. For patients at high risk of invasive ESBL infections, early carbapenem therapy should be considered. Our findings should not be extended to ß-lactam/ß-lactamase inhibitor combinations in development, as limited clinical data are available for these agents.

Treatment of multidrug-resistant Gram-negative infections in children.

Antibiotic resistance in conjunction with the erosion of the drug development pipeline may lead us into a bleak future, a "post-antibiotic era." Because of a shortage of studies addressing treatment options for multidrug-resistant Gram-negative (MDRGN) infections in children, data must be extrapolated from the adult literature. However, even adult studies are limited by significant methodological flaws. We are in urgent need of pediatric specific pharmacokinetic/pharmacodynamic data for agents with activity against MDRGN infections as well as improved clinical outcomes studies. For the time being, we must rely on in vitro studies, observational data, and clinical experience to guide our therapeutic decisions. In this review, we discuss treatment considerations for infections caused by extended-spectrum ß-lactamase-producing organisms, AmpC ß-lactamase-producing organisms, carbapenem-resistant Enterobacteriaceae, carbapenem-resistant Pseudomonas aeruginosa, and carbapenem-resistant Acinetobacter baumannii in the pediatric population.

Optimizing therapy for vancomycin-resistant enterococcal bacteremia in children.

PURPOSE OF REVIEW: Uncertainties exist regarding the optimal treatment for vancomycin-resistant enterococcal (VRE) bloodstream infections, particularly in settings in which ampicillin cannot be used. RECENT FINDINGS: Quinupristin-dalfopristin, linezolid, and daptomycin, all approved between 1999 and 2003, represent the mainstays of therapy for VRE bacteremia, although only linezolid has been specifically approved by the United States Food and Drug Administration for this indication. The main objective of this review is to compare the relative efficacies, dosing strategies, and side-effect profiles of quinupristin-dalfopristin, linezolid, and daptomycin for VRE bacteremia in the pediatric population. A brief description of recently approved broad-spectrum Gram-positive agents that may have a role in the management of VRE bacteremia in upcoming years is also provided. SUMMARY: Linezolid, despite its bacteriostatic activity against VRE, may be the most versatile of the available drugs. It has activity against both Enterococcus faecalis and E. faecium, can be administered orally, and resistance appears to be less of a concern with linezolid compared with the other agents. Additionally, the results of two recent meta-analyses demonstrate more favorable outcomes with linezolid compared with daptomycin for the treatment of VRE bacteremia. The clinical pharmacokinetics of linezolid have been well described in children. The most notable concern with linezolid, however, is toxicities associated with prolonged use. Until more prospective data are available, we favor linezolid as first-line therapy for the treatment of VRE bacteremia in children.

The Clinical Utility of MRSA Nasal Surveillance Swabs in Ruling-Out MRSA Infections in Children.

The utility of methicillin-resistant Staphylococcus aureus (MRSA) nasal surveillance swabs has not been well-described in children. This retrospective, cohort study yielded a negative predictive value of 99.4% for an initial negative MRSA nasal surveillance swab in 165 hospitalized children with a suspected infection and clinical cultures obtained from a likely site of infection.

Successful Treatment of Persistent Stenotrophomonas maltophilia Bacteremia With Cefiderocol in an Infant.

Stenotrophomonas maltophilia is an important nosocomial pathogen with limited treatment options. Trimethoprim-sulfamethoxazole (TMP-SMX) is generally regarded as the preferred therapy; however, treatment failures with TMP-SMX have been reported. Herein, we report a case of a 5-week-old infant with 8 days of S. maltophilia bacteremia while receiving TMP-SMX, despite in vitro susceptibility. Transitioning to cefiderocol monotherapy resulted in blood culture clearance within 24 hours, in the absence of any additional interventions. This is the first published case of the use of cefiderocol for a pediatric patient with an infection due to S. maltophilia. We review preclinical and clinical data that underscore why cefiderocol may be an effective treatment option for S. maltophilia infections.

Boosting of Voriconazole Levels With Omeprazole, A CYP450 2C19 Inhibitor.

Children metabolize voriconazole faster than adults and require higher weight-based doses and more frequent administration to achieve therapeutic troughs. We report a case of a 4-year-old girl with disseminated fusariosis with persistently undetectable voriconazole troughs. Omeprazole was added as a CYP2C19-inhibitor to increase voriconazole concentrations. This case highlights the role of omeprazole for voriconazole boosting in a child.

Does the piperacillin minimum inhibitory concentration for Pseudomonas aeruginosa influence clinical outcomes of children with pseudomonal bacteremia?

BACKGROUND: The Clinical and Laboratory Standards Institute (CLSI) recently elected to adjust the previous piperacillin susceptibility breakpoint of ≤64 µg/mL against Pseudomonas aeruginosa to ≤16 µg/mL, based largely on pharmacokinetic-pharmacodynamic (PK-PD) modeling studies. Data on whether PK-PD modeling correlates with clinical outcomes in children are needed before resorting to broader classes of antibiotics to treat P. aeruginosa. METHODS: We performed a retrospective cohort study of children with P. aeruginosa bacteremia between 2001 and 2010 who were prescribed piperacillin. Baseline characteristics and clinical outcomes of children with piperacillin minimum inhibitory concentrations (MICs) of ≤16 µg/mL and of 32-64 µg/mL were compared. The primary outcome was 30-day mortality. RESULTS: There were 170 children with P. aeruginosa bacteremia receiving piperacillin therapy who met inclusion criteria. One hundred twenty-four (72%) children had piperacillin MICs of ≤16 µg/mL and 46 (28%) children had piperacillin MICs of 32-64 µg/mL. There was no significant difference in baseline characteristics between the 2 groups. Thirty-day mortality was 9% and 24% in children with a piperacillin MIC of ≤16 µg/mL and of 32-64 µg/mL, respectively. Using multivariable logistic regression, children with elevated MICs had increased odds of mortality compared with children with lower MICs (odds ratio, 3.21; 95% confidence interval, 1.26-8.16). CONCLUSIONS: Our finding that elevated piperacillin MICs are associated with higher mortality in children supports the recent CLSI recommendation to lower the breakpoint of piperacillin against P. aeruginosa to ≤16 µg/mL. Alternate therapeutic choices should be considered when piperacillin MICs against P. aeruginosa are ≥32 µg/mL.

The Association of Antibiotic Duration With Successful Treatment of Community-Acquired Pneumonia in Children.

BACKGROUND: National guidelines recommend 10 days of antibiotics for children with community-acquired pneumonia (CAP), acknowledging that the outcomes of children hospitalized with CAP who receive shorter durations of therapy have not been evaluated. METHODS: We conducted a comparative effectiveness study of children aged ≥6 months hospitalized at The Johns Hopkins Hospital who received short-course (5-7 days) vs prolonged-course (8-14 days) antibiotic therapy for uncomplicated CAP between 2012 and 2018 using an inverse probability of treatment weighted propensity score analysis. Inclusion was limited to children with clinical and radiographic criteria consistent with CAP, as adjudicated by 2 infectious diseases physicians. Children with tracheostomies; healthcare-associated, hospital-acquired, or ventilator-associated pneumonia; loculated or moderate to large pleural effusion or pulmonary abscess; intensive care unit stay >48 hours; cystic fibrosis/bronchiectasis; severe immunosuppression; or unusual pathogens were excluded. The primary outcome was treatment failure, a composite of unanticipated emergency department visits, outpatient visits, hospital readmissions, or death (all determined to be likely attributable to bacterial pneumonia) within 30 days after completing antibiotic therapy. RESULTS: Four hundred and thirty-nine patients met eligibility criteria; 168 (38%) patients received short-course therapy (median, 6 days) and 271 (62%) received prolonged-course therapy (median, 10 days). Four percent of children experienced treatment failure, with no differences observed between patients who received short-course vs prolonged-course antibiotic therapy (odds ratio, 0.48; 95% confidence interval, .18-1.30). CONCLUSIONS: A short course of antibiotic therapy (approximately 5 days) does not increase the odds of 30-day treatment failure compared with longer courses for hospitalized children with uncomplicated CAP.

Antibiotic-Associated Adverse Events in Hospitalized Children.

BACKGROUND: Antibiotic-associated adverse events (AEs) in hospitalized children have not been comprehensively characterized. METHODS: We conducted a retrospective observational study of children hospitalized at The Johns Hopkins Hospital receiving ≥24 hours of systemic antibiotics. Consensus regarding antibiotic-associated AE definitions was established by 5 infectious diseases specialists prior to data collection. Two physicians reviewed potential AEs and determined whether they were more likely than not related to antibiotics after comprehensive manual chart review. Inpatient and post-discharge AEs were identified using the Epic Care Everywhere network. AEs evaluated from the initiation of antibiotics until 30 days after antibiotic completion included gastrointestinal, hematologic, hepatobiliary, renal, neurologic, dermatologic, cardiac, myositis, vascular access device-related events, and systemic reactions. Ninety-day AEs included Clostridioides difficile infections, multidrug-resistant organism infections, and clinically significant candidal infections. The impact of AEs was categorized as necessitating additional diagnostic testing, changes in medications, unplanned medical encounters, prolonged or new hospitalizations, or death. RESULTS: Among 400 antibiotic courses, 21% were complicated by at least one AE and 30% occurred post-discharge. Each additional day of antibiotics was associated with a 7% increased odds of an AE. Of courses complicated by an AE, 66% required further intervention. Hematologic, gastrointestinal, and renal AEs were the most common, accounting for 31%, 15%, and 11% of AEs, respectively. AEs complicated 35%, 35%, 19%, and 18% of courses of piperacillin-tazobactam, tobramycin, ceftazidime, and vancomycin, respectively. CONCLUSIONS: More than 1 in 5 courses of antibiotics administered to hospitalized children are complicated by AEs. Clinicians should weigh the risk of harm against expected benefit when prescribing antibiotics.

Comparative Effectiveness of Antibiotic Treatment Duration in Children With Pyelonephritis.

Importance: National guidelines recommend treating children with pyelonephritis for 7 to 14 days of antibiotic therapy, yet data are lacking to suggest a more precise treatment duration. Objective: To compare the clinical outcomes of children receiving a short-course vs a prolonged-course of antibiotic treatment for pyelonephritis. Design, Setting, and Participants: Retrospective observational study using inverse probability of treatment weighted propensity score analysis of data from 5 hospitals in Maryland between July 1, 2016, and October 1, 2018. Participants were children aged 6 months to 18 years with a urine culture growing Escherichia coli, Klebsiella species, or Proteus mirabilis with laboratory and clinical criteria for pyelonephritis. Exposures: Treatment of pyelonephritis with a short-course (6 to 9 days) vs a prolonged-course (10 or more days) of antibiotics. Main Outcomes and Measures: Composite outcome of treatment failure within 30 days of completing antibiotic therapy: (a) unanticipated emergency department or outpatient visits related to urinary tract infection symptoms, (b) hospital readmission related to UTI symptoms, (c) prolongation of the planned, initial antibiotic treatment course, or (d) death. A subsequent urinary tract infection caused by a drug-resistant bacteria within 30 days was a secondary outcome. Results: Of 791 children who met study eligibility criteria (mean [SD] age 9.2 [6.3] years; 672 [85.0%]) were girls, 297 patients (37.5%) were prescribed a short-course and 494 patients (62.5%) were prescribed a prolonged-course of antibiotics. The median duration of short-course therapy was 8 days (interquartile range, 7-8 days), and the median duration of prolonged-course therapy was 11 days (interquartile range, 11-12 days). Baseline characteristics were similar between the groups in the inverse probability of treatment weighted cohort. There were 79 children (10.1%) who experienced treatment failure. The odds of treatment failure were similar for patients prescribed a short-course vs a prolonged-course of antibiotics (11.2% vs 9.4%; odds ratio, 1.22; 95% CI, 0.75-1.98). There was no significant difference in the odds of a drug-resistant uropathogen for patients with a subsequent urinary tract infection within 30 days when prescribed a short-courses vs prolonged-course of antibiotics (40% vs 64%; odds ratio, 0.36; 95% CI, 0.09-1.43). Conclusions and Relevance: The study findings suggest that short-course antibiotic therapy may be as effective as prolonged-courses for children with pyelonephritis, and may mitigate the risk of future drug-resistant urinary tract infections. Additional studies are needed to confirm these findings.

Corrigendum to: Oral Vancomycin May Be Associated With Earlier Symptom Resolution Than Metronidazole for Hospitalized Children With Nonsevere Clostridioides difficile Infections.

[This corrects the article DOI: 10.1093/ofid/ofz492.].

Defining the Role of Novel ß-Lactam Agents That Target Carbapenem-Resistant Gram-Negative Organisms.

With the current carbapenem-resistant organism crisis, conventional approaches to optimizing pharmacokinetic-pharmacodynamic parameters are frequently inadequate, and traditional salvage agents (eg, colistin, tigecycline, etc) confer high toxicity and/or have low efficacy. However, several ß-lactam agents with activity against carbapenem-resistant organisms were approved recently by the US Food and Drug Administration, and more are anticipated to be approved in the near future. The primary goal of this review is to assist infectious disease practitioners with preferentially selecting 1 agent over another when treating patients infected with a carbapenem-resistant organism. However, resistance to some of these antibiotics has already developed. Antibiotic stewardship programs can ensure that they are reserved for situations in which other options are lacking and are paramount for the survival of these agents.

Oral Vancomycin May Be Associated With Earlier Symptom Resolution Than Metronidazole for Hospitalized Children With Nonsevere Clostridiodes difficile Infections.

OBJECTIVE: National guidelines recommend oral vancomycin over oral metronidazole as first-line treatment for nonsevere Clostridioides difficile infection (CDI) in adults. Guidelines recommend metronidazole for children with nonsevere CDI, emphasizing that comparative effectiveness studies comparing the relative efficacy of vancomycin and metronidazole are lacking in children. METHOD: We conducted an observational study of hospitalized children with nonsevere CDI treated with metronidazole versus vancomycin using an inverse probability of treatment-weighted propensity-score analysis. All of the following criteria had to be present for children with positive CDI testing for study eligibility: (1) ≥3 new-onset unformed stools within a 24-hour period; (2) 2-17 years of age; (3) hospitalization for ≥48 hours for CDI; (4) no laxative use ≤48 hours; (5) no alternate etiology for diarrhea; (6) no previous episode of CDI ≤3 months; (7) no concurrent non-CDI-targeted antibiotic therapy, and (8) no severe or fulminant CDI. RESULTS: One hundred ninety-two patients met eligibility criteria; 141 (73.4%) received oral metronidazole and 51 (26.6%) children received oral vancomycin. Baseline characteristics were similar between the 2 groups in the weighted cohort. Of 141 patients, 101 (71.7%) children receiving metronidazole had clinical improvement by day 5, whereas 44 of 51 (86.3%) cases resolved with vancomycin (odds ratio, 0.40; 95% confidence interval, 0.17-0.97; P = .04). The odds of CDI recurrence within 12 weeks were similar between the groups. CONCLUSIONS: Our study suggests that children with nonsevere CDI have earlier resolution of clinical symptoms when prescribed vancomycin compared with metronidazole. Large interventional studies are necessary to evaluate the reproducibility of our findings.

Association Between Vancomycin Trough Concentrations and Duration of Methicillin-Resistant Staphylococcus aureus Bacteremia in Children.

In a multicenter retrospective study, we sought to determine the optimal vancomycin trough concentration that would impact the duration of methicillin-resistant Staphylococcus aureus bacteremia in children. We found that a median vancomycin trough concentration of <10 µg/mL within the first 72 hours may be associated with a longer duration of bacteremia compared to a median trough concentration of ≥10 µg/mL.

Risk Factors for Non-Therapeutic Initial Steady-State Vancomycin Trough Concentrations in Children and Adolescents Receiving High Empiric Doses of Intravenous Vancomycin.

BACKGROUND: Achieving vancomycin troughs of 15-20 µg/mL remains challenging in children. Our objective was to identify risk factors associated with non-therapeutic initial vancomycin troughs in children. METHODS: We conducted a retrospective cohort study of children who received intravenous vancomycin with at least one initial steady-state trough obtained. Patients who achieved therapeutic troughs (15-20 µg/mL in the 20-mg/kg/dose sub-cohort and 10-15 µg/mL in the 15-mg/kg/dose sub-cohort) were compared with those with subtherapeutic troughs (<15 and <10 µg/mL, respectively) and supratherapeutic troughs (>20 and >15 µg/mL, respectively) separately to determine risk factors associated with non-therapeutic troughs. RESULTS: A total of 153 vancomycin courses in 140 patients met study eligibility criteria. Of 45 patients who received 20 mg/kg/dose of empiric vancomycin, 60, 16, and 24% were subtherapeutic, therapeutic, and supratherapeutic, respectively. Each 10-mL/min/1.73 m2 increase in initial creatinine clearance (CrCl) was associated with a 47% increase in the odds of an initial subtherapeutic trough (adjusted odds ratio [aOR] 1.47; 95% CI 0.98-2.22). Of 108 patients who received 15 mg/kg/dose of empiric vancomycin, 62, 19, and 19% were subtherapeutic, therapeutic, and supratherapeutic, respectively. Each 10-mL/min/1.73 m2 increase in initial CrCl was associated with an 18% increase in the odds of an initial subtherapeutic trough (aOR 1.18; 95% CI 1.02-1.37). CONCLUSION: Achieving vancomycin troughs of 15-20 µg/mL for severe Gram-positive infections continues to be challenging in children, even at higher empiric doses of 20 mg/kg/dose IV every 6-8 h. Children with higher initial CrCls are particularly susceptible to subtherapeutic initial steady-state vancomycin troughs.