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Article history:
Received 22 September 2014
Received in revised form 19 February 2015
Accepted 22 February 2015
Available online 4 March 2015
Keywords:
Antibiotics
Antimicrobial treatment
Multidrug-resistance
Neonate
Neonatal sepsis
a b s t r a c t
Severe infections represent the main cause of neonatal mortality accounting for more than one million neonatal
deaths worldwide every year. Antibiotics are the most commonly prescribed medications in neonatal intensive
care units. The benets of antibiotic therapy when indicated are clearly enormous, but the continued and widespread use of antibiotics has generated over the years a strong selective pressure on microorganisms, favoring the
emergence of resistant strains. Health agencies worldwide are galvanizing attention toward antibiotic resistance
in gram-positive and gram-negative bacteria. Infections in neonatal units due to multidrug and extensively
multidrug resistant bacteria are rising and are already seriously challenging antibiotic treatment options.
While there is a growing choice of agents against multi-resistant gram-positive bacteria, new options for
multi-resistant gram-negative bacteria in the clinical practice have decreased signicantly in the last 20 years
making the treatment of infections caused by multidrug-resistant pathogens challenging mostly in neonates.
Treatment options are currently limited and will be some years before any new treatment for neonates become
available for clinical use, if ever.
The aim of the review is to highlight the current knowledge on antibiotic resistance in the neonatal population,
the possible therapeutic choices, and the prevention strategies to adopt in order to reduce the emergency and
spread of resistant strains.
2015 Elsevier B.V. All rights reserved.
1. Introduction
Neonatal sepsis represents the main cause of neonatal mortality accounting for more than one million neonatal deaths worldwide every
year, and antibiotics are the most commonly prescribed medications
in neonatal intensive care units (NICU) [1,2]. The development of antibiotic resistance (resistance of a microorganism to an antimicrobial drug
Abbreviations: ASP, antimicrobial stewardship programs; CA-MRSA, communityassociated MRSA; CDC, Centers for Disease Control and Prevention of Atlanta; CONS,
coagulase-negative Staphylococcus; CPE, carbapenemase-producing Enterobacteriaceae;
CSF, cerebrospinal uid; ECDC, European Centre for Disease Prevention and Control; EMA,
European Medicines Agency; EOS, early-onset sepsis; ESBL, extended spectrum lactamase; FDA, the Food and Drug Administration; GBS, group B streptococcus; GNB,
gram-negative bacteria; GPB, gram-positive bacteria; HA-MRSA, hospital-associated
MRSA; IDSA, Infectious Diseases Society of America; KCP, Klebsiella pneumoniae
carbapenemase; KCP-Kp, KCP K. pneumonia; LOS, late-onset sepsis; MALDI-TOF MS,
matrix-assisted laser desorption ionization time-of ight mass spectrometry; MRSA,
Methicillin-resistant Staphylococcus aureus; MDR, multi-drug resistant; NICU, Neonatal intensive care unit; PCR, polymerase chain reaction; PVL, Panton-Valentine leukocidin;
VISA, vancomycin-intermediate S. aureus; VLBW, very low birth weight infants; VRE,
vancomycin-resistant enterococci; VRSA, vancomycin-resistant S. aureus; WHO, World
Health Organization; XDR, extensively drug-resistant.
Corresponding author at: Neonatal Intensive Care Unit, Fondazione IRCCS Policlinico
San Matteo, Piazzale Golgi 19, 27100 Pavia, Italy. Tel.: +39 0382 502704.
E-mail address: c.tzialla@smatteo.pv.it (C. Tzialla).
http://dx.doi.org/10.1016/j.cca.2015.02.038
0009-8981/ 2015 Elsevier B.V. All rights reserved.
72
Even though an increase in vancomycin MIC values, within the susceptible range, has been registered among isolates of MRSA, CONS or
S. aureus strains vancomycin-intermediate or vancomycin-resistant
haven't been documented in the NICU population [16,17].
2.2. Gram negative bacteria
Gram-negative bacteria are often resistant to at least one class of antibiotics usually used in health care settings, and bacteria multi- or
extensively-resistant to conventional antibiotics are frequently isolated.
Pan-resistant pathogens are rarely isolated in the NICUs [16,22] and the
most frequent resistance has been described against piperacillintazobactam, ceftazidime, and/or gentamicin [17].
Gentamicin resistance (antibiotic widely used for empiric therapy in
NICU due to aminoglycoside-converting enzymes) is increasing among
Enterobacteriaceae. Since the enzyme that confers resistance to gentamicin may not include other agents of antimicrobial category the
gentamicin-resistant bacteria could be still susceptible to tobramycin
or amikacin [22].
The emergence of ESBL-producing Enterobacteriaceae resistant
to penicillins and cephalosporins, and often to other antibiotic classes
(i.e. uoroquinolones and aminoglycosides) has become a problem
threatening health. ESBL-producing bacteria are found frequently in the
community meaning that they are possible causes of an EOS due to a vertical transmission [16,17,22]. E. coli and K. pneumonia are probable to acquire ESBLs, even if these enzymes are also noted in other species [16].
Even more threatening, is the increasing in the community as well as
in the hospital of carbapenemase-producing Enterobacteriaceae (CPE)
that are no susceptible to carbapenems. The European antimicrobial
resistance surveillance network report increasing percentages of
K. pneumoniae carbapenemase (KPC)-producing isolates between
2005 and 2010 in Europe even if these bacteria are not yet common in
neonatal population [9,16,17,22,23].
Failure to start early treatment with antibiotics active against resistant strains is linked with poorer prognosis [16,17].
A recent study conducted by Giuffr et al. [24] in a NICU shows the
colonization by KCP-K. pneumoniae (KCP-Kp), in 10 out of 54 neonates
admitted in the NICU in the period between September 18 and November 14, 2012, without occurs however, cases of infection. According to
the authors this is the rst report of a KCP-Kp colonization outbreak in
a NICU.
Rates of infection due to resistant P. aeruginosa and MDR
Acinetobacter spp continue to increase in US and globally. P. aeruginosa
is intrinsically resistant to many commonly used antibiotics. Resistance
to both quinolones and carbapenems is increasing among P. aeruginosa
isolates and recent reports document resistance to polymyxins [9].
However, resistance to multiple antibiotics is rare in neonates. Some
strains of MDR Acinetobacter baumannii exhibit discordant resistance
to carbapenems, being susceptible to impenem but resistant to
meropenem and doripenem due to increased expression of naturally
occurring carbapenemases [17].
3. Antibiotic use and emergence of resistant strains
The extensive and indiscriminate use of antibiotics over several decades in hospitals, outpatient regime in the territory and outside the
health care settings, to the farms to promote growth in food-producing
animals, has generated over the years a strong selective pressure on microorganisms, favoring the emergence of resistant strains [25].
The development of resistance is a normal evolutionary process for
microorganisms, but it is accelerated by the selective pressure exerted
by widespread use of antibacterial drugs.
Already in his Nobel Prize speech in 1945, Alexander Fleming, who
discovered penicillin, warned that bacteria could become resistant to
these remarkable drugs and that it was appropriate to reduce the use
of penicillin to slow the development of resistance [26].
The ECDC, drawing up a list of European countries for daily use of antibiotics in descending order, identies Italy as one of the countries
where consumption is higher on average 2630 daily doses per 1000 inhabitants between 2008 and 2010, compared with 1115 daily doses per
1000 inhabitants consumed in the same period in the Netherlands,
which is the most virtuous of the league [5].
The CDC reports that, in general, more than half of hospitalized patients receive at least one antibiotic during hospitalization, and of
these, about two-thirds receive broad-spectrum antibiotics [6].
In particular nearly all very low birth weight infants (VLBW) admitted
to NICUs receive empirical antibiotic treatment in the rst days of life, in
spite the evidence of sterile cultures and low incidence of cultureproven bacterial sepsis in this population [1,10]. Indeed more than 95%
of infant admitted to the NICU receive empiric antibiotics, but only 1%
to 5% have positive initial blood cultures [27].
Several studies show that widespread and inappropriate use of antibiotics is very common in NICUs.
In a national prevalence study conducted for the Pediatric Prevention
Network on 29 NICUs [28] in the United States, 43.3% of all patients
were receiving antimicrobials on the probing date; 22.7% were receiving
one agent, 58.5% two agents, 15.5% three, 2.9% four and 0.4% ve. The
most common agents were gentamicin (22.3%), ampicillin (20.4%),
vancomycin (10.9%), cefotaxime (6.6%), and tobramycin (3.1%).
Patel et al. [29], in a retrospective observational study of two hundred neonates admitted in 4 NICUs revealed that, in 323 antibiotic
courses, 35% of neonates received at least 1 inappropriate course due
to, more commonly, continuation of antibiotics than to initiation of
therapy (39% vs 4% respectively, P b 0.001). Vancomycin was the most
commonly used drug with 895 antibiotic-days, 284 of which were considered inappropriate. Carbapenems were the agents most frequently
used inappropriately (43% of antibiotic-days).
Of 6956 VLBW neonates included in a study of the National Institute
of Child Health and Human Development National Research Network, 56%
received at least one course of antibiotic treatment initiated after the
third day of postnatal life, even if culture-proven sepsis was diagnosed
in only 21% of all infants [30].
A recent review shows that even if screening for EOS were undertaken in approximately 1012% of all babies, only 3.2% of screened babies
had any microbiological or clinical and laboratory evidence of bacterial
infection, and they were all treated with antibiotics empirically for at
least two days [31].
A number of in vitro and in vivo studies have shown that, although
short courses of carbapanems and third-generation cephalosporins
cover a broad spectrum of bacteria, their prolonged and intensive use selects resistant bacteria. Overuse of third-generation cephalosporins favors
the emergence of extended spectrum -lactamase (ESBL)-producing
strains of GNB in NICUs [32].
de Man et al. [33] in order to investigate the effects of empiric antibiotic therapy on the selection of resistant bacterial strains, evaluated
436 infants admitted to 2 NICUs within the same hospital subjected to
two different regimes of empirical antibiotic therapy based on the spectrum of activity (narrow-spectrum vs broad-spectrum) and subsequently exchanged after 6 months. The investigators demonstrated
that the relative risk for colonization with resistant strains per 1000 patients at risk was 18-fold higher in the broad-spectrum regimen group
(penicillin or ucloxacillin plus tobramycin) than in the narrowspectrum regimen group (amoxicillin plus cefotaxime).
In another study, investigators reported a signicant reduction of colonization from 32% to 10.8% and of nosocomial infections from 18 to 2
cases per year caused by multi-resistant bacteria (oxacillin-resistant
S. aureus and GNB resistant either to aminoglycosides or to thirdgeneration cephalosporins), after institution of educational measures
and restriction in the use of third-generation cephalosporins [34].
In a prospective surveillance study conducted by Mammina et al.
[35] between 2003 and 2004, 55.2% of admitted neonates resulted
colonized with Gram-negative multidrug-resistant (MDR) bacteria.
73
74
Vancomycin is also the cornerstone for the treatment of penicillinresistant pneumococci infections combined with cefotaxime because
the majority of this bacteria show an intermediate resistance [17].
Several novel antibiotics active against gram-positive bacteria are
currently in diverse phases of development and undergoing clinical trials. In particular it has been reported advanced-generation cephalosporins like ceftaroline and ceftobiprole with antimicrobial activity against
multidrug-resistant staphylococci (including MRSA, vancomycinintermediate S. aureus [VISA], hetero-resistant VISA, and vancomycinresistant S. aureus VRSA) [4043], and lipoglycopeptides agents with
promising activity against multidrug-resistant gram-positive pathogens
like oritavancin and dalbavancin and telavancin [44,45]. All three of
these agents are promising alternatives for the treatment of complicated skin and soft-tissue infections in adults but there are no data on
their pharmacokinetics in neonates [17,44,45]. Other new agents
(omadacycline and tedizolid) as well as revisited older agents
(fosfomycin and fusidic acid) appear promising but require further
study for their potential role [46].
4.2. Treatment of infections with antibiotic-resistant GNB
GNB are often resistant to at least one class of antibiotic that is used as
standard, and may be from time to time resistant to all-rst-line antibiotics. The development of new antibiotics active against resistant GNB
has not progressed in parallel with increasing rates of resistance. Indeed
over the past 30 years only few new classes of antibiotics have been introduced and moreover pharmaceutical industry has reduced drug development programs leading to serious restriction of treatment options for
MDR-GNB in the future. This scenario of limited therapeutic options has
prompted renewed interest in older and more toxic antimicrobials [17].
In recent review Gray et al. [22] summarized the best antimicrobial
treatments for serious infections with antibiotic-resistant Gramnegative bacteria in neonates as follows:
1) Aminoglycoside-resistant GNB: in case of pan-aminoglycoside resistant bacteria alternative antibiotics include cefotaxime, piperacillintazobactam and carbapenems. It would be better to avoid the use of
piperacillin-tazobactam in case of suspected or conrmed meningitis because it is not sure that it can provide effective protection
against beta-lactamase enzymes in CSF.
2) ESBL-producing GNB: Carbapenems have high stability to hydrolysis
by ESBLs and penetrate easily porins. Based in this activity carbapenems are the cornerstone of treatment and should normally be used
as monotherapy. Meropenem is the most widely used carbapenem
in neonates. Doripenen is a new carbapenem with higher activity
against P. aeruginosa but with limited experience and with pharmacokinetic studies ongoing in neonates [47].
Recent publications in adults and children highlight the utility of
ertapenem, particularly in urinary tract infections but they are limited clinical data evaluating his role in invasive ESBL infections [48].
Other new carbapenems in different phases of clinical trials in adults
are biapenem, panipenem, tomopenem and FSI-1686 [49].
3) Carbapenem-resistant GNB: nonsusceptibility to carbapenems coexists with resistance to other classes of antibiotic like aminoglycosides
and uoroquinolones and optimal treatment is not established. The
use of ciprooxacine in neonatal life-threatening infections is supported from some information provided from current literature
and because it offers a good CFS penetration. For lower-level of resistance higher doses and/or continuous infusions of carbapenems plus
another active agent such as an aminoglycoside, uroquinolone or
colistin could be used but no trials conrm this treatment. Data on
prolonged infusion of doripenem exists in adult population but
there is limited published experience on its use in patients aged
b 18 years [48]. For higher-level of resistance colistin could be considered. Recent clinical reports have demonstrated a more favorable
tolerability and safety prole of colistin compared with reports from
several decades ago with nephrotoxity and neurotoxity varied in different studies from 3.5% to 22% and from 0% to 4% of children, respectively [50,51]. Colistin is largely experienced in the neonatal
population, but it must be kept in mind that is not effective against
Proteus and Serratia.
In case of MDR P. aeruginosa strains colistin is the drug of last resort,
although when MICs are elevated to all available -lactams,
prolonging the infusion of meropenem with the addition of an aminoglycoside, uroquinolone, or colistin can be considered.
Some carbapenem-resistant and MDR strains of A. baumanii remain
susceptible to some aminoglycoside, like tobramycin. In adults, intravenous tobramycin has been reported to be effective for treating
infections with susceptible strains but there is little experience in neonates. However colistin is the most reliable agent in vitro [29 17] although it has been used with variable success for treatment of
pneumonia, bacteremia and meningitis [48].
4) Extensively drug-resistant (XDR) GNB: last-resort treatments include chloramphenicole and trimethoprim or co-trimoxazolo even
if are lacking data on their efcacy in serious neonatal infections.
Fosfomycin is active against extensively drug-resistant Enterobacteriaceae, A. baumannii and P. aeruginosa with the ability to achieve adequate concentrations in urine, plasma, broncholaveolar lavage uid
and CSF with iv formulations. Resistance to fosfomycin can be developed rapidly when used as monotherapy; therefore, even if clinical
data are limited, most experts recommend to combine fosfomycin
with other antibiotic classes. Currently there is limited experience
of using fosfomycinin neonates.
Tigecycline, active against hard to treat pathogens like many
multidrug-resistant GPB e GNB, is inactive against P. aeruginosa [52],
and should be considered in patients infected with A. baumannii
when non other options are available [48]. Due to the possible effects
on the bone growth in children and because it determines permanent
teeth discoloration and enamel hypoplasia in children aged b8 years,
tigecycline use in neonates could only be justied in extreme cases.
Unfortunately, to date we cannot identify new candidate compounds
in late-stage development for the treatment of MDR Enterobacteriaceae.
The Infectious Diseases Society of America (IDSA) in a recent update
[53] has identied 7 parenteral drugs in phase 2 or 3 of clinical development for treatment of infections caused by MDR GNB: 4 -lactam plus
-lactamase inhibitor (ceftolozane/tazobactam, ceftazidime/avibactam,
ceftaroline/avibactam and MK-7655/imipenem) products that act by
inhibiting the -lactamases so the partner antibiotic can interfere with
cell wall synthesis; 2 protein synthesis inhibitors (plazomicin a next generation neoglycoside and eravacycline a broad-spectrum uorocycline
antibiotic that binds to bacterial ribosomes) and one peptide mimetic
(brilacidin a peptide mimetic that disrupts bacterial membranes). Unfortunately, none of the 7 drugs demonstrates activity against the entire
spectrum of clinically relevant GNB resistance. In addition the authors
report that some promising compounds like carbavance a -lactam/lactamase inhibitor, BAL30072 a siderophore sufactam and GSK052 a
novel tRNA synthesis inhibitor are in phase 1 development. Other
newer potent compounds such as carbapenemase inhibitors [54] and
novel polymyxin lipopeptides [55] against MDR and XDR gram-negative
microorganisms still necessitate the evaluation of clinical trials.
In the absence of an evidence-based strategy for treating multidrugresistant Enterobacteriaceae, Gray et al. [34] recommend that the microbiological response to treatment must be controlled trough repeat
cultures.
75
A way to slow spread of MDR bacteria is to reduce the number of infections. Whenever an infection is prevented, one less person may be
prescribed drugs. Infections can be prevented by vaccines, hygiene, sanitation as well as by isolation during infectivity [62,63]. Consistent hand
sanitation before and after interaction with patient or his environment
76
increased morbidity and mortality in clinical and community setting. Infections in neonatal units due to multidrug and extensively multidrug
resistant bacteria are also rising and are already seriously challenging
antibiotic treatment options. Treatment of neonates infected with
these pathogens is largely based on case reports and on experience of
treating other age groups.
The late-stage clinical development pipeline for antibacterials remains unacceptably lean. Although some important molecules are currently in diverse phases of development and undergoing clinical trials
for treatment of infections due to resistant GPB, very few drugs have
reached advanced stages of development for infection due to MDR
gram-negative bacilli.
At this point it is essential to preserve the efcacy of existing drugs
through measures to minimize the development and spread of resistance to them, while efforts to develop new treatment options proceed.
Antibiotic stewardship policies and improving infection prevention and
control on international, national and local level are the major recommended approaches. Moreover development of rapid, reliable, accurate,
simple tests that will reduce time to diagnosis and identify resistant
strains could improve the quality of care and patients outcome. Thorough understanding of resistance mechanism and innovation in new
drugs and vaccines is necessary.
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