New Antimicrobials for the Treatment of Neonatal Sepsis Caused by Multi-Drug-Resistant Bacteria: A Systematic Review

Background: Infections by multi-drug-resistant (MDR) organisms are sharply increasing in newborns worldwide. In low and middle-income countries, a disproportionate amount of neonatal sepsis caused by MDR Gram negatives was recently reported. Newborns with infections by MDR organisms with limited treatment options may benefit from novel antimicrobials. Methods: We performed a literature search investigating the use in newborns, infants and children of novel antimicrobials for the treatment of MDR Gram negatives, namely ceftazidime/avibactam, ceftolozane/tazobactam, cefiderocol, meropenem/vaborbactam, imipenem/relebactam, and Gram positives with resistance of concern, namely ceftaroline and dalbavancin. PubMed, EMBASE, and Web of Science were searched. Results: A total of 50 records fulfilled the inclusion criteria. Most articles were case reports or case series, and ceftazidime/avibactam was the most studied agent. All studies showed favorable efficacy and safety profile in newborns and across different age cohorts. Conclusions: novel antibiotics may be considered in newborns for the treatment of MDR Gram negatives with limited treatment options and for Gram positives with resistance concerns. Further studies are needed to address their effectiveness and safety in newborns.

Early-onset sepsis (EOS) is defined as a positive blood or cerebrospinal fluid culture taken within the first 72 h of life, while late-onset sepsis (LOS) occurs after the first 3 days of life [5,6]. Multi-drug resistance (MDR) bacteria were alarmingly reported in the latest years as causing agents of both EOS and LOS [6][7][8][9]. Moreover, several outbreaks caused by MDR organisms in Neonatal Intensive Care Units (NICUs) recently occurred in different regions, including high-income countries (HICs) [10][11][12][13][14], and consistent colonization of both patients admitted to NICUs [15][16][17] and of pregnant women [18] is reported, threatening the outcomes of both EOS and LOS cases.

Epidemiology
Among 0.68 million annual neonatal deaths associated with possible severe bacterial infection, an estimated 31% were attributable to resistant pathogens worldwide, with disproportionate risk in India, Pakistan, Nigeria, Congo, and China [1]. Studies from LMICs Different antimicrobials are approved in adults for the treatment of infections caused by organisms with unfavorable susceptibility profiles. Particularly, beta-lactams/betalactamase inhibitors and cefiderocol are currently the cornerstones of the treatment of bloodstream infections (BSIs) and infections of different sites caused by Gram-negative strains with limited treatment options [45][46][47][48][49]. Ceftaroline and dalbavancin are among the main treatment options for Gram-positive strains with resistance concern [50, 51], alongside with lipoglycopeptides such as televancin (not approved for use in EU) and oritavancin [52,53], the novel oxazolidinone tedizolid [54] and the 4th generation cephalosporin ceftobiprole [55]. Finally, eravacycline, a novel tetracycline with activity against Grampositive cocci and Gram-negative bacilli, is considered for the treatment of intra-abdominal infections caused by susceptible strains [56].
Given the shortage of current treatment options in newborns, newly available antimicrobials such as beta-lactams/beta-lactamase inhibitors, namely ceftazidime/avibactam, ceftolozane/tazobactam, meropenem/vaborbactam, imipenem/relebactam, or cefiderocol may represent promising tools for the treatment of MDR Gram negatives in NICU, while ceftaroline and dalbavancin may represent treatment options for Gram-positive strains with resistances of concern. Despite the use of these antimicrobials has been increasingly reported in latest years in newborns and infants, to date, the possibility to extend their use to these populations has not been assessed. Therefore, this study aimed to review the current knowledge of the use of these antimicrobials in newborns.

Study Selection
Among a total of 986 records retrieved, 749 records were removed (736 duplicates); therefore, 237 records were screened and 196 were removed as they did not meet eligibility criteria. Therefore, a total of 68 articles were sought for retrieval and 18 articles were excluded as commentaries or narrative reviews not reporting original data or as studies documenting only antimicrobial susceptibility data. We decided not to include susceptibility studies as they did not provide data directly related to antimicrobials administration in clinical settings. Instead, we decided to include studies on pharmacokinetic simulation models, although not enrolling patients in clinical settings, as they were considered useful for the validation of administration schedules in the age groups of interest. Finally, 50 articles  were included in the present systematic review ( Figure 1).
Doses and administration schedules for ceftazidime/avibactam in newborns are at present extrapolated from pharmacokinetic data obtained from patients ≥3 months old [57,68].

Ceftolozane/Tazobactam
Among 12 studies on ceftolozane/tazobactam (Table 2), we included 5 case reports or case series, 2 RCTs, and 5 pharmacokinetics studies. One RCT enrolled newborns with complicated UTIs [82] while the other one [83] enrolled patients >2 years of age with complicated intra-abdominal infections.   Case reports and case series and one retrospective study reported the use of ceftolozane/tazobactam in a total of 21 pediatric patients with infections of different sites (BSI, pneumonia, osteomyelitis, intra-abdominal infection) caused by MDR P. aeruginosa [72,73,75,76,79] with age ranging from 3 months to 18 years.
No severe drug-related AEs were reported, mild drug-related AEs included diarrhea, increased transaminases, and neutropenia [82].

Cefiderocol
Among the 6 included studies on cefiderocol (Table 3), 5 were case reports or series, and 1 was a pharmacokinetic study. In the case reports, 2/6 reported the use of cefiderocol in 2 preterm newborns with carbapenem-resistant K. pneumoniae [88,89], one with LOS [89], and one with LOS and necrotizing enterocolitis [88]. A pharmacokinetic simulation model validated doses and administration regimens for cefiderocol in newborns, providing specific doses basing on post-natal age and gestational age of the patients [84].

Ceftaroline
Among 11 studies on ceftaroline (Table 4), we included 3 RCTs, 1 clinical phase 2 trial, 3 case reports, 3 pharmacokinetics studies, and 1 retrospective study. Ceftaroline was studied in RCTs for the treatment of pneumonia and skin and skin structure infections (SSSIs) mostly caused by S. aureus, including MRSA, in patients ≥2 months of age [92][93][94], achieving clinical cure in 83-88% of cases [92][93][94]. Among case reports, 2/3 documented the use of ceftaroline in preterm newborns of 24-30 weeks of gestation infected by MRSA, one with LOS and pneumonia [96], and one with hepatic abscess and infected thrombus of the portal system [100].   Drug-related AEs were reported in 10-23% of treated patients [92,93]; the most frequently reported AEs were diarrhea, vomiting, dermatitis or rush, increased transaminases; two severe drug-related AEs were reported [92,93], one hypersensitivity event and one case of colitis by C. difficilis [94].
Pharmacokinetic studies specifically targeted to neonatal age [95,101,102] validated ceftaroline administration schedule of 8-10 mg/kg q8h [95,101] and demonstrated no differences in the probability of target attainment between 5 min or 60 min drug infusion [102].

Dalbavancin
We included 4 studies on dalbavancin (Table 4), 3 pharmacokinetic studies, and one RCT. In the included RCT [106] dalbavancin was administered for the treatment of BSI in patients from birth to 3 months and SSSIs from birth to 18 years.
Drug-related AEs were not reported.
Most articles were case reports or case series or other retrospective studies, while few neonatal patients were enrolled in RCTs; the most studied antimicrobials were ceftazidime/avibactam and ceftolozane/tazobactam. The most frequently isolated MDR organisms in the included studies were K. pneumoniae, P. aeruginosa, and E. coli among Gram negatives, and MSSA, MRSA, and Enterococcus spp. among Gram positives.
Ceftazidime/avibactam is a cephalosporin/beta-lactamase inhibitor, with excellent activity against KPC and OXA-48-like producing CRE and non-carbapenemase-producing CRE, and it is currently approved for use in patients ≥3 months for the treatment of complicated intra-abdominal infections, complicated UTIs, hospital-acquired pneumonia, and BSI associated with those conditions; it is also approved for treatment of infections caused by Gram negatives with limited treatment options [45]. Case reports on preterm infants [62,66,69,70] included newborns of 27-29 weeks, in whom treatment was started at 11-46 days of life and continued for 10 to 14 days in the case of UTI or BSI [66,70] and for 21 to 47 days in the case of meningitidis [62,69]. Among 11 patients treated with ceftazidime/avibactam 10 achieved microbiological and clinical cure, while one died. In 36 infants of 3 months-2 years of age with complicated UTIs, a clinical cure was observed in 99% of patients randomized to ceftazidime/avibactam vs. 90% of patients randomized to comparator cefepime [60]. Similar efficacy of ceftazidime/avibactam and meropenem was observed in 83 patients of 3 months-18 years of age with complicated intra-abdominal infections [61], indicating high efficacy of ceftazidime/avibactam in infants and children. Similarly, in adults, ceftazidime/avibactam showed higher efficacy in the treatment of infections caused by CRE in comparison with different combinations of colistin, tigecycline, fosfomycin, and carbapenems [43]. A recent meta-analysis [107] demonstrated that ceftazidime/avibactam was more effective than comparators to achieve clinical cure of infections caused by carbapenem-resistant K. pneumoniae, and patients treated with ceftazidime/avibactam also presented lower mortality rates at 28-30 days. Ceftazidime/avibactam was recently included in the treatment algorithm for both carbapenemase-positive and negative CRE infections in children, without restrictions of age [43]. It was also suggested to strongly consider the use of beta-lactams/beta-lactamase inhibitors, as ceftazidime/avibactam, imipenem/relebactam and meropenem/vaborbactam, for susceptible CRE isolates with MIC for meropenem ≥4 microg/mL or known to produce KPC based on rapid molecular diagnostic tests [43]. Meropenem/vaborbactam is at present approved for adult use in complicated UTIs, intraabdominal infections, hospital-acquired pneumonia, or BSI associated with the previous conditions, and in general for infections by Gram negatives with limited treatment options [46]; similarly, imipenem/relebactam is approved for adult use [47]. At present no data are available for newborns.
Ceftolozane/tazobactam is a cephalosporin/beta-lactamase inhibitor with enhanced activity against P. aeruginosa, approved for the treatment of complicated intra-abdominal infection, and complicated UTIs including pyelonephritis with no restrictions of age, provided the patients are ≥ 7 days and ≥ 32 weeks of gestation, and for the treatment of hospital-acquired pneumonia in adults [48]. Among 95 patients with complicated UTIs, including 20 patients with age birth-3 months randomized to ceftolozane/tazobactam or meropenem, a clinical cure was observed in 94% vs. 100%, respectively [82], suggesting that ceftolozane/tazobactam is an effective treatment option in newborns, infants, and children. In patients >2 years with complicated intra-abdominal infections ceftolozane/tazobactam in combination with metronidazole was effective as meropenem and well-tolerated [83]. One case series [79] reported 3 infants with age 3-10 months with comorbidities treated with ceftolozane/tazobactam for pneumonia, 2 of whom were clinically cured. These results are consistent with data from adult patients, indicating the high efficacy of ceftolozane/tazobactam in patients with MDR Gram negatives infections, such as lower and upper UTIs [108] and intra-abdominal infections [109]. A recent meta-analysis [110] showed that ceftolozane/tazobactam was more effective in achieving clinical cure or microbiological eradication in comparison to polymyxin/aminoglycoside and quinolones in adults with Gram negatives infections, including MDR P. aeruginosa.
Cefiderocol is a siderophore cephalosporin with excellent activity against carbapenemases and it is currently approved for the treatment of Gram negatives with limited treatment options in adults [49]. Two case reports documented the successful treatment of preterm newborns of 27-31 weeks of gestation with LOS by VIM metallo-beta-lactamase producing K. pneumoniae [89] and LOS and necrotizing enterocolitis caused by KPC-producing K. pneumoniae [88] after the failure of netilmicin [89] and meropenem and colistin [88]. Treatment with cefiderocol was started at 9 [88] and 20 days of life [89] and continued for 14 and 9 days, respectively. In adults, cefiderocol showed similar efficacy to other available best comparators in the case of infections by MDR Gram negatives [111] and showed non-inferiority in comparison to meropenem for the treatment of hospital-acquired pneumonia [112]. Cefiderocol also showed superiority to the best available therapy and high-dose meropenem for the outcomes of clinical cure, microbiological eradication, and mortality at 28 days in the case of infections caused by metallo-beta-lactamase-producing Gram negatives [113].
Noticeably, all antimicrobial targeting MDR Gram negatives considered in this review were recently included in the guidelines of the Infectious Disease Society of America applying both to adult and pediatric patients, with no further age cohort specification [114], with an indication that all of them may be considered for the treatment of CRE, and, except for meropenem/vaborbactam, for the treatment of P. aeuruginosa with "difficult-to-treat resistance". Cefiderocol is also recommended for the treatment of carbapenem-resistant A. baumannii [114].
Ceftaroline is a 5th generation cephalosporin with activity against Gram positives including MRSA and MDR S. pneumoniae, and it is currently approved for the treatment of patients of any age, including newborns, with SSSIs or community-acquired pneumonia [50]. In 11 infants of 7-60 days with LOS treated with ceftaroline plus ampicillin and optional aminoglycoside, no treatment failure was observed [98]. In patients ≥2 months with complicated community-acquired pneumonia, ceftaroline showed similar efficacy in comparison to vancomycin plus ceftriaxone, with clinical cure observed in 83% vs. 78% of cases, respectively [93]. Ceftaroline also showed similar efficacy in comparison to ceftriaxone for the treatment of community-acquired pneumonia, with clinical cure observed in 92% vs. 89% of cases, respectively [92]. Likewise, ceftaroline was proved highly effective for the treatment of adult pneumonia, and a recent meta-analysis found a higher probability of clinical cure with ceftaroline in comparison to ceftriaxone [115]. Moreover, ceftaroline recently showed non-inferiority in comparison to daptomycin for the treatment of BSIs caused by MRSA without pulmonary origin [116]. For the treatment of 159 patients ≥2 months of age with SSSIs ceftaroline achieved clinical cure in 96% vs. 88% of comparators, vancomycin or cefazolin [94], in accordance with data from adult patients [117][118][119]. In 2 case reports, ceftaroline was effective in preterm newborns of 24-30 weeks of gestation with BSI by MRSA, one with LOS and pneumonia [96], and one with hepatic abscess and infected thrombus of the portal system [100]. In one case [96], treatment with ceftarolin was started at 43 days of life, after failure of oxacillin, vancomycin, and rifampin, and administered for 21 days [96], while in the other case, treatment was started at 54 days of life, after failure of vancomycin, daptomycin, and linezolid, and continued for 18 days [100]. Successful pharmacokinetic target attainment was also reported with the administration of 8.5 mg/kg q8h [96].
Dalbavancin is a long-acting semisynthetic lipoglycopeptide antibiotic with bactericidal activity against Gram-positive pathogens, including S. aureus including MRSA, S. pneumoniae, S. agalactiae, S. pyogenes, and Enterococcus spp., and it is currently approved for the treatment of SSSIs in patients >3 months [51]. Dalbavancin was administered for the treatment of BSIs in patients from birth to 3 months and SSSIs from birth to 18 years known or suspected to be caused by susceptible Gram positives [106], mainly MSSA; 5 patients in the cohort birth-3 months, including 3 patients with age < 1 month, were treated with single dose dalbavancin, with excellent overall efficacy.
At present, the susceptibility of pediatric and neonatal isolates to novel antimicrobials is excellent in HICs. In studies on pediatric and neonatal isolates, Enterobacterales showed excellent susceptibility of 97-100% to ceftazidime/avibactam [120,121], while P. aeruginosa maintained high susceptibility of 96-100% in the general pediatric population including newborns [121] but showed poor susceptibility of 47% in colonized pediatric patients with cystic fibrosis [122]. At present overall susceptibility of pediatric Gram negatives isolates to ceftolozane/tazobactam is excellent in HICs [123][124][125]; however, slightly lower susceptibility has been shown for K. pneumoniae [125] and resistance to ceftolozane/tazobactam was reported in approximately half of the cases for pediatric cystic fibrosis patients colonized with MDR P. aeruginosa [122]. In 1460 isolates from pediatric respiratory tract infections and SSSIs, including 263 isolates obtained from patients <1 year, susceptibility to ceftaroline was 100% for H. influenzae, S. aureus, and E. coli, 99.6% for S. pneumoniae, and 97% for Klebsiella spp. [126].
No significant safety issues in newborns and infants emerged from the included studies. For the treatment of Gram negatives, the use of ceftazidime/avibactam was not associated with any drug-related AEs, in accordance with the re-assuring safety profile observed in adults [43,107]. In preterm newborns 2 AEs were reported to have an uncertain association with the drug, one case of thrombocytopenia not requiring transfusion [62], and one case of transient glycosuria [66]. Drug-related adverse events were reported for ceftolozane/tazobactam by 2 RCTs and included diarrhea, increased transaminases, and dermatitis or rush, similarly to AEs displayed by adult patients [82,83]. No AEs were reported for preterm newborns. Cefiderocol and meropenem/vaborbactam we not associated with any drug-related AEs. Mild drug-related AEs were reported in 10-23% of patients treated with ceftaroline, including diarrhea, vomiting, dermatitis or rush, and increased transaminases. Two severe ceftaroline-related AEs, one hypersensitivity event and one case of colitis by C. difficilis were observed, both beyond the neonatal period [94], indicating similar safety profile to adult patients [92,93].
This review has some limitations. First, a modest amount of data results from RCTs or clinical studies properly designed to assess the efficacy and safety of new antimicrobials in infants and newborns, while most of the included studies were case reports or case series. Second, included studies presented variable study designs, not allowing direct comparison of the results. Third, most RCTs enrolled infants ≥2 or 3 months of age, thus slightly beyond the neonatal period. However, newborns and particularly preterm newborns may significantly differ from slightly older patients in terms of pharmacokinetic variables [127]. Newborns, particularly if preterm, show a higher volume of distribution of antimicrobial drugs, but lower renal drug clearance, resulting in higher loading dose but lower maintenance dose of the drug [127], with poorly predictable effects on efficacy and toxicity [127]. Finally, most data on the use of novel antimicrobials in newborns were obtained from studies performed in HICs. However, patients who may benefit from new antimicrobials may partially differ across countries, as a particularly high rate of MDR organisms were found in EOS in term or mild preterm newborns in LMICs, while infections with MDR organisms in HICs usually occur in very preterm newborns with healthcare-associated LOS.
Overall, available data indicate that novel antimicrobials against MDR Gram-positive and Gram-negative organisms are effective and safe in the pediatric and neonatal population, and therefore, they can be considered a useful treatment in case of infections caused by MDR organisms in NICU, when other treatment options are limited or absent. However, data on the use of these antimicrobials are still limited for children and newborns; therefore, properly designed RCTs in these populations are warranted, including newborns and preterm newborns, to specifically assess efficacy and safety in these age groups. Finally, limited or no availability of novel antimicrobials in LMICs might represent a significant issue, as those areas would likely mostly benefit from novel agents in consideration of the high rates of MDR Gram negatives reported.

Search Strategy
This systematic review was carried out according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines (Figure 1). A literature search was conducted on 25 March 2023, using the following databases: PubMed Medline, EMBASE, and Web of Science.
The search strategy included the following terms and was performed for each considered antibiotic (ceftazidime/avibactam, ceftolozane/tazobactam, cefiderocol, meropenem/vaborbactam, imipenem/relebactam, ceftaroline, dalbavancin): "antibiotic of interest" AND "neonate" OR "newborn" OR "neonat" OR "infant" OR "child" OR "pediatric". No date restriction was applied. The literature search was limited to the English language. Articles were checked for duplication.

Eligibility
Two reviewers (C.P., C.D.) independently assessed eligibility. Titles and abstracts of all retrieved articles were screened to identify potentially eligible studies, and all selected articles were analyzed in full text for conclusive evaluation. Eligibility criteria for the present study were as follows: (1) studies investigating the use of new antimicrobials of interest (2) in newborns, infants, and children (3) with BSIs or infection of any site, or (4) pharmacokinetics studies in the same population. Based on the extremely recent introduction of novel antimicrobials in newborns and pediatric age in general, we decided to consider all studies on patients younger than 18 years, to collect all available data for the developmental age. The eligible study design included RCTs, retrospective studies, case reports/series, and pharmacokinetic studies. Reviews, commentaries, or meta-analyses were considered not eligible. Considered outcomes were clinical cure, microbiological eradication, safety issues, and pharmacokinetic target attainment or dose validation, depending on different types of considered studies.

Conclusions
In conclusion, robust evidence on the efficacy and effectiveness of novel antimicrobials for the treatment of MDR Gram positives and Gram negatives is lacking. However, all available data suggest high effectiveness and favorable safety profile of the considered novel antimicrobials in the neonatal population, including preterm newborns. Therefore, these drugs might be regarded as useful treatments in newborns and infants with infections caused by MDR organisms with limited treatment options. Further studies are warranted to specifically address indications and safety profiles in infants and newborns.