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Aminoglycosides: An Overview
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minoglycosides are potent, broad-spectrum provide broader coverage than the aminoglyco-
A antibiotics that act through inhibition of
protein synthesis. The class has been a corner-
sides. However, increasing resistance to these
classes of drugs, combined with more exten-
stone of antibacterial chemotherapy since strep- sive knowledge of the basis of aminoglycoside
tomycin (Fig. 1) was first isolated from Strepto- resistance, has led to renewed interest in the
myces griseus and introduced into clinical use legacy aminoglycosides and the development
in 1944. Several other members of the class of novel aminoglycosides such as arbekacin
(Fig. 1) were introduced over the intervening and plazomicin (Fig. 4). These latter agents
years including neomycin (1949, S. fradiae), were designed to overcome common amino-
kanamycin (1957, S. kanamyceticus), gentami- glycoside resistance mechanisms thereby main-
cin (1963, Micromonospora purpurea), netilmi- taining potency against multidrug-resistant
cin (1967, derived from sisomicin), tobramycin (MDR) pathogens.
(1967, S. tenebrarius), and amikacin (1972, de- Additionally, improved dosing schemes
rived from kanamycin). A shift away from sys- have been developed that attempt to reduce
temic use of the class began in the 1980s with aminoglycoside toxicity while maintaining effi-
the availability of the third-generation cepha- cacy. Specifically, clinical studies have reported
losporins, carbapenems, and fluoroquinolones, a lower incidence of nephrotoxicity with once-
which were perceived to be less toxic and/or daily dosing (Nicolau et al. 1995). These data
1
K.M. Krause et al.
NH
H2N OH
H H2N NH2
NH
HN N NH2
O O
NH 2 HO O OH
O OH H OH
HO H2N O
OH O O
O O H
HO HO O OH
N Apramycin
HO H Streptomycin OH HN
OH
OH
H2N H2N NH2
O
NH2 O
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H2N NH HO O OH
H2N
O O
HO NH2 OH
HO O O
OH O O
HO OH HO O
OH HO NH2
Amikacin H2N OH Neomycin B O
OH
NH2 OH
Figure 1. Structures of representative aminoglycosides, including the atypical aminoglycosides streptomycin and
apramycin, 4,6-substituted AGs tobramycin, gentamcin, and amikacin, and the 4,5-substituted AG neomycin.
The deoxystreptamine or streptidine rings are in bold.
are consistent with the concept that higher dos- available in the European Union (EU) and the
es given less often should reduce the risk of tox- United States for the treatment of patients with
icity while maintaining and possibly enhancing chronic Pseudomonas aeruginosa lung infection
efficacy (Drusano et al. 2007). The advantages associated with cystic fibrosis (CF), and inhaled
of once-daily dosing of aminoglycosides are amikacin and arbekacin are in development for
now widely accepted and, for many infection potential use in CF and acute respiratory tract
types, this dosing schedule has become the stan- infections.
dard of care (Avent et al. 2011). Additionally,
inhaled delivery of aminoglycosides has become
SPECTRUM OF ACTIVITY
an area of renewed interest because it allows for
greater local exposure within the lungs with re- Aminoglycosides are active against various
duced systemic toxicity. Inhaled tobramycin is Gram-positive and Gram-negative organisms.
Aminoglycosides are particularly potent against amikacin and gentamicin, respectively, accord-
members of the Enterobacteriaceae family, in- ing to the European Committee on Antimicro-
cluding Escherichia coli, Klebsiella pneumoniae bial Susceptibility Testing (EUCAST) criteria.
and K. oxytoca, Enterobacter cloacae and E. Among Klebsiella spp., 94.8% and 92.7% of
aerogenes, Providencia spp., Proteus spp., Mor- U.S. isolates and 90.5% and 83.3% of EU
ganella spp., and Serratia spp. (Ristuccia and isolates were susceptible to amikacin and gen-
Cunha 1985; Aggen et al. 2010; Landman et al. tamicin, respectively. Amikacin was one of
2010). Furthermore, aminoglycosides are ac- the few agents that retained activity against P.
tive against Yersinia pestis (Heine 2015) and aeruginosa (97.3% susceptibility in the United
Francisella tularensis (Ikäheimo et al. 2000), States and 84.9% in the EU according to CLSI
the causative agents of plague and tularemia, and EUCAST criteria, respectively). Similarly,
respectively. The class also has good activity aminoglycoside susceptibility rates were high
against Staphylococcus aureus, including meth- among isolates collected from U.S. medical cen-
icillin-resistant and vancomycin-intermediate ters in 2012 (Sader et al. 2015). In this study,
and -resistant isolates, P. aeruginosa and to a CLSI-based susceptibility rates were 99.0%,
lesser extent Acinetobacter baumannii (Ristuc- 88.2%, and 86.3% among E. coli and 88.2%,
cia and Cunha 1985; Karlowsky et al. 2003; 89.2%, and 82.4% against K. pneumoniae for
Aggen et al. 2010; Landman et al. 2011). amikacin, gentamicin, and tobramycin, respec-
Many Mycobacterium spp. are also susceptible tively. However, activity was reduced among
to aminoglycosides including Mycobacterium K. pneumoniae carbapenemase (KPC)-produc-
tuberculosis, M. fortuitum, M. chelonae, and ing K. pneumoniae, which are often resistant to
M. avium (Swenson et al. 1985; Ho et al. multiple classes of drugs, for amikacin (42.5%
1997). susceptible), gentamicin (50.0% susceptible),
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Active electron transport is required for ami- and tobramycin (25.0% susceptible). Amikacin
noglycoside uptake into cells, so the class inher- was the most active agent tested against P. aer-
ently lacks activity against anaerobic bacteria uginosa (98% susceptible), followed closely by
(Kislak 1972; Martin et al. 1972; Ramirez and tobramycin (90% susceptible) and gentamicin
Tolmasky 2010). Aminoglycosides are also inac- (88.0% susceptible). Broad potency was also
tive against most Burkholderia spp. and Steno- observed against S. aureus (96.0%, 95.0%, and
trophomonas spp. as well as Streptococcus spp. 76.0% for amikacin, gentamicin, and tobramy-
and Enterococcus spp. (Brogden et al. 1976; Va- cin, respectively), but these compounds were
kulenko and Mobashery 2003; Brooke 2012; less active against A. baumannii (58.0% sus-
Podnecky et al. 2015). ceptible).
Contemporary large-scale surveillance pro- The broad-spectrum activity of amino-
grams provide an understanding of current glycosides is enhanced in vitro through synergy
aminoglycoside susceptibility among impor- with other classes of antimicrobials. This phe-
tant pathogens associated with common infec- nomenon, in which the combined effect of
tion types. A recent surveillance study of Gram- two antimicrobial agents is greater than the
negative organisms isolated from patients sum of their individual effects, is particularly
hospitalized in intensive care units (ICUs) in well characterized between aminoglycosides
the United States and the EU found that ami- and cell-wall-active agents such as b-lactams.
kacin and gentamicin showed good activity In vitro synergy between aminoglycosides
against key Gram-negative pathogens (Sader and b-lactams has been observed in both
et al. 2014). In the United States, 99.5% and Gram-negative and -positive organisms, in-
87.9% of E. coli isolates were susceptible to ami- cluding wild-type and MDR isolates, using a
kacin and gentamicin, respectively, according to variety of methodologies (Eliopoulos and Eli-
the Clinical and Laboratory Standards Institute opoulos 1988). These in vitro observations
(CLSI) criteria. Likewise, 97.3% and 87.2% of have helped to stimulate the use of aminogly-
E. coli isolates from the EU were susceptible to coside-containing combination therapy in the
initiation (Davis 1987; Kotra et al. 2000; Wilson (Davis 1987; Taber et al. 1987; Ramirez and Tol-
2014). The exact mechanism of binding and the masky 2010). These cations are responsible for
subsequent downstream effects varies by chem- cross bridging and stabilization of the lipid
ical structure, but all aminoglycosides are rap- components of the bacterial membrane and
idly bactericidal (Davis 1987; Mingeot-Leclercq their removal leads to disruption of the outer
et al. 1999) and typically produce a prolonged membrane, enhanced permeability, and initia-
postantibiotic effect (PAE) (Zhanel et al. 1991) tion of aminoglycoside uptake (Hancock et al.
The PAE has been shown to be directly related 1981, 1991; Hancock 1984; Ramirez and Tol-
to the length of time that the bacteria take masky 2010). This phenomenon facilitates
to recover from the inhibition of protein syn- entry into the cytoplasm via a slow, energy-de-
thesis (Stubbings et al. 2006). It is hypothesized pendent, electron-transport-mediated process
that this is dependent on the eventual disasso- (Kislak 1972; Martin et al. 1972; Davis 1987;
ciation of the antibiotic from its target and exit Taber et al. 1987; Ramirez and Tolmasky
from the cell. 2010). Inhibition of protein synthesis and mis-
Aminoglycosides are characterized by a core translation of proteins occurs once aminogly-
structure of amino sugars connected via glyco- coside molecules access the cytoplasm. These
sidic linkages to a dibasic aminocyclitol, which mistranslated proteins insert into and cause
is most commonly 2-deoxystreptamine (Min- damage to the cytoplasmic membrane itself
geot-Leclercq et al. 1999). Aminoglycosides and facilitate subsequent aminoglycoside entry
are broadly classified into four subclasses based (Nichols and Young 1985; Davis et al. 1986).
on the identity of the aminocyclitol moiety: This then leads to rapid uptake of additional
(1) no deoxystreptamine (e.g., streptomycin, aminoglycoside molecules into the cytoplasm,
which has a streptidine ring); (2) a mono-sub- increased inhibition of protein synthesis, mis-
stituted deoxystreptamine ring (e.g., apramy- translation, and accelerated cell death (Davis
cin); (3) a 4,5-di-substituted deoxystreptamine et al. 1986; Davis 1987; Taber et al. 1987; Ra-
ring (e.g., neomycin, ribostamycin); or (4) a mirez and Tolmasky 2010).
AAC(6′) AAC(3)
N1
A O
OH OH
B
O O
NH2 NH2
H2N H2N NH H2N H2N NH
ATP ADP
O O
HO O O HO O O
OH O APH(3′) –O O OH O
HO OH HO P O OH HO
OH –O OH
H 2N OH H2N OH
C
H2N H2N NH2
H2N H2N NH2
O
O ATP PPi HO O O
HO O O O
OH
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OH O HO OH O O
HO OH HO OH
OH ANT(2′′) N O P
O O– H2N OH
H2N OH H2N N
N N
HO OH
of enzymes whose nomenclature is derived quently observed class members found among
from the specific amino group that is modified. Gram-negative bacteria include the AAC(60 )-1
Specifically, AAC(1) and AAC(3) target the ami- enzyme that leads to amikacin, netilmicin, and
no groups found at position 1 and 3, respective- tobramycin resistance, AAC(3)-IIa, which is
ly, of the 2-deoxystreptamine ring, whereas responsible for resistance to gentamicin, tobra-
AAC(20 ) and AAC(60 ) target amino groups mycin, and netilmicin, and AAC(3)-I, which
found at the 20 and 60 position of the 2,6-di- modifies gentamicin (Shaw et al. 1993; Cas-
deoxy-2,6-diaminoglucose ring (Mingeot-Le- tanheira et al. 2015). Less common are the
clercq et al. 1999; Wright and Thompson 1999; AAC(60 )-APH(200 ) hybrid enzyme responsible
Azucena and Mobashery 2001; Magnet and for high-level aminoglycoside resistance in
Blanchard 2005). Enterococcus faecalis (Culebras and Martı́nez
A representative of the AAC family 1999), the chromosomally encoded AAC(60 )-
(AAC(60 )-IV) was the first AME found in bac- Ii enzyme responsible for intrinsic resistance
teria to be described in the literature (Okamoto to aminoglycosides among E. faecium (Costa
and Suzuki 1965). Since then, .70 members et al. 1993) and the chromosomal AAC(20 ) en-
of the AAC family have been described. Fre- zyme found in Mycobacterium spp. and Provi-
dencia stuartii (Rather et al. 1993; Aı́nsa et al. ANT(200 ) broadly effects the activity of 4,6-
1997; Macinga and Rather 1999; Ramirez and di-substituted aminoglycosides (Gates 1988),
Tolmasky 2010). Last, a variant of AAC(60 )-Ib whereas ANT(40 ) targets kanamycin A, B, and
that has acquired the ability to modify fluoro- C, gentamicin A, amikacin, tobramycin, and
quinolones without significantly altering its neomycin B and C. Other members of this class
activity against aminoglycosides has been iden- include ANT(300 ), ANT(6), and ANT(9), which
tified in clinical isolates of Gram-negative bac- confer resistance to streptomycin and spectino-
teria (Robicsek et al. 2006; Strahilevitz et al. mycin (Hollingshead and Vapnek 1985; Mur-
2009). phy 1985; Ounissi et al. 1990).
the enzyme NpmAwas discovered encoded on a P. aeruginosa (63.5% AME positive) with a va-
plasmid in an aminoglycoside-resistant E. coli riety of aminoglycoside resistance profiles were
clinical isolate, also from Japan (Wachino et al. included. A diversity of AME genes were iden-
2007). This methyltransferase modifies the tified with the most prevalent being aac(6 0 )-Ib
A1408 nucleotide and, thus, impacts 4,6- and (n ¼ 75), ant(3 0 )-Ia (n ¼ 51), and aac(3)-IIa
4,5-di-substituted as well as monosubstituted (n ¼ 45), and with 26 isolates harboring more
aminoglycosides, conferring pan-aminoglyco- than one AME gene. In addition, 21 of the iso-
side resistance. To date, there has been only lates were found to carry an RMT including
one additional report of this enzyme in a clinical 12 Enterobacteriaceae, seven A. baumannii, and
isolate (Al Sheikh et al. 2014). two P. aeruginosa. Many of these isolates were
also resistant to other common antibiotics used
to treat Gram-negative infections, highlight-
Efflux-Mediated Resistance
ing the ability of these resistance mechanisms
Several members of the resistance– nodula- to spread through conjugation of plasmids and
tion – division (RND) family of efflux systems nonreplicative transposons among bacteria
have been shown to be involved in intrinsic ami- (Courvalin 1994; Waters 1999; Dzidic and Be-
noglycoside resistance in various pathogens deković 2003; Feizabadi et al. 2004).
(Aires et al. 1999; Westbrock-Wadman et al. AMEs are commonly found in association
1999; Rosenberg et al. 2000; Magnet et al. 2001; with other key resistance elements, such as
Hocquet et al. 2003; Islam et al. 2004). In the carbapenemases and extended spectrum b-lac-
opportunistic pathogen P. aeruginosa, intrinsic tamases (ESBLs). Among 50 carbapenem-resis-
low-level resistance to aminoglycosides, tetracy- tant K. pneumoniae clinical isolates from two
cline and erythromycin, is mediated by the ex- U.S. medical centers (80% possessing KPC-2,
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pression of the multiple efflux (Mex) XY-OprM 10% possessing KPC-3 with all KPCþ isolates
system. MexXY orthologs are found in other also expressing TEM-1 and SHV-12), 98% of
species of bacteria. For example, members of isolates expressed at least one AME (Alma-
the Burkholderia cenopacia complex are often ghrabi et al. 2014). Specifically, 98% were pos-
intrinsically resistant to aminoglycosides via itive for aac(6 0 )-Ib, 56% positive for aph(3 0 )-Ia,
RND efflux pumps (Buroni et al. 2009). A ho- 38% positive for aac(3 0 )-IV, and 2% positive for
mologous transporter in E. coli, AcrD, partici- ant(2 00 )-Ia. Overall, 40%, 98%, and 16% of the
pates in efflux of aminoglycosides (Rosenberg strains were nonsusceptible to gentamicin, to-
et al. 2000) as does the Acinetobacter drug efflux bramycin, and amikacin, respectively. Plazomi-
(Ade) ABC efflux system in A. baumannii cin, a novel aminoglycoside in clinical develop-
(Magnet et al. 2001) and the major facilitator ment that was designed to evade AME-based
superfamily (MFS) in Mycobacteria spp. resistance, had MICs that ranged from 0.25
to 1 mg/mL against this set of isolates. AME
characterization in 330 aminoglycoside-resis-
Molecular Epidemiology of Aminoglycoside
tant clinical Enterobacteriaceae isolates from
Resistance Mechanisms
Spain revealed the presence of aph(3 00 )-Ib and
Comprehensive molecular data regarding the ant(3 00 )-Ia genes in 65.4% and 37.5% of the
current prevalence of specific aminoglycoside isolates, consistent with 92% phenotypic resis-
resistance mechanisms among common patho- tance to streptomycin found in this strain col-
gens is sparse. One recent study evaluated the lection (Miró et al. 2013). These isolates were
aminoglycoside resistance mechanisms found resistant to other aminoglycosides to varying
among 200 Gram-negative bacilli isolates se- degrees, including gentamicin (18.4%), tobra-
lected at random from an extensive culture col- mycin (16.9%), and amikacin (1.5%), indicat-
lection (Castanheira et al. 2015). Ninety-nine ing the presence of other AMEs; aph(3 0 )-Ia was
Enterobacteriaceae (91.9% AME-positive), 49 found in 13.9% of isolates, aac(3)-IIa in 12.4%,
A. baumannii (79.6% AME-positive), and 52 aac(6 0 )-Ib in 4.2%, ant(2 00 )-Ia in 3.6%, and
pean medical centers (Wachino and Arakawa vious efforts to protect the 60 position and,
2012). Similar to the association between as predicted, lead to improved activity against
AMEs and other key resistance mechanisms, Enterobacteriaceae (MIC90 2 mg/L) that are
an association between RMTs and specific resistant to currently available aminoglycosides
b-lactamases has been described. Seventy-six (Nagabhushan et al. 1982; Aggen et al. 2010).
percent of the RMT containing isolates de- Plazomicin retains vulnerability to modifica-
scribed in the SENTRY surveillance study above tion by AAC(20 )-I, a chromosomal AME found
also possessed a CTX-M ESBL (Bell et al. 2010), in P. stuartii and some mycobacterial species.
and RMTs are frequently found in associa- However, this enzyme is rare, has not been
tion with the New Delhi metallo-b-lactamase found on a mobile element and has not been
(NDM) (Berçot et al. 2011; Livermore et al. shown to have clinical relevance in Mycobac-
2011; Mushtaq et al. 2011; Poirel et al. 2014). terium spp. In addition, plazomicin, like all
OH OH
HO
O O
NH2 NH2
HN H2N NH H2N NH
H2N
O O
O O O O
O O
OH OH
NH2 HO NH2 HO OH
OH
HN H2N OH
Plazomicin Arbekacin
including MDR strains, and has more recently ed with efficacy of aminoglycosides is the ratio
gained attention as a potential therapy for in- of area under the concentration – time curve
fections caused by these organisms. In a recent (AUC) to MIC, although peak concentration
surveillance study of isolates from hospitalized also appears to play a role. The magnitude of
patients with pneumonia, arbekacin was the the PK/PD target for aminoglycosides is not as
most potent aminoglycoside tested against well defined as it is for other antibiotic classes
ESBL-producing E. coli and was slightly more because of, until recently, the lack of develop-
active than amikacin and tobramycin against ment of new aminoglycosides. Available data
ESBL- and KPC-expressing K. pneumoniae. suggests that significant variations in the PK/
Similarly, arbekacin possessed greater activity PD target exist between species and body site
against P. aeruginosa and Acinetobacter spp., of infection. For example, an AUC/MIC target
including MDR isolates, than the other ami- of 100 was reportedly associated with a 1- to 2-
noglycosides tested (amikacin, gentamicin, log10 kill in the mouse neutropenic thigh infec-
and tobramcin) (Sader et al. 2015). Because tion model with amikacin and K. pneumoniae
of its broad-spectrum in vitro activity against (Craig 2011), whereas this same group reported
both MDR Gram-positive and Gram-negative better efficacy at the same dose level and with the
pathogens, arbekacin is currently under de- same strain in the mouse lung infection model
velopment as an inhalational agent for the (Craig et al. 1991). These results were potentially
treatment of mechanically ventilated patients a result of a longer measured PAE in the lung
with bacterial pneumonia (clinicaltrials.gov/ compared with the thigh (Craig et al. 1991).
ct2/show/NCT02459158) and is under study AUC/MIC thresholds have been correlated
at Walter Reed Army Medical Hospital for to efficacy in patients in whom extensive PK
the treatment of patients with infections caused sampling was also conducted. These case re-
by MDR organisms that have limited treat- ports and reviews describe a variety of different
ment options (clinicaltrials.gov/ct2/show/ ways that the AUC/MIC ratio might be used to
NCT01659515). predict outcomes in patients. Smith et al. (2001)
reviewed 23 patients with intra-abdominal in- reduced nephrotoxicity and equal, if not slightly
fections (n ¼ 16) or lower respiratory infec- improved, efficacy.
tions (n ¼ 7) treated with tobramycin infused Therapeutic drug management (TDM), the
.30 min to achieve a Cmax of between 4 and clinical practice of measuring drug concentra-
10 mg/L. A PK/PD model constructed from tions at designated intervals for use in optimiz-
these patients data showed that improved effi- ing individualized dosage regimens, has further
cacy was observed when an AUC/MIC ratio of improved the safety profile of aminoglycosides.
110 was achieved compared with AUC/MIC Older studies using multiple daily doses of these
ratios of ,110 (80% clinical cure rate compared drugs have shown nephrotoxicity rates of 10%
with 47%). Other investigators have found sim- to 20% (Humes et al. 1982; Moore et al. 1984),
ilar correlations between exposure and efficacy. whereas lower rates of nephrotoxicity ranging
Jacobs (2001) describes the need to achieve an from 0% to 14% have been reported with
AUC/MIC ratio of 25 for less severe infections once-daily dosing regimens with dose adjust-
or in immune competent patients and a ratio of ment guided by the use of TDM (Prins et al.
at least 100 in patients with severe infections 1993; Nicolau et al. 1995; Murry et al. 1999;
and/or those that are immune-compromised. Rybak et al. 1999; Buijk et al. 2002). The advan-
Zelenitsky et al. (2003) found significantly im- tages of once-daily or extended interval dosing
proved outcomes in patients with bacteremia of aminoglycosides combined with the use of
treated with gentamicin when AUC/MIC ratios TDM are now widely accepted and, for many
exceeded 70 compared with AUC/MIC ratios infection types, this dosing approach has be-
,70 (90% cure vs. 45.5%, respectively). How- come the standard of care (Avent et al. 2011).
ever, a much stronger correlation with outcome
was noted for Cmax/MIC with 84% and 90%
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sides are often combined with b-lactams for the bacteria, amikacin is the preferred agent for in-
empirical treatment of severe sepsis and certain fections because of M. fortuitum or M. abscessus,
nosocomial infections in patients with a high whereas tobramycin is the most active agent
risk of mortality or when there is concern that against M. chelonae (Griffith et al. 2007).
the causative pathogen may be resistant to more Aminoglycosides remain the preferred
commonly used agents (American Thoracic therapy for certain zoonotic infections such as
Society; Infectious Diseases Society of America plague and tularemia. Although streptomycin
2005; Dellinger et al. 2013). More recently, ami- has traditionally been the agent of choice for
noglycosides have increasingly become impor- these infection types, gentamicin is now widely
tant components of therapy for patients infected used because of the broader availability of this
with MDR pathogens, such as carbapenem- agent as well as data suggesting similar efficacy
resistant Enterobacteriaceae (CRE), for whom to streptomycin (Mwengee et al. 2006; Snowden
few treatment options remain. In a retrospective and Stovall 2011). Aminoglycosides are bacter-
cohort study of 50 cases of sepsis caused by car- icidal against these organisms and the use of
bapenem- and colistin-resistant K. pneumoniae, bacteriostatic agents, such as doxycycline or
the receipt of gentamicin as part of definitive chloramphenicol has led to treatment failures
therapy was associated with lower mortality (Dennis et al. 2001; Snowden and Stovall 2011).
compared with the receipt of non-gentamicin- Inhaled tobramycin therapy in CF patients
containing regimens (Gonzalez-Padilla et al. with chronic lung infection caused by P. aerugi-
2015). The novel aminoglycoside plazomicin nosa has been shown to improve respiratory
(see section on Agents in Development) is cur- function, decrease hospitalizations, and reduce
rently under phase 3 study for the treatment of systemic antibiotic use (Ramsey et al. 1999), and
serious infections caused by CRE (clinicaltrials has contributed to a significant increase in sur-
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tion regimens is to eradicate potential pathogens pared with control therapy in patients with
from the oropharynx and digestive tract of pa- cutaneous leishmaniasis caused by Leishmania
tients at risk for nosocomial or postoperative major (Ben Salah et al. 2013). Intramuscular
infections. Selective digestive decontamination paromomycin monotherapy was noninferior
(SDD) consists of the oropharyngeal and gastric to standard amphotericin B therapy in a ran-
administration of non-absorbable antibiotics domized control trial in patients with visceral
lacking anaerobic activity (often a polymyxin, disease in India (Sundar et al. 2007) and short-
an aminoglycoside, and amphotericin) along course combination regimens containing this
with a short course of systemic antibiotic thera- agent were also noninferior to standard therapy
py, whereas selective oropharyngeal decon- with fewer adverse events (Sundar et al. 2011).
tamination (SOD) consists of application of
non-absorbable antibiotics to the oropharynx
CONCLUSIONS
alone. More than 50 randomized studies and
10 meta-analyses of SDD/SOD have been pub- The aminoglycosides are a critical component
lished. Overall, these data suggest that SDD/ of the current antibacterial arsenal. Their broad
SOD are associated with improved survival in spectrum of activity, rapid bactericidal action,
ICU patients (Price et al. 2014) and SDD is as- and favorable chemical and pharmacokinetic
sociated with a reduction in the rate of post- properties make them a clinically useful class
operative infection, including anastomotic leak- of drugs across numerous infection types, in-
age, in patients undergoing elective GI surgery cluding certain protozoal infections. The use
(Abis et al. 2013; Roos et al. 2013). Despite these of aminoglycosides waned as a result of the
successes in the use of SOD and SDD to improve emergence of other classes of broad-spectrum
patient outcomes in the setting of low levels agents with improved safety profiles, but the
of antibiotic resistance, controversy remains re- emergence of MDR pathogens has led to re-
garding their effectiveness in the setting of high newed interest in this class of drugs. Improved
levels of antibiotic resistance as well as their im- understanding of the drivers of toxicity and
efficacy has led to the implementation of opti- Avent ML, Rogers BA, Cheng AC, Paterson DL. 2011. Cur-
rent use of aminoglycosides: Indications, pharmacoki-
mized dosing regimens that improve safety netics and monitoring for toxicity. Intern Med J 41:
while maintaining efficacy. Increased under- 441 –449.
standing of key aminoglycoside resistance Azucena E, Mobashery S. 2001. Aminoglycoside-modifying
mechanisms combined with innovative me- enzymes: Mechanisms of catalytic processes and inhibi-
tion. Drug Resist Updat 4: 106 –117.
dicinal chemistry approaches have led to the
Barclay ML, Kirkpatrick CM, Begg EJ. 1999. Once daily
synthesis and development of novel agents aminoglycoside therapy. Is it less toxic than multiple dai-
specifically designed to evade resistance while ly doses and how should it be monitored? Clin Pharma-
maintaining potency against fully susceptible cokinet 36: 89–98.
isolates. Given the dearth of new agents in the Beauclerk AA, Cundliffe E. 1987. Sites of action of two ri-
bosomal RNA methylases responsible for resistance to
antibiotic pipeline and the ever-increasing spec- aminoglycosides. J Mol Biol 193: 661– 671.
ter of resistance, further optimization of the Bell J, Andersson P, Jones R, Turnidge J. 2010. 16S rRNA
aminoglycoside scaffold to generate new agents methylase containing Enterobacteriaceae in the SENTRY
with superior potency against MDR pathogens Asia-Pacific region frequently harbour plasmid-mediat-
ed quinolone resistance CTXM types. 20th European
as well as an improved safety profile is warranted. Congress of Clinical Microbiology and Infectious Diseases
(ECCMID), Abstract O559. Vienna, April 10– 13.
Ben Salah A, Ben Messaoud N, Guedri E, Zaatour A, Ben
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