Infecciones Por Gram Negativos Resistentes A Carbapenemicos en Niños

AAC Accepted Manuscript Posted Online 16 December 2019
Antimicrob. Agents Chemother. doi:10.1128/AAC.02183-19

Copyright © 2019 American Society for Microbiology. All Rights Reserved.
1 Title Page
2 Complete manuscript title: Carbapenem-Resistant Gram-Negative Infections in

3 Children.
Downloaded from http://aac.asm.org/ on December 19, 2019 at Chalmers University

5 Authors' full names and affiliations:
6 - David Aguilera-Alonso, Pediatric Infectious Diseases Unit. Gregorio Marañón Hospital,

7 Madrid, Spain.
8 E-mail: david.aguilera@salud.madrid.org
9 - Luis Escosa-García, Department of Infectious Diseases and Tropical Pediatrics. La Paz

10 Hospital, Madrid, Spain.
11 E-mail: luis.escosa@salud.madrid.org
12 - Jesús Saavedra-Lozano, Pediatric Infectious Diseases Unit. Gregorio Marañón Hospital.

13 Complutense University. Madrid, Spain.
14 E-mail: jesaave@yahoo.es
15 - Emilia Cercenado, Department of Infectious Diseases and Clinical Microbiology.

16 Complutense University. Gregorio Marañón Hospital, Madrid, Spain.
17 E-mail: emilia.cercenado@salud.madrid.org
18 - Fernando Baquero-Artigao, Department of Infectious Diseases and Tropical Pediatrics.

19 La Paz Hospital, Madrid, Spain.
20 E-mail: fbaqueroartigao@gmail.com
21
22 Name and address for correspondence: David Aguilera-Alonso. Telephone number:

23 +34 606663030. Email: david.aguilera@salud.madrid.org. Address: Hospital General
24 Universitario Gregorio Marañón, Servicio de Pediatría, Calle O'Donnell, 28009, Madrid, Madrid,
25 Spain.
26 Alternate corresponding author: Fernando Baquero-Artigao. Telephone number: +34

27 619059881. Address: Hospital Infantil La Paz, Paseo de la Castellana, 261, 28046, Spain.
28
29
30 Key words: carbapenem-resistant Enterobacterales, antimicrobial resistance,
31 antibacterial agents, children, epidemiology.
32
33 Running head title: Carbapenem-Resistant Gram-Negative Infections in Children.

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39
40 ABSTRACT
41 Carbapenem-resistant organisms (CRO) are a major global public health threat.

42 Enterobacterales through carbapenemase production hydrolyze almost all β-lactams.
43 Infections caused by CRO are challenging to treat due to the limited number of antimicrobial
44 options. This leads to significant morbidity and mortality. Over the last few years, several new

45 antibiotics effective against CRO have been approved. Some of them (e.g., plazomicin or
46 imipenem-cilastatin-relebactam) are currently only approved for adults; others (e.g.,
47 ceftazidime-avibactam) have recently been approved for children. Recommendations for
48 antibiotic therapy of CRO infections in pediatric patients are based on evidence mainly from
49 adult studies. The availability of pediatric pharmacokinetics and safety data is the cornerstone
50 to broaden the use of proposed agents in adults to the pediatric population. This article
51 provides a comprehensive review of the current knowledge regarding infections caused by
52 CRO with a focus on children which includes epidemiology, risk factors, outcomes and
53 antimicrobial therapy management, with particular attention to new antibiotics.
54
55
56 Carbapenem-Resistant Gram-Negative Infections in Children
57 Introduction
58 Carbapenem-resistant organisms (CRO) are a major global public health threat. Specific
59 pediatric reviews and recommendations have been established for the diagnosis and

60 treatment of infections by CRO in children(1, 2). However, the most relevant information
61 regarding this topic has been generated from observational studies conducted predominantly
62 in adults(3). Furthermore, new knowledge about the epidemiology and therapy of these
63 infections, including new drug combinations (e.g., ceftazidime-avibactam or meropenem-
64 vaborbactam), have emerged over the past years, making it necessary to update this topic in
65 the pediatric field.
66 Microbiology
67 Among Enterobacterales (previously known as the order Enterobacteriaceae), at present, the

68 most frequent mechanism of resistance to carbapenems is the production of carbapenemases.
69 Carbapenemases are β-lactamases that hydrolyze penicillins, in most cases cephalosporins,
70 and to various degrees carbapenems and monobactams. These enzymes are usually acquired,
71 encoded by genes on transposable elements located on plasmids, and readily transferable.
72 Furthermore, carbapenemase-producing strains frequently possess resistance mechanisms to
73 a wide-range of antimicrobial agents, including aminoglycosides, fluoroquinolones and
74 trimethoprim-sulfamethoxazole. Carbapenemases are classified into 3 main groups (table
75 1)(4). Decreased susceptibility to carbapenems may also be caused by the production of
76 extended spectrum β-lactamases (ESBLs) or AmpC enzymes combined with decreased
77 permeability due to the modification or down-regulation of porins. Carbapenemases differ in
78 their activity against specific β-lactams.
79 Although the most frequent mechanisms of resistance of Pseudomonas aeruginosa to

80 carbapenems are non-transferable, including porine production (loss or reduced copy numbers
81 of OprD), an overproduction of active efflux pumps, AmpC β-lactamase and ESBLs have been
82 reported as main contributors to multidrug resistance phenotypes in P. aeruginosa isolates. In
83 addition, over the last decade an increasing prevalence of carbapenemases among P.
84 aeruginosa has been reported, mainly VIM and NDM. Resistance to carbapenems among
85 Acinetobacter baumannii is very frequent and, in general, chromosomally encoded and non-
86 transferable. However, this species can also carry plasmid-mediated carbapenemases(5).
87 Epidemiology
88 In parallel to what has been observed in adult populations, a progressive increase in the
89 incidence of infections due to multidrug-resistant (MDR) microorganisms has occurred in
90 children. Published studies during the last decade reported that the frequency of carbapenem
91 resistance (CR) in children in the USA increased from 0% in 1999–2000 to 0.47 % in 2010–2011
92 among Enterobacterales isolates(6), from 9.4% in 1999 to 20% in 2012 among P.

93 aeruginosa(7), and from 0.6% in 1999 to 6.1% in 2012 among A. baumannii (8). An Italian
94 nationwide survey among centers participating in a pediatric hematology-oncology
95 cooperative study group reported a two-fold increase in the carbapenem-resistant
96 Enterobacterales (CRE) colonization rate and a four-fold increase in the incidence of CRE
97 bloodstream infections (BSIs) from 2012 to 2013(9).
98 In most settings, colonization and infection by CRO mainly occur in the adult population. An
99 active surveillance system involving 7 USA states detected a total of 599 isolates of CRE
100 occurring in 481 patients during the 2012-2013 period(10). However, only 3 of those cases
101 (0.6%) were under 18 years of age. In fact, with the exception of some CRE highly-endemic
102 countries (e.g., India or Turkey) where these microorganisms are frequently isolated in
103 pediatric units, CRE are mainly found in adult intensive care units (ICUs) and oncology
104 wards(11)(12)(13)(14). Thus, pediatric data reported worldwide (including countries such as
105 UK, USA, Spain or Italy) has mostly been consistent with sporadic spread and outbreaks of CRE
106 infections (15)(16)(17)(18).
107 Comparative surveillance data in routine bloodstream isolates in Europe demonstrated a

108 different antimicrobial resistance pattern in children compared with adults. The prevalence of
109 CR in K. pneumoniae was higher in adults (13.5% vs 6.5%), whereas CR in P. aeruginosa was
110 more frequent in children (30.7% vs 23%)(19). A literature review of bacteremia in oncology
111 patients also described a difference in prevalence among age groups(20). In two additional
112 studies, the median rate of CR among Gram-negative isolates in adults was 20% (range 11-
113 72%), whereas in children it was 9-10%(21)(22). Several centers in different countries have
114 described pediatric epidemiological peculiarities, with different bacterial clones in pediatric
115 units than in adult units within the same center or different regional epidemiology among
116 children and adults(21)(22).
117 Infections due to CRO in children are primarily healthcare-associated (17). A recent Greek
118 report on active surveillance of central line-associated BSIs (CLABSIs) in children conducted
119 from 2016 to 2017 including neonatal ICUs (NICUs), pediatric ICUs (PICUs) and oncology wards,
120 described the impressively high prevalence of CRO: 45% CR among Klebsiella spp, 36% in
121 Enterobacter spp and 38% in P. aeruginosa(23). A study from Lake et al assessed the pathogen
122 distribution and antimicrobial resistance among pediatric healthcare-associated infections
123 reported to the US national healthcare safety network(24). It highlighted the notable
124 difference in the prevalence of CRO isolates among different sources and locations. In the case
125 of pathogens from CLABSIs, CR K. pneumoniae prevalence was higher in the oncology ward
126 (3.3%), whereas CR P. aeruginosa was higher in the general ward (22.2%).

127 A considerable number of studies have described the high prevalence and outbreaks of CRO
128 infections in NICUs(11)(13)(25)(26)(27)(28). This population deserves special consideration
129 because of the high risk of complications and mortality. Indeed, the highest burden of
130 attributable deaths and disability-adjusted life-years caused by infections with antibiotic-
131 resistant bacteria in Europe has been described in infants (<1 year), with CR or colistin-
132 resistant E. coli, K. pneumoniae, Acinetobacter spp and P. aeruginosa being the third cause of
133 attributable deaths and disability-adjusted life-years within this age group(29). Several studies
134 have highlighted the importance of MDR Gram-negative microorganisms as a cause of sepsis in
135 NICUs in developing countries(13)(25). The high prevalence of CR in NICUs in these countries
136 nowadays is quite remarkable given that in reviews published just 10 years ago evaluating
137 antimicrobial resistance among neonatal pathogens in developing countries, this type of
138 resistance was not even mentioned(30). A cohort study characterizing the antimicrobial
139 resistance profile of pathogens causing sepsis in neonates admitted to three NICUs in India
140 showed an alarming CR rate of 78% (174/222) for Acinetobacter spp, 31% (21/68) for
141 Pseudomonas spp, 35% (59/169) for Klebsiella spp, 20% (9/44) for Enterobacter spp and 15%
142 (21/137) for E. coli(13). This high prevalence of CR isolates in neonatal sepsis has notable
143 implications since empirical treatment proposed by the WHO would not be adequate in these
144 settings. Suboptimal infection-control programs have been one of the most important factors
145 proposed in relation to the high burden of CRE found in in NICUs and PICUs in some hospitals
146 compared to the prevalence in adult units from the same hospital(14).
147 Mortality
148 CRO infections in the pediatric population have been shown to increase the risk of mortality 6
149 to 11-fold compared to non-CR infections(31)(32), but on the other hand, a number of studies
150 were unable to document worse outcomes in pediatric patients with CRO infections(33).
151 Mortality rates in children with CRO infections range from 8% to 52% (100% in a small case
152 series) (9)(18) (31)(32)(34)(35)(36)(37)(38)(39) (table 2), depending on the source of infection,
153 underlying diseases and age. One study that evaluated 50 healthcare-acquired CRE BSIs in
154 children from a tertiary hospital in India, mostly by NDM-producing K. pneumoniae, found
155 several significant risk factors for mortality including pediatric PICU admission, intubation,
156 inotropic support, respiratory source and failure to clear bacteremia(35). Meropenem MIC >8
157 mg/L for the isolate considerably increased the risk of mortality (OR: 13.9 [CI 95%: 1.5–125.6],
158 p=0.008) in this study. Regarding the difference in mortality between children and adults, a
159 multicenter national study based in Greece showed higher mortality among infections caused
160 by CRO in adults compared to children (34.9% vs 21.1%)(37).

161 Risk factors for infection or colonization
162 Risk factors for infection or colonization by CRO in children mirror those described for adults.
163 In most cases patients suffer from underlying comorbid conditions or were admitted to the
164 PICU or NICU(37)(16)(40). Specific risk factors for colonization or infection with CRO in children
165 include previous antibiotic exposure (mainly broad spectrum and extended duration), use of
166 medical devices (mostly mechanical ventilation), ICU stay, prior surgery and prolonged
167 hospitalization(18)(31)(33)(41)(25)(42)(43)(44)(45) (table 3).
168 Regarding previous antimicrobial exposure, in a recent comparative study performed in

169 children, only carbapenem exposure was significantly associated with CRO infections in the
170 multivariate analysis(41). Other studies in the pediatric population have also observed that
171 prior use of carbapenems was a risk factor for CRO infection (31)(33)(25)(43)(44)(45).
172 However, the relation with non-carbapenem antibiotics is less clear(33)(43)(42).
173 Patients from CRO endemic countries (e.g. India, Turkey or Egypt) (11)(12)(13)(14)(25) may
174 introduce CRO into pediatric institutions of non-endemic countries, suggesting the need for
175 specific interventions such as screening for colonization and specific empirical antimicrobial
176 treatment in newly admitted patients from these countries with infectious
177 diseases(36)(40)(42).
178 Although being born to a mother colonized with extended-spectrum β-lactamase-producing

179 Enterobacterales increases the risk of colonization in the newborn(46)(47), current data does
180 not support significant mother to newborn transmission of CRE(48)(49), with only one case(50)
181 reported so far. Therefore, there must be other risk factors related to colonization in these
182 newborns.
183 Treatment
184 Introduction
185 Specific recommendations in antibiotic therapy for infections due to CRO in pediatric patients
186 are based on studies including only adults(3) (table 4). The availability of pediatric
187 pharmacokinetics and safety data is the cornerstone to broaden the use of proposed agents in
188 adults into the pediatric population. Only scarce observational studies, case series and single
189 reports describe the efficacy of these treatments in infected
190 children(17)(18)(32)(34)(35)(36)(38)(40)(26)(51)(52)(53) (table 2). Furthermore, the regulatory
191 approval status of antibiotics in under 18-year-old patients makes the treatment of infections
192 caused by CRO more complicated in children. Antimicrobial treatment has to be individualized

193 to the severity, source of infection (table 5) and susceptibility profile of isolated bacteria. In
194 addition to antimicrobial treatment, other strategies like source control, when possible, and
195 supportive therapy, if needed, is mandatory. In children, when a CRO is isolated, expert
196 consultation is always warranted(1). Furthermore, the emergence of resistance to new
197 antibiotics further highlights the need of a rationalized antimicrobial treatment approach in
198 children(54). Proposed dosing of antibiotics for infections due to CRO are shown in table 6.
199 Combination therapy
200 Several studies conducted in adults have evaluated the combination of classic antibiotics with
201 different mechanism of action (e.g., polymyxins, aminoglycosides, fosfomycin, carbapenems,
202 etc) for CRO. Although combination therapies have better outcomes in some groups of adults
203 with CRE infections(55)(56), this has not been thoroughly evaluated in children. Additionally,
204 some data from adult studies suggest that combination treatment may not be beneficial in all
205 settings(57). Notably, the lack of enough knowledge regarding the optimal dose of several
206 antibiotics prescribed for the treatment of CRO infections in children raises the concern about
207 suboptimal treatment if only one antibiotic with limited documented experience is prescribed.
208 Furthermore, inappropriate empirical treatment has been associated with higher mortality
209 among CRE BSIs in pediatric patients (58). Therefore, the implementation of better methods to
210 rapidly identify CRE may improve outcomes(59).
211 Over the past few years, the use of combined treatment for CRO infections has increased in
212 children(38). An observational study in India assessing risk factors for mortality in CRE BSIs in
213 children found that mortality rates were significantly lower in the univariate analysis when ≥2
214 effective drugs were used in combination(35). However, given the small number of patients
215 included in the study and the lack of details regarding the monotherapy regimens provided, it
216 is difficult to draw any conclusions.
217 An Italian multicenter study that included 34 children with CRE infections evaluating the
218 influence of combined treatment on survival rate did not find any difference between patients
219 treated with monotherapy versus combination therapy(18). Nevertheless, the heterogeneity
220 of the sample could not exclude if patients with more severe infections may have benefited
221 from combination therapy. Indeed, studies in adults have proven that only high-risk patients
222 can benefit from combined treatment(55)(60). Unlike adult patients, mortality risk indexes
223 (e.g., Pitt or Charlson score in adults) are not broadly used in children, making this approach
224 more difficult to apply.
225 Data from clinical trials and observational studies conducted in adults have demonstrated the

226 non-inferiority of monotherapy with newer agents, such as ceftazidime-avibactam, compared
227 to combination therapy(61). The general consensus for the treatment of CRO infections in
228 adults is that susceptible strains could be treated in most cases with monotherapy with new
229 agents (i.e., ceftazidime-avibactam, meropenem-vaborbactam or ceftolozane-tazobactam),
230 but nothing is known with certainty in children.
231 Taking into account this knowledge regarding treatment of non-severe infections, and
232 according to the source of the infection, monotherapy could be an option in certain
233 circumstances, while avoiding monotherapy with potentially suboptimal drugs (e.g., tigecycline
234 or colistin). However, due to the limitations of most of the published pediatric studies, such as
235 small sample sizes or selection bias, further studies in pediatric patients are needed.
236 Carbapenems
237 Several studies have evaluated the safety and pharmacokinetics of meropenem in pediatric
238 patients(62)(63). Due to the higher probability of reaching the pharmacodynamic target for
239 isolates with MIC 8 mg/L when meropenem is administered at a higher dose by extended
240 infusion in adults(64), this approach has been extrapolated to pediatric patients with CRO
241 infections(2). Extended infusion and higher dosing (40 mg/kg/8h) strategies have proven to
242 increase the likelihood of obtaining bactericidal targets for meropenem in Monte Carlo
243 simulated pediatric population (from preterm neonates to adolescents)(65)(66).
244 Similarly to clinical data from adults(67), infections with isolates with meropenem MIC >8 mg/L
245 were associated with increased mortality in two pediatric studies(35)(68), and all children with
246 MIC ≥32 mg/L died(35). Mortality in children who received meropenem for an isolate with
247 MIC >8 was higher than when MIC ≤8 mg/L in this study (100% vs 45.5%, p=0.014).
248 Additionally, some concerns have arisen regarding a lower probability of reaching the target
249 for Gram-negative organisms with MICs 4-8 mg/L in critically ill pediatric patients(66).
250 Considering the lack of pediatric indications for many of the new drugs due to the scarce
251 experience in pediatric patients with most of them, along with the good clinical outcomes for
252 isolates with a meropenem MIC 8 mg/L in adults studies, we consider that meropenem at a
253 high dose by extended infusion is still the recommended treatment backbone until more
254 pediatric evidence is attained with new antibiotics. Backbone alternatives may be considered
255 with a meropenem MIC of 4-8 mg/L, especially in critically ill patients.
256 Ceftazidime-avibactam
257 Avibactam, a β-lactamase inhibitor, inhibits class A β-lactamases (e.g., KPC), class C β-

258 lactamases (e.g., AmpC), and certain class D β-lactamases (e.g., OXA-48), but it does not
259 restore activity against MBLs(69)(70). Data from adults consider ceftazidime-avibactam the
260 new cornerstone in the treatment of severe infections caused by KPC- and OXA-48-producing
261 Enterobacterales(3). Furthermore, combination therapy for the treatment of a susceptible
262 isolate, according to adult data, may be unnecessary (61). Ceftazidime-avibactam retains
263 adequate in vitro activity against CRE and CR P. aeruginosa, except for MBL-producing Gram-
264 negative bacilli. A surveillance of Gram-negative isolates collected from pediatric patients
265 hospitalized in US medical centers reported high in vitro activity of this antibiotic against
266 Enterobacterales and P. aeruginosa, with >99.9% and 99.1% susceptibility of strains,
267 respectively(71).
268 The safety profile in one phase I and two phase II trials including children from 3 months to 18
269 years was similar to that observed in the adult population(72)(73)(74). Based on the results
270 from these trials, the FDA has recently approved its use for pediatric patients >3 months of age
271 with complicated intraabdominal infections (cIAIs), in conjunction with an anti-anaerobic
272 agent, and also for urinary tract infections (UTIs). Currently, clinical data in the pediatric
273 population for the treatment of CRE infections with ceftacidime-avibactam is limited to a few
274 case reports(32)(75)(76)(77)(78).
275 Of concern is the emergence of resistant isolates during ceftazidime-avibactam treatment,

276 which occurs in as many as 10% of cases(54). This emerging resistance most commonly occurs
277 in KPC-producing organisms, especially in KPC-3(79), but not for OXA-48-producing
278 Enterobacterales(80). This resistance is mainly due to a mutation in the blakpc gene(81).
279 Ceftolozane-tazobactam
280 Ceftolozane-tazobactam has broad-spectrum activity against Gram-negative pathogens,

281 including many strains of MDR P. aeruginosa isolates(82)(83)(84). Ceftolozane is stable against
282 common resistant mechanisms of P. aeruginosa (e.g., AmpC or alterations of porin OprD).
283 Tazobactam, a classic β-lactamase inhibitor, inhibits non-carbapenemase β-lactamases (e.g.,
284 ESBLs), enhancing the activity of the combination. Therefore, this agent lacks activity against
285 carbapenemase-producing Gram-negative bacilli(69)(70).
286 Ceftolozane-tazobactam has shown greater in vitro activity than currently available
287 alternatives against P. aeruginosa isolates in some countries(85). An observational cohort
288 study suggested the preferential use of ceftolozane-tazobactam over polymyxin- or
289 aminoglycoside-based regimens for the treatment of drug-resistant P. aeruginosa
290 infections(86).

291 A single-dose phase I trial evaluated the administration of ceftolozane-tazobactam in children
292 from birth (7 days postnatal) to <18 years of age, including 6 preterm infants (≤32 weeks
293 gestational age)(87). The doses evaluated yielded exposure levels generally comparable with
294 those previously observed in adults. This dosage was included in two phase II clinical trials in a
295 pediatric population, demonstrating the safety and efficacy of ceftolozane-tazobactam for the
296 treatment of cUTI and cIAI(88). Furthermore, a new clinical trial awaiting the start of
297 recruitment , will evaluate the pharmacokinetics and safety of ceftolozane-tazobactam in
298 neonates and infants(89). Current clinical experience in children is scarce and limited to case
299 reports of MDR P. aeruginosa infections(90)(91)(92).
300 Similar to the development of resistance to ceftazidime-avibactam, acquired resistance to

301 ceftolozane-tazobactam also remains a relevant threat. Emerging resistance during therapy
302 has been mostly related to AmpC mutations associated with overexpression of the
303 enzyme(81)(93). Importantly, this mechanism may have cross-resistance to ceftazidime-
304 avibactam, making this emerging resistance even more difficult to treat(94).
305 Meropenem-vaborbactam
306 Meropenem-vaborbactam is another novel β-lactam-β-lactamase inhibitor, exerting potent

307 and specific activity against class A (e.g., KPC) carbapenemase-producing CRE, but not against
308 MBLs or class D β-lactamases (e.g., OXA-48)(95). It has already been approved for adults but
309 not for children. Currently, a study is underway evaluating the pharmacokinetics of
310 meropenem-vaborbactam in patients <18 years of age with serious bacterial infections(96).
311 The Tango II trial compared meropenem-vaborbactam to the best available therapy in patients
312 with serious CRE infections, showing a trend to lower mortality and a significantly higher
313 clinical cure in the group that received meropenem-vaborbatam(97). So far, a 4-year-old
314 patient has been treated for KPC-producing K. pneumoniae BSI with meropenem-vaborbactam,
315 with microbiological and clinical resolution(98).
316 Polymyxins
317 Since the advent of a growing number of MDR infections, polymyxins have been studied in
318 different pediatric ages(99)(100). Nephrotoxicity is one of the main concerns(99), with a higher
319 risk among adolescents(101). A huge diversity of doses among studies and resulting
320 recommendations makes it hard to establish the optimal dose for children.
321 Although colistin (polymyxin E) is more broadly used, polymyxin B could offer some
322 advantages(102), such as lower risk of nephrotoxicity. Although both antibiotics may need
323 drug adjustment in patients with renal impairment, since polymyxin B clearance is not affected

324 by renal function, polymyxin B may not require such a drastic renal adjustment. However, no
325 differences in mortality have been observed when treatment with these antibiotics was
326 compared(102), and there is less experience with the use of polymyxin B for the treatment of
327 MDR infections.
328 Most of the observational studies in children described a favorable outcome in >70% of
329 pediatric patients treated with polymyxins for MDR infections(103)(104)(101). Colistin has also
330 shown to be effective and safe against MDR infections in neonates(104).
331 Some studies suggest that traditional lower doses of colistin could be suboptimal(99). This
332 seems especially relevant when treating MDR infections located in tissues where penetration
333 of colistin is low (e.g., lung). In the case of central nervous system infections, other routes for
334 colistin administration (e.g., intraventricular/intrathecal) may be considered(105). In critically
335 ill patients with life-threatening infections, it is recommended to start treatment with a
336 loading dose in order to achieve therapeutic concentrations more quickly(100)(106), although
337 there is no data that supports this recommendation in children.
338 In a pediatric study, patients receiving an antibiotic regimen containing colistin for CRE
339 infections had an increased risk of mortality(18). This together with the adult
340 evidence(55)(107) (86), makes it recommendable to use colistin as an alternative to β-lactams
341 only in combination treatment for infections caused by CRO until enough evidence regarding
342 the optimal dose in children could be ascertained through appropriate clinical trials.
343 Emerging polymyxin resistance is considered a serious public health problem. Polymyxin
344 resistance is mainly mediated by modifications in lipopolysaccharides, which can be acquired
345 chromosomally or as a transferable mechanism (plasmid-mediated mcr gene)(108).
346 Tigecycline
347 Tigecycline has excellent in vitro activity against a significant proportion of pediatric CRO
348 isolates(17)(18)(37)(42)(53)(104)(109)(110), but some concerns exist about poorer outcomes
349 compared to other alternatives(111). Some reasons given have been the pharmacokinetics of
350 the drug, which has a large volume of distribution with low serum levels(112). However, some
351 studies have suggested that these therapeutic failures may be due to tigecycline
352 underdosing(113).
353 Due to a higher risk of mortality in adults when prescribed in monotherapy(114), it is mostly
354 used in combination therapy in children. Alarmingly, mortality among children who received
355 tigecycline for MDR/XDR infections was 86% in BSIs and 24% in non-bacteremic

356 infections(115). The dose of tigecycline in children is based on one PK study conducted in
357 children aged 8 to 11 years old(116). The use of higher doses has led to lower mortality among
358 ICU adult cases(114), and observational studies suggest a similar impact in critically ill
359 children(115). These results altogether suggest the need for higher doses in severe infections,
360 particularly pneumonia and BSIs, both in adults and children(3)(115)(117); nevertheless, its use
361 for these sources should be avoided if other antibiotics are available. In addition, tigecycline
362 might have adverse effects in children <8 years (tooth discoloration and enamel
363 hypoplasia)(118) and, therefore, it should be used only when other alternatives do not exist.
364 Fosfomycin
365 Fosfomycin retains activity against numerous pediatric CRO isolates(15)(40)(119)(120) and
366 should be considered in the absence of other alternatives based on some experience for the
367 treatment of CRO infections in children(26)(120). Interestingly, fosfomycin has shown
368 synergistic in vitro activity with meropenem against MBL-producing P. aeruginosa(121). All 28
369 neonates from a center in China who were treated with fosfomycin-containing regimens in
370 combination with meropenem for CR-producing K. pneumoniae infections (mediated by NDM-
371 1) survived(26).
372 Due to the concern of developing resistance while on therapy(122), it is recommended to use
373 it in combination therapy(2). Recommended doses for fosfomycin in pediatric patients vary
374 widely. A PK study concluded that the currently recommended doses could be suboptimal in
375 children and neonates, suggesting the need for more frequent dosing intervals and higher
376 dosages(123). Oral fosfomycin has been proposed for MDR Gram-negative uncomplicated
377 lower UTIs due to fosfomycin-susceptible organisms in older children and adolescents(1)(124).
378 Imipenem-cilastatin-relebactam
379 Imipenem-cilastatin-relebactam has recently been approved by the FDA in adults. It has good
380 activity against KPC carbapenemases but poor activity against OXA-48-like carbapenemases
381 and lacks activity against MBLs(125)(126). This combination enhances the activity of imipenem
382 against P. aeruginosa isolates(127). Notably, it restores activity against mutated KPC-3
383 carbapanemase, which increases the MIC of ceftazidime-avibactam(125). The RESTORE-IMI 1
384 trial demonstrated better clinical response and lower nephrotoxicity for imipenem-cilastatin-
385 relebactam compared to imipenem combined with colistin in patients with imipenem-non
386 susceptible bacterial infections(107). A phase I study and a phase II/III study are currently
387 investigating imipenem-cilastatin-relebactam for children <18 years of age(128)(129).
388 Other antibiotics

389 Aminoglycosides and, less frequently, fluoroquinolones are used with a backbone drug for
390 combination therapy for the treatment of CRO infections in
391 children(17)(18)(32)(34)(35)(36)(38)(40)(26)(51)(52). CRO isolates among children frequently
392 maintain susceptibility to aminoglycosides (mostly amikacin) and, in a variable proportion of
393 isolates, to fluoroquinolones(18)(37)(42)(26)(27)(51). Among aminoglycosides, plazomicin is a
394 semisynthetic aminoglycoside recently approved by the FDA in adults, which is active against
395 most CRE isolates except strains producing New Delhi MBLs(70).
396 Limited experience with fluoroquinolones for CRO infections makes this option less
397 recommendable. Eravacycline is a novel fluorocycline with in vitro activity against
398 carbapenemase-producing Enterobacterales and CR A. baumannii, but not against P.
399 aeruginosa (70)(130).
400 Aztreonam is not efficiently hydrolyzed by MBLs; however, these strains usually coproduce
401 other β-lactamases (i.e., ESBLs, AmpC), making them non-susceptible to this antibiotic. The
402 combination with avibactam frequently restores its activity(131)(132) and is an alternative
403 against MBLs-producing Enterobacterales when meropenem MIC is >8 mg/L due to the lack of
404 therapeutic possibilities. The combination of aztreonam-avibactam is currently undergoing
405 two phase III clinical trials in adults evaluating the treatment of serious Gram-negative
406 bacterial infections(133)(134). Several case reports combining aztreonam with ceftazidime-
407 avibactam has shown promising results(135). However, there is no published experience with
408 this combination in children.
409 Cefiderocol is a siderophore cephalosporin with broad activity against broad spectrum MDR
410 Gram-negative bacteria, including serine carbapenemases (i.e., KPC or OXA-48-like
411 carbapenemases) and MBL-producing Enterobacterales, P. aeruginosa and A.
412 baumannii(136)(137). It has recently been approved by the FDA for the treatment of cUTI in
413 adults. There are some concerns due to higher mortality reported in a clinical trial (CREDIBLE-
414 CR) for BSIs and pneumonia; therefore, caution should be used when it is prescribed for severe
415 infections(138). To date, the company (Shionogi Inc.) has provided information about the
416 compassionate use of cefiderocol in 9 cases of patients under 18-years-old who did not have
417 other options, with six of them surviving(138). Pediatric trials whit cefiderocol have yet to be
418 initiated and no specific pharmacokinetic information is known in this population.
419 Inhaled antibiotics
420 Some inhaled antibiotics, mainly tobramycin and colistin, have been used successfully in

421 pediatric cystic fibrosis and non-cystic fibrosis populations as an adjunctive therapy for
422 treatment of Gram-negative bacterial lung infections(139)(140)(141). Currently, there is
423 insufficient information to recommend systematic use of inhaled antibiotics for the therapy of
424 CRO in lung infections. However, it is reasonable to consider adjunctive inhaled antibiotic
425 treatment as a last resort for lung infections caused by CRO in children who are not responding
426 to intravenous antibiotics.
427 Carbapenem-resistant organisms
428 Carbapenem-resistant Enterobacterales
429 Most of the data about treatment of CRO infections is focused on CRE and the majority of
430 information from this review may apply to this group of microorganisms. Notably, almost all of
431 the new developed antibiotics are focused on the treatment of infections due to
432 Enterobacterales. However, epidemiological surveillances will be useful to assay potential
433 clonal changes and to improve the development of new drugs, as the emergence of resistance
434 to newer antibiotics will probably occur when these new agents are used more broadly.
435 Carbapenem-resistant P. aeruginosa
436 P. aeruginosa exhibits a huge diversity in its world distribution, with different circulating clones
437 that harbor a high diversity of the mechanisms involved in resistance against carbapenems.
438 This means an even higher challenge for treatment. The prevalence of susceptible in vitro
439 isolates to different drugs shows a broad variability. Ceftolozane-tazobazam has good in vitro
440 and clinical activity against several CR P. aeruginosa isolates not mediated by carbapenemases
441 (e.g., OprD deficiency). Ceftazidime-avibactam is a good alternative for CR P. aeruginosa
442 harboring class A carbapenemases (e.g., GES enzymes). Other newer β-lactam-β-lactamase
443 inhibitors, such as imipenem-cilastatin-relebactam, may play an important role against CR P.
444 aeruginosa infections, but little data is currently published against MDR/XDR P. aeruginosa
445 isolates.
446 For resistant isolates to all β-lactams, classic drugs such as polymyxins or aminoglycosides, and
447 synergistic combinations (142)(143), may be considered. From the agents commented in this
448 review, tigecycline and eravacycline do not exhibit relevant activity against P. aeruginosa.
449 Although high-dose extended infusion of carbapenems combined with a second active
450 antibiotic may be considered for the treatment of CR P. aeruginosa
451 infections(2)(144)(142)(143), less is known compared to CRE, making this option less
452 attractive.
453 Carbapenem-resistant A. baumannii

454 Sulbactam provides an additional option against CR A. baumannii, with some reports
455 suggesting better outcomes compared to alternatives for susceptible isolates(145)(146).
456 Higher doses have been suggested in the adult population, taking into account a PK/PD
457 benefit(147). Other alternatives are polymyxins, aminoglycosides and tigecycline(148).
458 Additionally, cotrimoxazole may be an optimal option for UTIs. The debate about combination
459 therapy vs monotherapy deserves the same considerations as for Enterobacterales, but with
460 even less evidence for CR A. baumannii infections. Generally, for severe infections or
461 immunosuppressed patients, combination therapy should be considered. Cefiderocol is being
462 used as compassionate use for pan-drug resistant isolates without other options(148).
463 Conclusions
464 The rate of CRO infections has greatly increased in the last years, representing a major public
465 health problem. These infections are difficult to treat, leading to high mortality. The evaluation
466 of risk factors for developing a CRO infection could provide individualized empirical broad-
467 spectrum antibiotic therapy, according to local epidemiology. Clinical evidence regarding
468 treatment of CRO infections remains scarce, and it mainly comes from observational studies,
469 which are even more limited in children. New antibiotics may open the door to highly effective
470 treatments, but the delay in conducting pediatric trials is leading to off-label use in this
471 population. Antibiotic stewardship programs remain a key element to preserving current
472 antibiotic activity through a rational approach in antimicrobial treatment.
473
474 ACKNOWLEDGMENTS
475 We thank Cindy McCoig, MD, for kindly reviewing the manuscript.
476
477 CONFLICTS OF INTEREST
478 The authors have no conflicts of interest to disclose.
479
480 FUNDING
481 This study did not receive any funding. DAA is funded by the Spanish Ministry of Health
482 – Instituto de Salud Carlos III (ISCIII) and co-funded by the European Union (FEDER) [Contrato
483 Río Hortega CM18/00100].

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1069 145. Oliveira MS, Prado GVB, Costa SF, Grinbaum RS, Levin AS. 2008.
1070 Ampicillin/sulbactam compared with polymyxins for the treatment of infections
1071 caused by carbapenem-resistant Acinetobacter spp. J Antimicrob Chemother
1072 61:1369–1375.
1073 146. Zalts R, Neuberger A, Hussein K, Raz-Pasteur A, Geffen Y, Mashiach T, Finkelstein
1074 R. 2016. Treatment of Carbapenem-Resistant Acinetobacter baumannii
1075 Ventilator-Associated Pneumonia: Retrospective Comparison between
1076 Intravenous Colistin and Intravenous AmpicillinSulbactam. Am J Ther 23:e78–
1077 e85.
1078 147. Jaruratanasirikul S, Wongpoowarak W, Aeinlang N, Jullangkoon M. 2013.
1079 Pharmacodynamics modeling to optimize dosage regimens of sulbactam.
1080 Antimicrob Agents Chemother 57:3441–3444.
1081 148. Piperaki ET, Tzouvelekis LS, Miriagou V, Daikos GL. 2019. Carbapenem-resistant
1082 Acinetobacter baumannii: in pursuit of an effective treatment. Clin Microbiol
1083 Infect. Elsevier B.V.
1084 149. Dirajlal-Fargo S, DeBiasi R, Campos J, Song X. 2014. Carbapenem-Resistant
1085 Enterobacteriaceae in Pediatric Patients: Epidemiology and Risk Factors. Infect
1086 Control Hosp Epidemiol 35:447–449.
1087 150. Singh NP, Choudhury D Das, Gupta K, Rai S, Batra P, Manchanda V, Saha R, Kaur
1088 IR. 2018. Predictors for gut colonization of carbapenem-resistant
1089 Enterobacteriaceae in neonates in a neonatal intensive care unit. Am J Infect
1090 Control 46:e31–e35.
1091 151. Mashni O, Nazer L, Le J. 2019. Critical Review of Double-Carbapenem Therapy
1092 for the Treatment of Carbapenemase-Producing Klebsiella pneumoniae. Ann

1093 Pharmacother 53:70–81.
1094 152. Papp-Wallace KM, Zeiser ET, Becka SA, Park S, Wilson BM, Winkler ML, D’Souza
1095 R, Singh I, Sutton G, Fouts DE, Chen L, Kreiswirth BN, Ellis-Grosse EJ, Drusano GL,
1096 Perlin DS, Bonomo RA. 2019. Ceftazidime-Avibactam in Combination With
1097 Fosfomycin: A Novel Therapeutic Strategy Against Multidrug-Resistant
1098 Pseudomonas aeruginosa. J Infect Dis 220:666–676.
1099 153. Committee on Infectious Diseases; American Academy of Pediatrics. 2018. Red
1100 Book 2018, 31st ed.
1101 154. Zobell JT, Young DC, Waters CD, Ampofo K, Stockmann C, Sherwin CMT,
1102 Spigarelli MG. 2013. Optimization of anti-pseudomonal antibiotics for cystic
1103 fibrosis pulmonary exacerbations: VI. Executive summary. Pediatr Pulmonol
1104 48:525–537.
1105
1106 TABLES
1107 Table 1. Molecular classification of carbapenemase enzymes.
Ambler Common Microorganisms Hydrolyzing Carbapenem Aztreonam Novel active β-lactams Novel active Non-β-
class enzymes mechanism resistance lactams
A KPC, NMC, GES, K. pneumoniae, E. coli, S. Serine-based High Resistant Ceftazidime-avibactam, Eravacycline, plazomicin
SME, IMI marcescens, E. cloacae, P. aztreonam-avibactam2,
aeruginosa, A. baumannii imipenem-relebactam,
meropenen-vaborbactam,
cefiderocol
B VIM, IMP, NDM K. pneumoniae, E. coli, S. Zinc-based Variable Susceptible1 Aztreonam-avibactam2, Eravacycline, plazomicin3
marcescens, E. cloacae, cefiderocol
Citrobacter spp, Proteus spp,
Morganella spp, Providencia
spp, P. aeruginosa
D OXA (most K. pneumoniae, E. coli, Serine-based Medium Susceptible1 Ceftazidime-avibactam, Eravacycline, plazomicin
common OXA-48- Citrobacter spp, Proteus spp aztreonam-avibactam2,
like) cefiderocol
1108 (1) Several strains coproduce other β-lactamases (ESBLs, AmpCs…), making them non-susceptible to aztreonam. (2) Currently not approved by FDA/EMA. (3)
1109 Not active against many NDM-producing strains due to the frequent coproduction of 16S ribosomal RNA methyltransferase.
1110
1111
1112 Table 2. Case series that describe treatment of pediatric infections produced by carbapenem-resistant Gram-negative microorganisms.
Ref. Years Country Cases Age Source(s) Isolates Resistance mechanism Combined treatment* Mortality**
(40) 1999- USA 6 3.5-18 y 5 BSIs, 1 UTIs S. marcescens, E. coli, KPC, IMP, and others non- 83% (5/6) 17% (1/6)
2010 K. pneumoniae carbapenemases
(51) 2002- Several 64 (24 treatment 0-17 y 30% BSIs, 25% UTIs, 19% Enterobacterales KPC, NDM, VIM and others 21% (5/24) 10% (5/52)
2010 countries data) gastrointestinal, 17% non-carbapenemases
(review) respiratory, 9% others
(53) 2010 USA 5 (3 infected) 3-11 y 2 BSIs, 2 respiratory, 1 K. pneumoniae KPC 66.7% (2/3) No deaths related
peritoneal to infection
(17) 2011- UK 24 (9 treatment 0-12 y 5 urine, 2 BSIs, 2 skin Enterobacterales KPC, NDM, and others non- 20% (1/5) 11% (1/9)
2012 data) (infected carbapenemases
cases)
(52) 2012- Italy 15 (6 treatment Mean age 47% urine, 27% BSIs, 26% 11 K. pneumoniae, 4 12 KPC, 2 OXA-48, 1 MBL 66% (4/6) 33% (2/6)
2013 data) 10.6 y (SD others E. coli
1.8)
(38) 2008- Colombia 43 episodes (34 <15 y 35% UTIs, 23% IAIs, 18% K. Pneumoniae KPC 51.2% (22/43) 38% (11/34)
2013 infected) BSIs, 14% pneumonia,
10% others
(36) 2002- USA 15 episodes (12 4 m-11 y 4 urine, 4 BSIs, 3 K. pneumoniae, E. coli VIM, NDM and IMP 41.7% (5/12) 16.7% (2/12)
2014 treatment data) respiratory, 1 peritoneal and E. cloacae
(18) 2011- Italy 74 isolates (69 0-18 y 35% BSIs and CLC tip, 38% Enterobacterales KPC (61.4%), OXA-48 (13.6%), 61.8% (21/34) 23.5% (8/34)
2014 cases; 34 infections) respiratory, 6% CSF, 21% MBL
others
(68) 2011- China 138 (54 infected) <18 y BSIs K. pneumoniae NDM, IMP, KPC and others 38.9% (21/54) empirical 18.5% (10/54)
2014 treatment, 63% (34/54)
targeted treatment
(34) 2011- China 52 0-16 y BSIs K. pneumoniae NDM, IMP, KPC and others 38.5% (20/52) combined 11.5% (6/52)
2014 non-carbapenemases treatment, 13
monotherapies changed to
combined therapy after
isolation of bacteria
(35) 2014- India 50 <17 y BSIs K. pneumoniae (66%) Mostly NDM. Also, OXA and 68% (34/68) empirically 52% (26/50)
2015 and E. coli (34%) non-carbapenemases
(39) 2015 Morocco 6 1-13 days 5 BSIs, 1 urine K. pneumoniae OXA-48 100% (6/6) empirically 100% (6/6)
(32) 2011- USA 103 (31 infections) <21 y 39% urine, 35% Enterobacterales Mostly KPC. Also, NDM, OXA 32.2% (10/31) 6.5% (2/31)
2016 respiratory, 13% wound, and non-carbapenemases
11% BSIs, 3% peritoneal
(26) 2015- China 88 (39 infections) Neonates 50% pneumonia, 43% K. pneumoniae NDM (87.2%) 94.9% (37/39) 2.7% (1/37)
2016 UTIs, 7% others
(78) 2017- Greece 9 episodes (8 cases) 13 days- 6 BSIs (2 also CSF), 2 K. pneumoniae 7 CR-K. Pneumoniae 100% (8/8); all received 0% (0/8)
2018 4.5 y rectal, 1 urine (mechanism not described) ceftazidime-avibactam
1113
1114 *Combination treatment described in different ways (i.e., empirically/targeted), not always specified. **Mortality among infected patients.
1115 BSIs, blood stream infections; CLC, central line catheter; CSF, cerebrospinal fluid; KPC, Klebsiella pneumoniae carbapenemases; MBL, metallo-β-
1116 lactamase, NDM, New Delhi metallo-β-lactamase; OXA-48, oxacillinase-48; IAIs, intraabdominal infections; IMP, imipenemase, UTIs, urinary
1117 tract infections; VIM, Verona integron-encoded metallo-β-lactamase.
1118
1119
1120 Table 3. Studies that evaluate risk factors for carbapenem-resistant infection or colonization in children.
Ref. Years Country Populatio Cases (n) Controls (n) Evaluation Risk factors
n Univariate analysis Multivariate analysis
(44) 1991- Thailand NICU CR A. CS A. Infection (BSIs) - Lower birth weight Not reported
2010 baumannii baumannii/n - Lower duration of CVC
(14) o isolation - Antibiotics*: Use of cefoperazone/sulbactam or imipenem
(38/44)
(149) 2009- USA Pediatric CRE (13) Not isolated Infection or - Previous colonization/infection with vancomycin-resistant Not reported
2011 CRE (52) colonization Enterococcus species or ESBL-producing Enterobacteriaceae
- Antibiotics*: penicillin, third-generation cephalosporin,
carbapenem, fluoroquinolone or trimethoprim-sulfamethoxazole
(45) 2012 Turkey Pediatric CR K. Non-CR K. Colonization - Transfer from another institution - Transfer from another institution
pneumonia pneumoniae - Antibiotics*: carbapenem - Antibiotics*: carbapenem
e (83) (198)
(41) 2014 Turkey <18 y CR-GNB CS-GN (28) Infection - Length of hospital stay before onset of infection >21 days - Foley catheter
(27) - Prior hospitalization - Prior prolonged hospitalization
- Foley catheter - Antibiotics*: carbapenem or
- Antibiotics*: carbapenem or glycopeptide glycopeptide
(33) 2008- USA <23 y KPC-CRE CSE/No Infection - Pulmonary and neurologic comorbidities Not reported
2015 (18) isolation - GI and pulmonary devices
(18/54) - Antibiotics*: carbapenem or aminoglycoside
(25) 2014- Egypt NICU CR-GNB CS-GN LOS Infection (LOS) - Feeding: longer time to start enteral feeds, exclusive breast milk, - Duration of total parenteral nutrition
2016 patients LOS (100) (58) formula feeds - Antibiotics*: carbapenem
(late- - Previous corticosteroid use
onset - Antibiotics*: cephalosporin or carbapenem, and previous longer
sepsis) antibiotic duration
- Duration of total parenteral nutrition
- CVC and longer duration of CVC
- Gastrointestinal congenital anomalies
(15) 2010- Turkey NICU and CR-K. CR-K. Infection - Diseases: Neurological or metabolic disease - Metabolic disease
2014 PICU pneumonia pneumoniae - Neutropenia - Neutropenia
e infected colonized - Devices: urinary catheterization or tracheostomy - Surgery
(24) (61) - Surgery - Antibiotics*: carbapenem
- Antibiotics*: carbapenem
(18) 2011- Italia Pediatric CRE CRE colonized Infection and - Admission in PICU or NICU and length of hospital stay Not reported
2014 infected (35) colonization
(34)
(68) 2011- China <18 y CR-K. CS-K. Infection - Older age - Hematologic malignancies
2014 pneumonia pneumoniae - Underlying disease - Antibiotics*: cephalosporines
e (54) - Hematologic malignancies
- CVC
- Previous immunosuppressive therapy
- Previous neutropenia
- Antibiotics*: cephalosporin, antifungal agents or glycopeptide
(42) 2011- USA Pediatric CRE (63) CSE (126) Infection and - Male sex - Antibiotics*: antipseudomonal
2015 colonization - Prior surgery - Prior surgery
- ICU admission - Mechanical ventilation
- Longer length of stay before culture
- Prematurity
- Devices: CVC, endotracheal tube or Foley catheter
- Antibiotics*: carbapenem or antipseudomonal
(43) 2014- Turkey 1m-18 y CR-GNB CS-GNB Infection (BSIs) - Longer hospital stay Not reported
2015 bacteremia bacteremia - Antibiotics*: carbapenem, fluoroquinolones or glycopeptide
(31) (66)
(31) 2012- Brazil PICU CR-GNB HA- CS-GNB HA- Infection (HA- - Surgery Not reported
2016 BSIs (19) BSIs (43) BSIs) - Antibiotics*: carbapenem
(150) Not India NICU CRE No CRE Colonization - Longer duration of hospital stay. - Top feeding
report colonized colonized - Feeding: lower breastfeeding - Antibiotic administration
ed (36) (274) - Devices: NG tube or ventilation
- Antibiotic administration
1121 * Antibiotics referred as previous exposure, with variable time criteria among studies.
1122 BSI, bloodstream infections; CR, Carbapenem-resistant; CRE, Carbapenem-resistant Enterobacterales; CS, Carbapenem-sensitive; CSE,
1123 Carbapenem-sensitive Enterobacterales; CVC, Central vascular catheter; ESBL, Extended-spectrum β-lactamase; GNB, Gram-negative bacteria;
1124 LOS, Late-onset neonatal sepsis, NICU, Neonatal intensive care unit; PICU, Pediatric intensive care unit.
1125 Table 4. Proposed treatment for carbapenem-resistant Gram-negative infections in children.
1126 Adapted with permission from Rodríguez-Baño J(3).
Backbone recommended: Meropenem in extended and high dose infusion
Meropenem
Backbone alternatives (consider Ceftazidime-avibactam3, meropenem-
MIC ≤8 mg/L
specially when meropenem MIC 4-8)1,2: vaborbactam4, ceftolozane-tazobactam5,
Susceptible to a
Meropenem aztreonam6, ceftazidime7, ampicillin-sulbactam8
β-lactam Backbone recommended:
MIC >8 mg/L or imipenem-cilastatin-relebactam9

Accompanying
Aminoglycoside, polymyxin11, fosfomycin, tigecycline or fluoroquinolone
drug10:
Susceptible to Backbone recommended: Polymyxin11
10
Resistant to all β- polymyxins Backbone alternatives:
lactam, Resistant to Aminoglycoside, tigecycline or fluoroquinolone
10 Backbone recommended:
susceptible to at polymyxins
least 2 drugs Accompanying
Aminoglycoside, polymyxin11, fosfomycin, tigecycline or fluoroquinolone
drug10:
Combination of ≥2 drugs with in vitro activity, including experimental drugs12.
Pandrug-resistant
Consider in vitro testing of combinations for synergy (e.g., aztreonam + ceftazidime-avibactam13(131),
or susceptible to
meropenem-ertapenem(151), meropenem-fosfomycin(121), ceftazidime-avibactam-
only one drug
fosfomycin(152),meropenem-colistin(142)
1127 (1) Currently, meropenem-vaborbactam or ceftolozane-tazobactam, and ceftazidime-avibactam in
1128 some countries, as off-label use in children, should be limited to severe infections if other β-
1129 lactams have not in vitro activity, or to isolations with meropenem MIC ≥4 mg/L. Imipenem-
1130 cilastatin-relebactam, although is approved in some countries for adults (e.g. USA), has scarce
1131 evidence on pharmacokinetics, safety and effectivity in children, so it should be avoided until more
1132 evidence is available. (2) Data from adults suggest that combination therapy are not needed if new
1133 β-lactam-β-lactamase inhibitor are used as backbone. For the treatment of non-severe infections,
1134 and according to the source of the infection, monotherapy treatment may be an option, avoiding
1135 monotherapy with potentially suboptimal drugs (e.g., tigecycline or colistin). (3) Ceftazidime-
1136 avibactam could be used for non-MBLs carbapenemase-producers; (4) meropenem-vaborbactam
1137 for KPC-carbapenemase-producers; (5) ceftolozane-tazobactam for non-carbapenemase-producing
1138 P. aeruginosa; (6) aztreonam for MBLs (VIM, NDM and IMP) or OXA-48-producers if no
1139 coproduction of ESBLs or AmpC is detected; if coproduction is detected and synergistic in vitro
1140 activity with avibactam is detected, combination of aztreonam + ceftazidime-avibactam could be
1141 an alternative; (7) ceftazidime for OXA-48-producers if no coproduction of ESBLs or AMPc is
1142 detected; (8) ampicillin-sulbactam for susceptible Acinetobacter spp; (9) Imipenem-cilastatin-
1143 relebactam for KPC-producers or MDR P. aeruginosa. (10) Consider source of infection for
1144 backbone and accompanying drug (table 5). (11) Colistin (polymyxin E) or polymyxin B. (12) For
1145 these isolations cefiderocol may be an option. (13) Currently, aztreonam-avibactam is not available.
1146 Alternatively, it could be used with the combination of aztreonam + ceftazidime-avibactam.
1147
1148
1149
1150
1151
36
1152 Table 5. Recommended drugs according to infection source for carbapenem-resistant Gram-
1153 negative infections in children
Accompanying Alternative accompanying Other alternatives
Source Backbone
drug drug (1)
Polymyxin (2)(4) or Fosfomycin or

Respiratory β-lactam Fluoroquinolone
aminoglycoside (2) tigecycline (2)

Polymyxin (2)(4) or
UTIs Aminoglycoside (3) β-lactam Fosfomycin or fluoroquinolone
tigecycline (2)
Fluoroquinolone or
CLABSI/BSIs β-lactam Polymyxin (4) Fosfomycin or aminoglycoside
tigecycline (2)
Polymyxin (4) or Aminoglycoside or

IAIs (5) β-lactam Tigecycline
fluoroquinolone Fosfomycin
1154 BSIs, bloodstream infections, CLABSI, central line-associated bloodstream infections; IAIs,
1155 intraabdominal infections; UTIs, urinary tract infections.
1156 (1) Consider using if other alternatives are not available.
1157 (2) For the treatment of these sources, consider optimizing the dosage (see table 6).
1158 (3) For the treatment of non-severe UTIs (without sepsis, septic shock or other complications) consider
1159 using monotherapy treatment.
1160 (4) Colistin (polymyxin E) or polymyxin B.
1161 (5) For intraabdominal infections, an anti-anaerobic drug (e.g. metronidazole) should be included, unless
1162 either meropenem or tigecycline are prescribed.
1163
1164
1165
1166
1167
1168
1169
1170
37
1171 Table 6. Proposed dosing for the most frequently used drugs against carbapenem-resistant
1172 Gram-negative bacilli in children.
Drug Dose Regulatory approval status Comments
Meropenem 40 mg/kg/dose IV over 3 hours q8h (max: 2 EMA: >3 m
g/dose) FDA: All ages (<3 m only for IAI)
Neonates <32 wk gestation and <2 wk old:
same dose q12h
Ertapenem ≥13 y and adults: 1 g q24h EMA and FDA: >3 m Combined ertapenem-

<13 y: 30 mg/kg/day q12h (max 1 g/day) meropenem regimen for
extensive drug-resistant
isolates (consider higher dose,
max. 2g/day)
Gentamicin 5-7.5 mg/kg q24h. FDA and EMA: all ages (caution Desired serum levels: peak 6-
Neonates: dose by gestational and postnatal in premature infants) 12 μg/mL, through <2 μg/mL
age(153) Consider higher doses (7.5–10
mg/kg/day) for shock, lung
infections and cystic fibrosis
patients.
Amikacin 15-20 mg/kg q24h FDA and EMA: all ages (caution Desired serum levels: peak 20-
Neonates: dose by gestational and postnatal in premature infants) 35 μg/mL, through <5 μg/mL
age(153) Higher doses (25–30
mg/kg/day) might be
considered in shock, lung
infections and cystic fibrosis
patients.
Colistin Maintenance: 75,000-150,000 IU/kg/day q8- FDA and EMA: all ages for the Higher maintenance doses
(Colistimethate 12h treatment of serious infections (150,000-250,000 IU/kg/day)
sodium) A loading dose of 75,000-150,000 IU/kg is due to Gram-negative pathogens should be considered in shock,
recommended in critically ill patients in patients with limited lung infections and cystic
(Max. daily dose: 10,800,000 IU) treatment options fibrosis patients.
Polymyxin B Maintenance: FDA: all ages for the treatment
≥2 years: 15,000-25,000 IU/kg/day q12h. of serious infections due to
<2 years: 25,000-40,000 IU/kg/day q12h. Gram-negative pathogens in
Consider a loading dose of 25,000/kg in patients with limited treatment
critically ill patients options
(Max. daily dose: 2,000,000 IU) EMA: not available in Europe
Tigecycline ≥12 years: 100 mg loading dose and then 50 EMA: restricted to children >8 Consider higher dose for lung
mg q12h years with infections without infection, cUTI, BSI, or shock: 8
8 to 11 years: 2 mg/kg loading dose and then alternative antibacterial therapy to 11 years: 3 mg/kg loading
1.2 mg/kg/dose q12h (max. 50 mg/dose) available dose (max. 200 mg) and then 2
FDA: not recommended unless mg/kg/dose (max. 100 mg)
alternative treatment is not q12h; ≥12 years: 200 mg
suitable loading dose and then 100 mg
q12h
Fosfomycin >12 years (>40 kg): 12–24 g/day IV q6-8h EMA: all ages Consider higher dose (400
1–12 years (10-40 kg): 200-400 mg/kg/day q6- FDA: not available in USA (IV mg/kg/day q6-8h in
8h formulation) patients >12 months, max. 8g
1–12 months (≤10 kg): 200-300 mg/kg/day q8h q8h) for severe infections, in
Neonates (Postnatal age 40-44 wk old): 200 particular when caused by
mg/kg/day q8h organisms with moderate
Premature neonates (Postnatal age<40 wk susceptibility. Serum
old): 100 mg/kg/day q12h electrolyte levels and water
balance must be monitored
during therapy.
Aztreonam 120-150 mg/kg/day q8h (max 8 g/day) FDA and EMA: all ages The highest dose might be
Neonates: dose by gestational and postnatal considered in severe infections
age(153)
38
Ceftazidime- 2-hour IV infusion q8h: FDA: >3 m Consider 3-hour infusion for
avibactam 1) 6 months to <18 years: 50 mg/kg EMA: not approved <18 y severe infections.
ceftazidime (max. 2 g/dose)/12.5 mg/kg
avibactam (max. 0.5 g/dose)
2) 3 to <6 months: 40 mg/kg ceftazidime/10
mg/kg avibactam
Ceftolozane- 1-hour IV infusion q8h of ceftolozane 20 FDA and EMA: not approved <18 For severe lung infections
tazobactam mg/kg/dose (max. 1 g/dose) and tazobactam y consider ceftolozane 40

10 mg/kg/dose (max. 0.5 g/dose) mg/kg/dose and tazobactam
20 mg/kg/dose (max.
ceftolozane 2 g/dose and
tazobactam 1 g/dose) q8h.
Pediatric dose from phase I
clinical trial(87) and two phase
II clinical trials(88)
Meropenem- 3-hours IV infusion q8h of meropenem 40 FDA and EMA: not approved <18 Dose from an ongoing phase I
vaborbactam mg/kg/dose (max 2 g/dose) and vaborbactam y clinical trial in children <18
40 mg/kg/dose (max. 2 g/dose) years of age(96)
Imipenem- 1 month to <18 years old: imipenem 15 FDA and EMA: not approved <18 Dose from a phase I clinical
cilastatin- mg/kg/dose (max. 500 mg/dose) with y trial in children <18 years of
relebactam cilastatin 15 mg/kg/dose (max. 500 mg/dose) age(128)
with relebactam 7.5 mg/kg/dose IV q6h
Ampicillin- 400 mg/kg/day q6h of ampicillin (max. FDA and EMA: >12 months
sulbactam ampicillin 8 g/day).
1173
1174 BSI, bloodstream infection, cUTI, complicated urinary tract infection; EMA, European Medicines
1175 Agency; FDA, Food and Drug Administration; IV, intravenous.
1176 Colistin may be labelled as IU of colistimethate sodium (CMS), mg of CMS or as mg of colistin base
1177 activity (CBA). The conversion is as follows: 1,000,000 IU of CMS = 80 mg of CMS = 30 mg of ACB.
1178 Polymyxin B may be labelled as IU or mg. The conversion is as follows: 10,000 IU = 1 IU.
1179 Children with cystic fibrosis, in general, require higher dosages to achieve equivalent
1180 therapeutic serum concentrations due to enhanced clearance(154).
1181
1182
1183
1184
39

Infecciones Por Gram Negativos Resistentes A Carbapenemicos en Niños

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Infecciones Por Gram Negativos Resistentes A Carbapenemicos en Niños

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AAC Accepted Manuscript Posted Online 16 December 2019

Antimicrob. Agents Chemother. doi:10.1128/AAC.02183-19

2 Complete manuscript title: Carbapenem-Resistant Gram-Negative Infections in

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6 - David Aguilera-Alonso, Pediatric Infectious Diseases Unit. Gregorio Marañón Hospital,

9 - Luis Escosa-García, Department of Infectious Diseases and Tropical Pediatrics. La Paz

12 - Jesús Saavedra-Lozano, Pediatric Infectious Diseases Unit. Gregorio Marañón Hospital.

15 - Emilia Cercenado, Department of Infectious Diseases and Clinical Microbiology.

18 - Fernando Baquero-Artigao, Department of Infectious Diseases and Tropical Pediatrics.

22 Name and address for correspondence: David Aguilera-Alonso. Telephone number:

26 Alternate corresponding author: Fernando Baquero-Artigao. Telephone number: +34

33 Running head title: Carbapenem-Resistant Gram-Negative Infections in Children.

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41 Carbapenem-resistant organisms (CRO) are a major global public health threat.

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67 Among Enterobacterales (previously known as the order Enterobacteriaceae), at present, the

79 Although the most frequent mechanisms of resistance of Pseudomonas aeruginosa to

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107 Comparative surveillance data in routine bloodstream isolates in Europe demonstrated a

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168 Regarding previous antimicrobial exposure, in a recent comparative study performed in

178 Although being born to a mother colonized with extended-spectrum β-lactamase-producing

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199 Combination therapy

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275 Of concern is the emergence of resistant isolates during ceftazidime-avibactam treatment,

280 Ceftolozane-tazobactam has broad-spectrum activity against Gram-negative pathogens,

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300 Similar to the development of resistance to ceftazidime-avibactam, acquired resistance to

306 Meropenem-vaborbactam is another novel β-lactam-β-lactamase inhibitor, exerting potent

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388 Other antibiotics

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419 Inhaled antibiotics

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427 Carbapenem-resistant organisms

428 Carbapenem-resistant Enterobacterales

435 Carbapenem-resistant P. aeruginosa

453 Carbapenem-resistant A. baumannii

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477 CONFLICTS OF INTEREST

478 The authors have no conflicts of interest to disclose.

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487 1. Chiotos K, Han JH, Tamma PD. 2016. Carbapenem-Resistant Enterobacteriaceae

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Downloaded from http://aac.asm.org/ on December 19, 2019 at Chalmers University

Downloaded from http://aac.asm.org/ on December 19, 2019 at Chalmers University

Downloaded from http://aac.asm.org/ on December 19, 2019 at Chalmers University

Downloaded from http://aac.asm.org/ on December 19, 2019 at Chalmers University

Downloaded from http://aac.asm.org/ on December 19, 2019 at Chalmers University

Downloaded from http://aac.asm.org/ on December 19, 2019 at Chalmers University

Downloaded from http://aac.asm.org/ on December 19, 2019 at Chalmers University

Downloaded from http://aac.asm.org/ on December 19, 2019 at Chalmers University

Downloaded from http://aac.asm.org/ on December 19, 2019 at Chalmers University

Downloaded from http://aac.asm.org/ on December 19, 2019 at Chalmers University

Downloaded from http://aac.asm.org/ on December 19, 2019 at Chalmers University

Downloaded from http://aac.asm.org/ on December 19, 2019 at Chalmers University

Downloaded from http://aac.asm.org/ on December 19, 2019 at Chalmers University

Polymyxin (2)(4) or Fosfomycin or