Therapeutic Options and Outcomes for the Treatment of Neonates and Preterms with Gram-Negative Multidrug-Resistant Bacteria: A Systematic Review

Abstract

Background: Infections caused by multidrug-resistant (MDR) or extensively drug-resistant (XDR) bacteria represent a challenge in the neonatal population due to disease severity and limited therapeutic possibilities compared to adults. The spread of antimicrobial resistance and drug availability differ significantly worldwide. The incidence of MDR bacteria has constantly risen, causing an increase in morbidity, mortality, and healthcare costs in both high-income (HIC) and low- and middle-income countries (LMIC). Therefore, more evidence is needed to define the possible use of newer molecules and to optimize combination regimens for the oldest antimicrobials in neonates. This systematic review aims to identify and critically appraise the current antimicrobial treatment options and the relative outcomes for MDR and XDR Gram-negative bacterial infections in the neonatal population. Methods: A literature search for the treatment of MDR Gram-negative bacterial infections in neonates (term and preterm) was conducted in Embase, MEDLINE, and Cochrane Library. Studies reporting data on single-patient-level outcomes related to a specific antibiotic treatment for MDR Gram-negative bacterial infection in children were included. Studies reporting data from adults and children were included if single-neonate-level information could be identified. We focused our research on four MDROs: Enterobacterales producing extended-spectrum beta-lactamase (ESBL) or carbapenemase (CRE), Pseudomonas aeruginosa, and Acinetobacter baumannii. PROSPERO registration: CRD42022346739 Results: The search identified 11,740 studies (since January 2000), of which 22 fulfilled both the inclusion and exclusion criteria and were included in the analysis. Twenty of these studies were conducted in LMIC. Colistin is the main studied and used molecule to treat Gram-negative MDR bacteria for neonate patients in the last two decades, especially in LMIC, with variable evidence of efficacy. Carbapenems are still the leading antibiotics for ESBL Enterobacterales, while newer molecules (i.e., beta-lactam agents/beta-lactamase inhibitor combination) are promising across all analyzed categories, but data are few and limited to HICs. Conclusions: Data about the treatment of Gram-negative MDR bacteria in the neonatal population are heterogeneous and limited mainly to older antimicrobials. Newer drugs are promising but not affordable yet for many LMICs. Therefore, strategies cannot be generalized but will differ according to the country’s epidemiology and resources. More extensive studies are needed to include new antimicrobials and optimize the combination strategies for the older ones.

Use of Newer and Repurposed Antibiotics against Gram-Negative Bacteria in Neonates

“…According to a recent systematic review aiming to identify the current antimicrobial treatment options for MDR and XDR GNB infections in the neonatal population, colistin in combination with meropenem, amikacin, ciprofloxacin, or tigecycline is used for CRE neonatal infections, whereas, in association with other antimicrobials such as ciprofloxacin, it is prescribed for DTR and XDR P. aeruginosa. Furthermore, the most active antimicrobial for XDR A. baumannii seems to be colistin, whereas novel antimicrobials such as ceftazidime–avibactam are infrequently used as salvage therapy [ 21 ]. Novel antimicrobials seem to be promising based on experience from studies in adults and lately from a very small but increasing number of trials including neonates.…”

“…Not surprisingly, the above guidance reports are not addressed to neonates. According to recent systematic reviews about therapeutic options in neonates, the limited number of published articles, the low quality of evidence (retrospective data, heterogenous study design, and outcome definition, case series, or reports), and the very small sample size not permitting any statistical analysis further suggest that neonates remain “therapeutic orphans” in the fight against AMR [ 17 , 21 ]. A lack of evidence regarding pharmacokinetics (PK), safety, route (continuous or intermittent), dose and duration of administration, and the guidelines of using specific antibiotic(s) are the causes of the common off-label/unlicensed antibiotic use in neonates [ 22 ].…”

Antibiotic Analgesic-Sedative and Antiseizure Medications Frequently Used in Critically Ill Neonates: A Narrative Review

“…Colistin in combination with other antimicrobials such as meropenem, amikacin, ciprofloxacin, or tigecycline were used for carbapenem-resistant Enterobacterales infections, whereas colistin plus ciprofloxacin were prescribed for difficult-to-treat resistant and extensively drug-resistant P. aeruginosa. Authors concluded the following: (a) in the last two decades, colistin is the most frequently studied and used antimicrobial, especially in low -middle income countries, with variable evidence of efficacy; (b) carbapenems are still the leading antibiotics for extended-spectrum beta-lactamase Enterobacterales; and (c) newer antibiotics, such as beta-lactam agents / beta-lactamase inhibitor combination (e.g., ceftazidime-avibactam infrequently used as salvage therapy), are promising, but data are few and limited to high income countries [43,44]. Indications, dosing regimens, and side effects of antibacterial agents are summarized in Table 1, while more details are presented in the Supplementary Table S1 [25,31,36,[44][45][46][47][48][49][50].…”

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

“…To date, treatment options for MDR organisms in NICU are alarmingly limited [ 38 , 39 , 40 ], particularly for Gram-negative strains. Colistin is the main used antimicrobial for the treatment of MDR P. aeruginosa, A. baumannii, and CRE in newborns in the two last decades, with 75–100% of clinical success [ 41 ]. Meropenem at high doses or as an extended infusion or in association with other antimicrobials is the second most reported agent [ 40 , 41 ], while the use of tigecycline, fluoroquinolones, and polymyxin B is less frequently documented [ 24 , 40 , 42 , 43 ].…”

“…Colistin is the main used antimicrobial for the treatment of MDR P. aeruginosa, A. baumannii, and CRE in newborns in the two last decades, with 75–100% of clinical success [ 41 ]. Meropenem at high doses or as an extended infusion or in association with other antimicrobials is the second most reported agent [ 40 , 41 ], while the use of tigecycline, fluoroquinolones, and polymyxin B is less frequently documented [ 24 , 40 , 42 , 43 ]. However, the polymyxins safety profile is not optimal, as nephrotoxicity has been reported in newborns in 10–19% of cases [ 42 ] along with significant electrolyte imbalances [ 42 ].…”