Advanced Drug Delivery Reviews 78 (2014) 14–27

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Advanced Drug Delivery Reviews

journal homepage: www.elsevier.com/locate/addr

Therapeutic strategies to combat antibiotic resistance☆

Benjamin D. Brooks a, Amanda E. Brooks b,c,⁎
a
Wasatch Microfluidics, Salt Lake City, UT 84112, USA
b
Department of Pharmaceutics and Pharmaceutical Chemistry, University of Utah, Salt Lake City, UT 84112, USA
c
Department of Pharmaceutical Sciences, North Dakota State University, Fargo, ND58108, USA

a r t i c l e i n f o a b s t r a c t

Available online 28 October 2014 With multidrug resistant bacteria on the rise, new antibiotic approaches are required. Although a number of new
small molecule antibiotics are currently in the development pipeline with many more in preclinical develop-
Keywords: ment, the clinical options and practices for infection control must be expanded. Biologics and non-antibiotic
Antibiotics adjuvants offer this opportunity for expansion. Nevertheless, to avoid known mechanisms of resistance, intelligent
Antimicrobial polymers combination approaches for multiple simultaneous and complimentary therapies must be designed. Combination
Biofilm
approaches should extend beyond biologically active molecules to include smart controlled delivery strategies.
Quorum sensing
Combination therapy
Infection control must integrate antimicrobial stewardship, new antibiotic molecules, biologics, and delivery strat-
Nanoparticle delivery egies into effective combination therapies designed to 1) fight the infection, 2) avoid resistance, and 3) protect the
natural microbiome. This review explores these developing strategies in the context of circumventing current
mechanisms of resistance.
© 2014 Elsevier B.V. All rights reserved.

Contents

1. Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 15
2. Antibiotic resistance: a global health threat . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 15
2.1. Resistance on the rise . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 15
2.2. Classes of antibiotics . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 16
2.3. Mechanisms of resistance . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 16
2.4. Antibiotic stewardship . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 16
3. Addressing antibiotic resistance . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 16
3.1. New drugs . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 16
3.1.1. Quorum sensing inhibitors . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 17
3.1.2. Biologics . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 17
4. Dual drug delivery approaches . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 18
4.1. Combination approaches that target different pathways . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 19
4.1.1. Combinations with non-antibiotic adjuvants . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 19
4.2. Combination approaches that act on the same pathway . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 19
4.3. Combination approaches that act on the same target . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 19
4.4. Combination approaches to address polymicrobial infections . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 20
4.5. Resistance and synergistic drug combinations . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 20
4.6. Pitfalls of combination drug delivery . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 20
5. Antibiotic delivery . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 20
5.1. Systemic versus local antibiotic delivery . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 20
5.1.1. Antimicrobial polymers . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 21
5.2. A unique local delivery system—nanoparticle/liposome delivery . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 21
5.2.1. Nanoparticles . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 21
5.2.2. Liposomes . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 21

☆ This review is part of the Advanced Drug Delivery Reviews theme issue on “Emergence of multidrug resistance bacteria: Important role of macromolecules as a new drug targeting mi-
crobial membranes”.
⁎ Corresponding author at: 1401 Albrecht Blvd, Fargo, ND, 58108, USA. Tel.: +1 701 231 7906.
E-mail address: Amanda.e.brooks@ndsu.edu (A.E. Brooks).

http://dx.doi.org/10.1016/j.addr.2014.10.027
0169-409X/© 2014 Elsevier B.V. All rights reserved.
 B.D. Brooks, A.E. Brooks / Advanced Drug Delivery Reviews 78 (2014) 14–27 15

5.3. Impact of local drug delivery pressure on the development of resistance . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 21

6. Conclusions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 22
Conflict of interest statement . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 23
Acknowledgments . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 24
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 24

1. Introduction
The growing tide of bacterial resistance imposes a tremendous
economic and social burden on the healthcare system worldwide and
unfortunately, the development of new antibiotics is vastly outpaced
by current therapies that are losing their efficacy (Fig. 1). This review
covers both current antibiotic therapies in the context of rising multi-
drug resistance, but also emerging therapeutic alternatives seeking to
address antibiotic resistance and prolong the effective life of an antibiot-
ic. Combination therapies, alternate delivery systems, and alternative
antimicrobial molecules in the pipeline will be discussed. Ultimately,
fighting multidrug resistance necessitates a paradigm shift in therapy,
including mounting a local antimicrobial attack when possible, a
strategic fight against resistance, and protecting the delicate symbiotic
host-microbial balance (Fig. 2).
2. Antibiotic resistance: a global health threat
2.1. Resistance on the rise
The emergence of multidrug resistance pathogens is an increasingly
significant global economic and healthcare crisis [1,2]. Listed by the
World Health Organization as one of the top 3 threats to global public
health [3], more than 2 million Americans suffer from an antibiotic
resistant infection at a direct cost of over $20 billion [4] with over
23,000 dying annually [2]. Analogous worldwide statistics are staggering,

Fig. 1. A) Antibiotic resistance is increasing while the number of antibiotics is decreasing (modified from [40]). B) At most there is roughly 60 years between antibiotic discovery to the first
incidence of resistance to that same antibiotic (modified from [11]).
16 B.D. Brooks, A.E. Brooks / Advanced Drug Delivery Reviews 78 (2014) 14–27
Fig. 2. Conceptual diagram outlining the three criteria (on the left) necessary for any strategy designed to circumvent the four recognized modes of antibiotic resistance (on the right).
prompting intense multidisciplinary efforts by scientific and clinical
communities to develop innovative products and tools to address the
threat (Fig. 1). The CDC has recently classified emergent resistant species
as urgent, serious, or concerning with a generalized picture of the cycle
of resistance shown in Fig. 3 [2]. Antibiotic surveillance programs, such
as the SENTRY program, have monitored worldwide Methicillin Resis-
tant Staphylococcus aureus (MRSA) statistics (MRSA in hospitals be-
tween 1997 and 1999 was 22.4% in Australia, 66.8% in Japan, 34.9% in
Latin America, 40.4% in South America, 32.4% in the USA and 26.3% in
Europe [5–7]) and noted with horror the necessity of elevated antibiotic
concentrations to effectively kill many common human pathogens
(e.g., Pseudomonas aeruginosa, Klebsiella pneumoniae and Acinetobacter
baumannii, Enterobacter and Escherichia coli) (i.e., MIC creep) [8,9],
prompting concerns of reverting to a pre-antibiotic era [10].
2.2. Classes of antibiotics
Resistance has developed to virtually every class of antibiotics in
current use. Development of bacterial resistance to a given antibiotic
is anticipated to evolve within an average of 50 years after initial use
[11]. Figs. 4 and 5 graphically depict current drug mechanisms of action.
Resistance to certain antibiotics (e.g. tetracyclines, etc.), often develop
in at least one bacterial species within a year of drug FDA approval
[12] with clinically significant levels of resistance appearing within
months to years [13,14]. The prevalence of bacterial multidrug resis-
tance now vastly outpaces the advent of new antibiotic classes and
alternatives (Fig. 1) [8]. Since a 2009 report on antibiotic resistance
from the Infectious Disease Society of America, only 2 new antibiotics
(telavancin in 2009 and ceftaroline fosamil in 2010) have been intro-
duced to the market (Fig. 1).
2.3. Mechanisms of resistance
Drug discovery and development are locked in a co-evolutionary
battle with natural bacterial compounds [15]. Extensive studies on anti-
biotic resistance mechanisms have not only provided valuable insight
into the underlying evolutionary processes that govern the develop-
ment and spread of antibiotic resistance [16,17], but have also allowed
antibiotic resistance to be broadly classified as occurring via either:
1) innate resistance [18], 2) acquired resistance (e.g., by horizontal gene
transfer [19–21] or elevated mutation rates [22–24]), or 3) adaptive re-
sistance (environmentally induced genetic changes [25]) [26,27], which
includes the conversion from a planktonic life cycle to a sessile biofilm
life cycle [28–30]. Within these broad classifications, bacteria can mod-
ify the antibiotic by: 1) inactivation or enzymatic modification [31–33],
2) alteration of the antibiotic target [34], or 3) changes in cell perme-
ability and efflux [35–37]. These mechanisms are pictorially described
in Fig. 3. However, for an in depth description of antibiotic resistance
mechanisms, the reader is referred to several excellent articles and
reviews as cited above.
2.4. Antibiotic stewardship
Considering the rising inventory of multidrug resistant microbes, an-
tibiotic stewardship, as defined by a number of preventative measures,
is not just a formal and practical strategy, but must now be implement-
ed out of necessity [38]. Recently, the Transatlantic Taskforce on Antimi-
crobial Resistance (TATFAR) outlined the most pressing needs to fight
antimicrobial resistance. These include (1) appropriate therapeutic use
in human and veterinary medicine, (2) prevention of drug-resistant in-
fections, and (3) strategies for improving the pipeline of new antimicro-
bial drugs [39]. The Infectious Diseases Society of America has mirrored
these recommendations along with providing additional surveillance
measures [40]. While each of these recommendations is commonly ac-
cepted as necessary for infection control, several barriers to antibiotic
stewardship programs remain, including lack of clinician participation
[41], an absence of formal diagnostic standards, and non-uniform
reporting guidelines [38]. Nevertheless, appropriate antibiotic use is crit-
ical as are prescreening microbiological tests with appropriate antibiotic
follow-up [7] and stringent hand-washing guidelines and enforcement.
The use of combinations, particularly those with non-antibiotic adju-
vants, offers a more effective long-term solution to address multidrug
resistant variants via de novo drug delivery. Regardless, each strategy re-
quires a major change in antibiotic-prescribing patterns [42]. Ultimately,
antibiotic resistance is not just a medical crisis, but must encompass a
worldwide societal change at all levels to combat the evolution of antibi-
otic resistance.
3. Addressing antibiotic resistance
3.1. New drugs
While new approaches to avoid drug resistance are researched and
developed continually, antibiotic discovery is not keeping pace with
rates of drug resistance (Fig. 1). Combating the complex issue of antibiotic
resistance must go beyond the mechanistic development of new
 B.D. Brooks, A.E. Brooks / Advanced Drug Delivery Reviews 78 (2014) 14–27
Fig. 3. Graphic depicting the behavioral and molecular mechanisms of resistance. Modified from the Center for Disease Control [2].
pharmaceuticals and incorporate a multidisciplinary culture of change.
Thus, the third aim arising out of TATFAR seeks to provide (1) incentives
to stimulate the development of new antibacterial drugs in human
medicine, (2) research to support the development of new antibacte-
rials, and (3) publication of funding opportunities to EU and US research
communities [39,40]. Despite these recommendations, the develop-
ment of new antimicrobials or modifications of the current arsenal
may not be able to effectively address the trends in resistance. Instead,
antibiotic resistance may better be addressed with “smart” delivery sys-
tems and innovative combinations of biologically inspired molecules
(e.g., quorum sensing inhibitors, biosurfactants, bacteriophage, enzymes,
etc.). Table 2 summarizes some of the more traditional drugs currently in
the development pipeline while the sections below explore some of the
more nontraditional drugs being researched.
3.1.1. Quorum sensing inhibitors
Considering its role as a master switch, interrupting quorum sensing
with quorum quenchers (QQ) or quorum sensing inhibitors (QSI) is a fea-
sible alternative to antibiotics [9,43]. Three general approaches are ap-
plied to quench or suppress microbial quorum sensing: 1) disruption of
autoinducer synthesis, 2) inhibition of ligand/receptor interactions, and
3) destruction of the autoinducer via enzymatic cleavage and degrada-
tion [9,44]. A combination of approaches may be necessary to overcome
17
redundancy in bacterial communication and kill persisters [45]. In an ef-
fort to identify novel inhibitors, natural and small molecule libraries have
been explored, identifying several promising candidates (e.g., HT61, C30
furanone [46–49], etc.). Although some molecules have been tested in
preclinical animal models [50–52], clinical application is far from certain.
The quorum inhibitor, FS3, was evaluated in a rat model and showed
good efficacy and synergy with daptomycin [50]. An agent that does
not impose life or death selective pressure but instead disrupts bacterial
communication and virulence may circumvent the majority of the
known resistance mechanisms [53]. Unfortunately, despite this promise,
increasing evidence suggests that quorum quenching may provoke a re-
sistant phenotype [54,55], although the mechanism is not clear.
3.1.2. Biologics
3.1.2.1. Antimicrobial peptides. Four main classes of antimicrobial pep-
tides (AMPs) exist in nature including (1) anionic peptides, (2) cationic
peptides with high molar percents of proline, arginine, phenylalanine,
glycine, or tryptophan, (3) anionic and cationic peptides that contain
cysteine and form disulfide bonds, and (4) linear cationic alpha-helical
peptides [56,57]. The mechanism of AMPs includes cell membrane dam-
age, inhibition of cell wall synthesis formation of pores, and disruption of
the membrane bilayer [58], and inhibition of nucleic acid and protein
18 B.D. Brooks, A.E. Brooks / Advanced Drug Delivery Reviews 78 (2014) 14–27

synthesis [56]. These antimicrobial peptides, 12 to 50 amino acids in

length, are potent (at micromolar concentrations), broad-spectrum anti-
biotics and function as an integral component of the innate immune sys-
tem. Unfortunately, these drugs are expensive, often antigenic [59], and
have limited stability. Some of these disadvantages can be circumvented
by covalently grafting the AMP to a biomaterial surface [60,61]. Thus, due
to their role in the innate immune system and minimal risk of antibiotic
resistance [62,63], this class of natural antibiotics provides an excellent re-
source for future drug development [64]. Current AMPs approved by the
FDA include bacitracin, colistin, and polymyxin B; however, additional
synthetic molecules are being designed to mimic the architecture and
charge of natural AMPs [65–69].

3.1.2.2. Bacteriophage. Bacteriophage, a virus specifically designed to

infect bacteria through recognition of a cell surface receptor, pre-
sents one of the most attractive alternatives to combating antimicro-
bial resistance. Unlike more traditional antibiotic strategies,
bacteriophage titer and its subsequent efficacy change in direct pro-
portion to bacterial populations, and increase to combat the patho-
gen re-emergence [70]. Bacteriophages have been reported
effective in a variety of gram-negative (e.g., E. coli, P. aeruginosa,
A. baumannii, K. pneumoniae, Vibrio vulnificus, Salmonella spp) and
gram-positive bacteria (e.g., Enterococcus faecium and S. aureus)
[71–75]); however, bacteriophage use is not recommended without
reservation. Although not a complete litany of their disadvantages, of
primary concern is the integration of phage DNA into the bacterial
genome, the failure of bacteriophage therapy due to restrictive
specificity, and the development of bacterial resistance based on al-
teration of the bacterial cell surface receptor [70,76]. A cocktail
containing several different phages, especially when used in
conjunction with a traditional antibiotic [77] may circumvent these Fig. 5. Three of the main antibiotic resistance strategies used by bacteria (modified from
disadvantages. Alternatively, using bacteriophage components [11]).
(e.g., virolysin, antimicrobial peptides, etc.) may circumvent many,
if not most, of these pitfalls [70], serving as a significant source of po-
tent new antimicrobials. Furthermore, using a modified phage coat 4. Dual drug delivery approaches
to display an antigenic peptide, in conjunction with its natural bacte-
rial targeting specificity, may potentially provoke the host immune In the face of rising concerns over the development of antibiotic
response at the site of infection [78,79]. resistance, single drug clinical treatment strategies may not be adequate

Fig. 4. Summary of the different mechanisms of antibiotic action and examples of the different drugs that act via each mechanism. Modification of Fig. 20-14 from Brock Biology of Micro-
organisms [193].
 B.D. Brooks, A.E. Brooks / Advanced Drug Delivery Reviews 78 (2014) 14–27
to combat the problem. Several strategies exist to address resistance
beyond simply filling of the new drug pipeline. Based on the scientific
literature and clinically proven recommendations and treatments [80,
81], combination approaches are more effective to combat multidrug
resistance [82,83]. Over 7 decades of experience has proven that drug
combinations are key tools in the clinical arsenal against viruses [84]
(e.g., Stribild, a 4-drug cocktail for HIV), cancers [85] and microbes
(e.g., Menhibrix, a combination vaccine for meningococcal disease and
type B influenza) [86,87]. In fact, among these classes, bacteria seem
to be particularly hard hit by combinatorial approaches. Additionally, a
combinatorial approach can effectively prolong the effective life-
time of a drug [12] in a landscape of antibiotic resistance as well as
restore efficacy to a drug which bacteria have developed resistance
(e.g., antibiotics with nanoparticles) [88]. Regardless of the specific
cocktail, strategies can be divided into three categories based on the
drug target: 1) antibiotic targets in different pathways (e.g., isoniazid,
rifampicin, ethambutol, and pyrazinamide for the treatment of M.
tuberculosis infections), 2) different targets in the same pathway
(e.g., sulfamethoxazole and trimethoprin), and 3) the same target
with multiple mechanisms (e.g., streptogramins and virginamycin
[81,89]) [90] (Fig. 4).
4.1. Combination approaches that target different pathways
Dual drug delivery approaches that combine antibiotics targeting
different pathways are the most studied and successful approaches for
creating multidrug cocktails to combat antibiotic resistance [90]. To fur-
ther enhance efficacy while minimizing necessary drug concentrations,
coupling a multidrug combinatorial approach with local drug delivery
may prove the most efficacious dosing regimen to prolong and restore
the efficacy of the current antibiotic arsenal [91]. Regardless of the ad-
ministration route, many effective combinations that target different
pathways are not strictly confined to antibiotics but extend to combina-
tions with non-antibiotic adjuvants.
4.1.1. Combinations with non-antibiotic adjuvants
Often the combination of an antibiotic with a non-antibiotic
adjuvant—defined as any compound used to assist in the amelioration,
prevention, or cure of disease—is the most effective way to combat multi-
drug resistance due to the diversity of mechanisms. Such combinations
(e.g., minocycline, rifampin, and chlorhexidine [92]), are designed to com-
bat the redundancy of biological systems. Three common adjuvants that
have had some clinical success are antiseptics inhibitors, and other bio-
logical (e.g., bacteriophage) or natural (e.g., plant-derived) moieties.
Additionally, several known classes of compounds, e.g., antihistamines,
tranquilizers, anti-hypertensives, antispasmodics, and anti-inflammatory
drugs, are now being explored as antibiotic adjuvants [93].
4.1.1.1. Antiseptic adjuvants. One of the most clinically familiar classes of
non-antibiotic adjuvants is the antiseptics or biocides [94]. Chlorhexi-
dine, a bisbiguanide, is the most commonly used antiseptic. Also de-
signed to kill or inhibit the proliferation of microorganisms, antiseptics
are reported to be more indiscriminate in their mode of actions, having
multiple targets [95]. Efficacy is thought to derive from an ability to per-
meate and disrupt the membrane as well as inactivate ATPase [95]. This
favors combination approaches that exploit the complimentary phar-
macodynamics of antibiotics. One of the most clinically successful com-
bination approaches is an antibiotic/antiseptic combination catheter
coating, which has proven effective against a variety of pathogens [83].
Alternatively, local delivery of an antibiotic/antiseptic combination via
a chitosan sponge has also been explored as an effective treatment
[91]. Despite these successful strategies, concerns about resistance aris-
ing locally due to selective pressures are not completely mitigated and
has been observed in vitro with combinations of chlorhexidine or silver
sulfadiazine (antiseptics) and minocycline or rifampicin (antibiotics)
[96].
19
4.1.1.2. Inhibitor adjuvants. Using a combination therapy capable of
delivering a bactericidal antibiotic while concurrently inhibiting the
mechanism of resistance is a very effective strategy to overcome certain
resistance mechanisms [97,98]. This approach is particularly useful in
cases of potential enzymatic disruption of the antibiotic, such as in the
case of Augmentin, which pairs a β-lactam antibiotic (amoxicillin)
with a β-lactamase inhibitor (e.g., clavulanic acid). Alternatively, com-
pounds that inhibit efflux pumps have also been used in several antibi-
otic combinations to suppress a resistant phenotype. Reserpine, an MDR
pump inhibitor, used in conjunction with ciprofloxacin has been ob-
served to suppress resistance in both S. aureus and Streptococcus
pneumoniae [99]; whereas, celecoxib, a nonsteroidal anti-inflammatory
drug (NSAID) that inhibits the MDR1 efflux pump, enhances the sensi-
tivity of S. aureus to a variety of antibiotics, including ampicillin,
kannamycin, chloramphenicol, and ciprofloxacin [100]. Most efflux
pump inhibitors increase sensitivity by allowing the intracellular accu-
mulation of drugs, providing a complimentary mechanism to prolong
the life of a drug and stifle multidrug resistance [101]. Using an inhibitor
as a non-antibiotic adjuvant has two important distinctions: 1) unlike an
antiseptic adjuvant, which itself has antimicrobial potential, inhibitors
circumvent or repress a mechanism of resistance but do not themselves
have antimicrobial potential [81] and 2) the complementary mechanism
of an inhibitor adjuvant directed at antibiotic resistance not only
enhances the efficacy of its antimicrobial delivery partner but does
not necessarily provoke a new mechanism of resistance [90]. These
two distinctions indicate a great deal of promise in this approach.
4.1.1.3. Natural and biological adjuvants. One of the more novel
approaches to combination therapy has been the use of natural and
biological adjuvants. The pairing of an antibiotic with a bacteriophage
adjuvant, or a bacteriophage component adjuvant may prove more
effective than either component delivered individually and is now avail-
able in Georgia (PhagoBioDerm uses a combination of a lytic phage
cocktail and ciprofloxacin in a biodegradable polymer matrix [102])
[70,103]. Alternative approaches to using biological compounds as syn-
ergistic adjuvants have led to the use of the plant-derived thymol, in com-
bination with vancomycin and EDTA [90], and the use of biosurfactants
such as sophorolipid, which has no inherent antimicrobial activity [104].
The use of plant-derived compounds and biosurfactants is considered
very safe. Biosurfactants have been approved by the FDA for use in phar-
maceuticals and food [104]. Using biological adjuvants takes advantage of
natural processes to enhance antimicrobial efficacy and provides a fea-
sible alternative to combat antimicrobial resistance. Antibodies (IgG
classes) have also been proposed for use as an adjuvant to promote a
host immune response and circumvent antibiotic resistance develop-
ment since the selective pressure is not placed directly on the bacteria
[105].
4.2. Combination approaches that act on the same pathway
A combination strategy can also target different molecules in the
same pathway. Although this presents a less diversified strategy than
targeting different pathways, if the proper pathway is chosen, this can
prove a very effective strategy. Two parameters confine the choice of
pathway. First, the targeted pathway must represent an absolute surviv-
al requirement, such as a requirement for folate to synthesize dTMP, a
precursor for DNA synthesis. Second, the pathway cannot be redundant,
as redundancy predisposes the strategy to resistance [89]. Targeting two
steps in the same pathway presents a more risky strategy in the face of
rising antibiotic resistance, yet it is still more effective than monothera-
pies in many cases [87,106,107].
4.3. Combination approaches that act on the same target
Although targeting two different molecules in the same bacterial
pathway is a less diversified approach than targeting two completely
20 B.D. Brooks, A.E. Brooks / Advanced Drug Delivery Reviews 78 (2014) 14–27
different pathways, it is more diversified than using a combination ther-
apy where both mono therapies inhibit the same molecule. The classic
example revolves around the host of antibiotics that target the bacterial
ribosome. A case study of synercid, a semisynthetic two-drug combina-
tion in which the components bind to adjacent regions in the 50S ribo-
somal subunits proves the utility of this approach, as they are 10–100
fold more effective than either drug individually [89]. Using a combina-
tion of two drugs that target the ribosome may prove effective because
of the critical and conserved nature of the bacterial ribosome. Thus, once
again it is clear how proper target selection is critical in this strategy.
4.4. Combination approaches to address polymicrobial infections
In addition to combinations effective against a single species of path-
ogen, combination therapies are also critical for the treatment of poly-
microbial infections [108]. Between 4 and 27%, with another study
suggesting numbers as high as 37% [109], of peri-prosthetic joint infec-
tions result from the presence of more than one pathogen [110,111];
thus, the ability to target multiple pathogens concurrently and quickly
is emerging as a valuable tool in fighting infections. Importantly, combi-
nation therapies need not be limited to only two component drug cock-
tails. Triple antibiotic combinations such as a combination of β-lactam, a
glycopeptide, and an aminoglycoside have proven much more effective
against MRSA strains when compared to two antibiotic combinations
[112]. Furthermore, combinations composed of antibiotics with varying
mechanisms of action (i.e., protein synthesis inhibitors (macrolides,
aminoglycosides, tetracyclines, lincosamides, and chloramphenicol),
DNA synthesis inhibitors (fluoroquinolones and quinolones), folic acid
synthesis inhibitors (sulfonamides and diaminopyrimidines), cell wall
synthesis inhibitors, polypeptide antibiotics, preservatives, and analge-
sics) may prove particularly effective for polymicrobial infections due
to their varied modes of action [112].
4.5. Resistance and synergistic drug combinations
Although it initially appears that using a drug combination would
serve to circumvent many resistance mechanisms, a drug cocktail may
in fact promote the evolution of drug resistance, despite multiple selec-
tive pressures [87,113–115]. This may be related to the fact that resis-
tance to certain antibiotics in vitro, particularly aminoglycosides,
enhances the sensitivity to other antimicrobial agents, as indicated by
an increase in the minimum inhibitory concentration [116]. Drug cock-
tails can also increase the danger of super-infection due to the co-
evolution of multi-drug resistant variants and sensitization to other an-
tibiotics in the same class as the treatment [108]. In order to overcome
this threat, designing effective drug combinations is an important
approach to reducing the emergence of antibiotic resistant bacteria
while increasing the efficacy of the treatment and prolonging the utility
of individual agents.
4.6. Pitfalls of combination drug delivery
All contemplated drug combinations must carefully consider the
impact of drug–drug interactions, compound ratios, and dosing regimens
on the adsorption, metabolism and excretion of each drug individually
[98,117,118]. The relatively simplistic approach of concurrently adminis-
tering two or more synergistic (i.e., the efficacy of the drugs together is
greater than the effect of either drug individually) antibiotics may not
only alter the pharmacokinetics of drug delivery based on drug–drug
interactions but may also prove toxic to the bacteria as well as to the
host cells and valuable symbiotic microbes in the host microbiome.
Sequential synergistic drug dosing may avoid some of these common pit-
falls as can hybrids (i.e., a single antibiotic with two distinct functions),
such as the lantibiotic, nisin [14,119]. Notably, certain drug combinations
can actually mitigate the toxicity of individual drugs in the cocktail
(e.g., metallic nanoparticles and antibiotics), often due to decreasing
requisite dosing and concentration [88]; moreover, individual drug
mechanisms of action must be weighed so as not to introduce antagonis-
tic interactions, such as that which has been observed between certain
DNA synthesis inhibitors and protein synthesis inhibitors [120]. Ulti-
mately, a better mechanistic understanding of antibiotic combinations
in addition to more creative combinations, such as pairing an antibiotic
with non-antibiotic adjuvant or a quorum sensing inhibitor, is necessary.
5. Antibiotic delivery
5.1. Systemic versus local antibiotic delivery
Traditionally, systemic antibiotic administration has been the foun-
dation of clinical therapies to address the ever-present infectious on-
slaught. Unfortunately, poor penetration to ischemic or post-operative
tissue, inappropriate prescribing patterns, systemic toxicity, and poor
patient compliance, have predominated the conversation and limited
the usefulness of certain antibiotics. Furthermore, systemic administra-
tion is often not effective, as it does not provide local tissue concentra-
tions sufficient to kill bacteria prior to incurring serious side effects, such
as renal and liver damage. Sub-therapeutic or sub-inhibitory antibiotic
concentrations are known to inadvertently exacerbate infectious compli-
cation and promote antibiotic resistance [83,121]. Local delivery of cur-
rent antibiotics and other antimicrobial biologics (e.g., antimicrobial
peptides (AMPs), anti-quorum sensors, bacteriophage, etc.) may preserve
and extend their efficacy in the evolutionary race between antimicrobial
development and bacterial resistance. In fact systemic toxicity, and to a
lesser extent, antibiotic resistance is rarely seen for local applications of
the same drugs, achieving locally higher concentrations and overcoming
the reducing effects of lowered bacterial metabolism [91,122–124].
Thus, device integrated, local delivery strategies to mitigate the unaccept-
able consequences of systemic antibiotic delivery (e.g., development of
multi-drug resistant bacteria, systemic toxicity, and rising healthcare
costs, etc.) are urgently needed to keep pace with the rising demand for
medical devices.
The concept of locally and sustainably delivering an anti-infective
agent is not new. Vancomycin, tobramycin, amoxicillin, gentamicin,
cefamandol, caphalothin, and carbenicillin have all been incorporated
into commercially available local release systems [125–127]. As early
as the 1940s, efforts were made in dentistry and orthopedics to endow
implantable materials (e.g., cements and resins) with biological activi-
ty [128,129]; however, it quickly became apparent that the efficacy of
these systems in locally combating a pathogenic infection was largely
dependent on the pharmacokinetics of the system [83]. Ideally, local an-
tibiotic release kinetics should exhibit an initial high dose, well above
the minimal inhibitory concentration (MIC) of the offending bacteria
but below the toxic threshold of the surrounding host cells, followed
by a sustained release of antibiotic sufficient to address the later emer-
gence of any latent bacteria. The duration and level of sustained release
are dependent on the host tissue matrix, the type and mechanism of the
antibiotic, and the clinically established critical postoperative period
[127]. Unfortunately, many local antibiotic delivery technologies have
suffered from early burst release with subsequent sub-therapeutic activ-
ity, inadvertently evoking bacterial antibiotic resistance. This quandary
is epitomized by aminoglycoside delivery from (poly)methyl methacry-
late (PMMA) for the treatment of osteomyelitis. Once the drug has
leached through small pores to a sustained sub-inhibitory level, PMMA
acts as a foreign body and nidus of infection, promoting the evolution
of multidrug resistant bacteria [130,131]. Consequently, degradable
polymers have been sought in order to achieve sustainable high local
concentrations while still avoiding the pitfalls of systemic administra-
tion [30,132–134]. Many different natural and synthetic biodegradable
polymers (e.g., collagen [135,136], chitosan [123,124,137,138], silk
[139], hydroxyapatite [140], fibrin clots [141,142], polyurethane [143],
polycaprolactone [144,145], PLGA [146] etc.) have been explored for
local antibiotic release.
 B.D. Brooks, A.E. Brooks / Advanced Drug Delivery Reviews 78 (2014) 14–27
5.1.1. Antimicrobial polymers
Unlike many classic antimicrobial compounds that are not capable of
adequately addressing surface bound bacteria, antimicrobial polymers
were designed for just such a scenario [147–150]. These biologically ac-
tive polymers fill a critical niche in the development of new biocompat-
ible, active medical devices. Such antimicrobial devices may effectively
ease the burden on systemic antibiotics, essentially promoting antibiot-
ic stewardship, prolonging the life of conventional antibiotic therapies,
and curbing the evolution of antibiotic resistant microbes. Historically,
cationic poly-amino acids and polyelectrolytes have been the molecules
of choice for development of antibiotic polymers; however, recent
efforts have expanded this narrow focus to include polymers with anti-
microbial chemical modifications, polymers containing antimicrobial
organic compounds and those that incorporate antibacterial inorganic
compounds. Integrating an antibiotic agent into a polymer matrix
serves to minimize antibiotic toxicity, increase antibiotic stability, and
improve antibiotic half-life and efficacy [150–152].
5.1.1.1. Polymers with intrinsic antimicrobial activity. Certain polymers
can be exploited based on their inherent antibiotic activity, which
often includes chemical and other structural elements. Among those
most studied are polymers mimicking natural peptides (e.g., peptoids
(oligo-N-substitutes glycines [69,153]), etc.), cyclic peptides [154], hal-
ogen polymers (fluorine or chlorine-containing polymers, polymeric
N-halamines [155], phenylene ethynylenes [156], and organometallic
polymers. This group can also include polymers with cationic groups
(e.g., biguanide, quaternary ammonium salts, quarternary pyridinium
salts, and phosphonium salts) [157,158] or cationic conjugates
(e.g., polyelectrolytes, polysiloxanes, polyoxazolines, polyionenes, etc.).
5.1.1.2. Polymers with antimicrobial chemical modifications. Since 1965,
polymers have been covalently modified to endow them with bacteria
resistant and bactericidal properties [159]. Traditionally, these chemical
modifications have fallen into 3 primary categories: 1) covalently at-
tached small molecules on a polymer backbone [160,161], 2) attached
antimicrobial peptides to a biologically inactive polymer [162,163], or
3) grafted antimicrobial polymer on a biologically inactive polymer
[164,165].
5.1.1.3. Polymers containing antimicrobial organic compounds. Nonco-
valently linked antimicrobial agents can be released from a polymer
matrix offering a very versatile strategy to combat device-associated in-
fections. Despite being one of the most common approaches to create an
antimicrobial polymer, inadequate release kinetics, governed by the
complexities of polymer/drug/solvent interactions, may inadvertently
promote the evolution of bacterial resistance [131,144,145,166]. This
classification can also include physical blends or mixtures of antimicro-
bial and non-antimicrobial polymers [167], but blending distinct com-
pounds poses its own problems with homogeneity and consistency.
5.1.1.4. Polymers incorporating antimicrobial inorganic compounds. Inor-
ganic compounds such as metals or metallic oxides can be embedded
in a polymer matrix analogous to organic antibiotic agents. The history
of antimicrobial silver, in its various forms (ions, salts, nanoparticles,
etc.) is deeply entwined with that of polymers, offering some of the
most fundamental studies of antimicrobial polymers [168]. Other suc-
cessful strategies use zinc oxide [169], gold, and titanium oxide [170].
Regardless, almost all of these strategies employ the use of nanoparti-
cles [171].
5.2. A unique local delivery system—nanoparticle/liposome delivery
Local drug delivery systems take a variety of forms from topical
applications to coatings on biomedical implants to bulk implantable de-
vices; however, nanoparticle and liposome based drug delivery systems
21
are unique in their varied administration routes, drug elution kinetics
and intracellular delivery capability.
5.2.1. Nanoparticles
Nanoparticle drug delivery systems can claim most of the same
advantages of liposome delivery systems (e.g., cellular penetration,
surface modification for targeting to increase therapeutic efficacy,
etc.); however, their polymer composition provides additional stability
not seen in liposome drug preparations to increase their resident circu-
lation time and protect their drug payload from degradation [172].
Nanotechnology-based drug delivery systems are an emerging approach
to improve: 1) the therapeutic index thereby decreasing the dose and
frequency of administration, 2) intracellular delivery to mitigate the de-
velopment of multidrug resistant bacteria [173], and 3) targeted organ
accumulation to limit systemic side effects [174,175] (Fig. 6). Metal ion
nanoparticles, especially silver compounds, have an established history
of use in medicine and pharmaceutics and have been explored as adju-
vants and carriers for antibiotic delivery [176,177]. Recent efforts have
attempted to couple gold nanoparticles with a variety of antibiotics
(e.g., ciprofloxacin and other fluoroquinolones [178], vancomycin [179],
gentamicin [180], etc.) with inconsistent results. Gu et al. found enhanced
activity against vancomycin resistant gram-negative bacteria when
decorating the surface of gold nanoparticles with vanomycin [179]; how-
ever, Burygin et al. showed no enhanced activity of gentamicin gold
nanoparticles over that of the unbound drug [180]. These inconsistencies
may be attributable to the characteristics of the antibiotics used as well as
the experimental conditions and the size of the nanoparticles, all param-
eters known to affect efficacy. Although not a factor in this particular case,
it is important to note that nanoparticle drug delivery is generally more
active against gram-negative species [90]. Nevertheless, despite the po-
tential for nanoparticle drug delivery systems and clinical success, partic-
ularly with metallic nanoparticles, there are relatively few marketed
nanoparticle based drug delivery systems [181]. This may be a conse-
quence of the complicated characterization and analyses necessary for
nanoparticle technologies and their limited targeting efficiency and
short half-life (for a review of these issues please see [182]).
5.2.2. Liposomes
Intravenous injection is the most popular route for liposome drug
delivery and provides some advantage over traditional systemic deliv-
ery systems. Both targeted delivery to the lungs via inhalation [172]
and local application in the eye [183] highlight the multiple advantages
of liposomes to: 1) deliver biologics and hydrophilic compounds, 2) sta-
bilize antibiotic compounds, 3) reduce toxicity and increase therapeutic
index, and 4) target delivery [184,185]. Many of these advantages are
thought to stem from their membrane-like structure that allows them
to fuse with the cellular membrane and deliver a drug payload directly
to the cytoplasmic compartment, potentially saturating the bacterial
drug-efflux pumps and circumventing a primary mechanism of antibi-
otic resistance [172]. Unfortunately, lipid drug delivery systems also
have limited encapsulation efficiency [175], a relatively short half-life
due to opsonization, filtration, and the hydrolytic instability of lipid
ester bonds, aggregation and fusion of liposomes, and temperature sen-
sitivity [186]. These limitations can lead to inadequate delivery partially
due to drug leakage in circulation. Liposome stability can be improved
with a variety of modifications (e.g., incorporation of hydrophilic long
chain polymers in the lipid bilayer, cholesterol, anionic charged groups,
targeting ligands, etc.) to create stealth liposomes [187]. An extensive
discussion of liposome antibiotic encapsulation and delivery optimi-
zation is outside the scope of this review but has been previously ad-
dressed in several reviews [175,185].
5.3. Impact of local drug delivery pressure on the development of resistance
Local drug release systems can deliver antibiotics without incurring
the same toxicity or provoking the same level of antibiotic resistance
22 B.D. Brooks, A.E. Brooks / Advanced Drug Delivery Reviews 78 (2014) 14–27
Fig. 6. Nanoparticle mechanism of action as an antibiotic or antibiotic carrier (modified from [11]).
that plagues systemic drug administration; however, the presence of any
antibiotic, regardless of its route of administration, exerts some degree of
evolutionary pressure for bacteria to develop a multidrug resistant phe-
notype. This concern is particularly voiced by epidemiologists when
using antibiotic-carrier biomaterials prophylactically as there is evidence
that prophylactic antibiotic use may contribute to the problem [122]. This
view is slightly tempered by the regional prevalence of multidrug resis-
tant (MDR) species, highlighting the necessity for epidemiological sur-
veillance and clinical cognizance of regional microbiome. Furthermore,
it is important to note that both in vitro and in vivo evidence has identified
the presence of heterogeneous populations in large bacterial loads, some
of which are capable of surviving the initial antibiotic burst despite their
lack of antibiotic resistance genes. Shortly after the first widespread use
of antibiotics and local antibiotic delivery systems in humans, pre-
existing resistant variants were recognized following exposure to lethal
antibiotic doses [15], indicating that otherwise healthy individuals harbor
a small number of resident bacteria intrinsically resistant to antibiotics
[42]. The more prevalent, antibiotic-susceptible host flora is able to keep
this small number of resistant microbes in check in the absence of antibi-
otic selective pressure. However, regardless of the route of administration,
emergence and proliferation of the resistant population occur upon
antibiotic administration when the normal flora decreases [42]. It is
imperative that one of the main criteria in emerging antimicrobial tech-
nologies, designed to circumvent the overwhelming wave of antibiotic
resistance, must be to protect the natural flora of the host, as there is a
relatively clear connection between protecting the host microbiome
and the prevention of multidrug resistant bacterial colonization [188].
Systemic antibiotic treatment threatens this symbiotic relationship
and allows opportunistic infections to flourish unchecked. Local deliv-
ery might best achieve this goal.
6. Conclusions
Infection control has long been a product of an evolutionary arms
race. Despite clinical evidence that small molecule monotherapy ap-
proaches are limited in this landscape of resistance, an evaluation of
the infection control candidates in the development pipeline indicates
that research remains focused on discovery and development of new
drugs. Unfortunately, as demonstrated in Tables 1 and 2, antibiotic
biotherapeutics, new combination therapies, and drug delivery mecha-
nisms still lag behind the development of new small molecule drugs that
are often an extension of existing drug classes. No longer are systemic
monotherapy approaches adequate in a world where resistance outpaces
new drug development. Thus, instead of fighting microbial evolution, in-
fection control efforts may be better served by targeting mechanisms of
resistance based on biological inspiration (e.g., furanones deployed by
red sea algae to interrupt quorum sensing, etc.).
 B.D. Brooks, A.E. Brooks / Advanced Drug Delivery Reviews 78 (2014) 14–27 23

Table 1
New antimicrobial drugs in the development pipeline. Importantly, only small molecules and biologics in phase trials are included [194–196]. This table does not capture all candidates in
pre-clinical testing and development.

New antibiotic candidate pipeline [195–197]

Phase I Phase II Phase III

Candidate (company) Family Candidate (company) Family Candidate (company) Family

BAL30072 (Basilea) Monosulfactam GSK-2696266 (Shionogi/GSK) Cephem Omadacycline (Paratek) Tetracycline

XF-73 (Destiny Pharma)
NVB302 (Novacta)
POL7080 (Polyphor)
LCB01-0371 (LegoChem)
MRX-I (MicuRx)
ACHN-975 (Achaogen)
GSK-214094 (GSK)
KPI-10 (Kalidex)
DS-8587 (Daiichi)
KRP-AM1977 (Kyorin)
Porphyrin SMT-19969 (Summit) Bibenzo[d]-imidazole Eravacycline (Tetraphase) Tetracycline
Lantibiotic LFF-571 (Novartis) Solithromycin (Campra) Erythromycin
Protegrin I Auriclosene (Novabay) Chlorotaurine Tedizolid phosphate (Trius Pharma) Oxazolidinone
Oxazolidinone Sarecycline (Warner Chilcott) Tetracycline Delamanid (Otsuka) Nitroimidazole
Oxazolidinone BC-3781 (Forest) Pleuromutilin Perchlozone (USC Pharmasyntez) Thiosemicarbazone
Plazomicin (Achaogen) Aminoglycoside SQ109 (Sequlla/Infectex) Ethambutol
GSK1322322 (GSK) Actinonin Finafloxacin (MerLion) Fluoroquinolone
Fluoroquinolone DPK-060 (Pergamum) Kinigongen Delafloxacin (Rib-X) Fluoroquinolone
Fluoroquinolone PA-824 (Global Alliance TB Drug Avarofloxacin (Furiex) Fluoroquinolone
Quinolone Development) Nitroimidazole Zabofloxacin (Dong Wha) Fluoroquinolone
Radezolid (Rib-X) Oxazolidinone Nemonoxacin (TaiGen) Quinolone
Sutezolid (Pfizer) Oxazolidinone Ozenoxacin (Grupo Ferner) Quinolone
Posizolid (AstraZeneca) Oxazolidinone
Cadazolid (Actelion) Oxazolidinone
AFN-1252 (Affinium)
CG400549 (Crystal Genomics) Triclosan)
WCK-771 (Wockhardt) Fluoroquinolone
WCK-2349 (Wockhardt) Fluoroquinolone

Biologics
Brilacidin (PolyMedix) Defensin Dalbavancin (Durate Therapeutics) Glycopeptide
LTX-109 (Lytix Bio) Peptide Oritavancin (The Medicines Company) Glycopeptide
LL-37 (Pergamum) Cathelicidin Surotomycin (Cubist) Lipopeptide

Although use of biologics in infection control is still in its infancy, its
potential for combating multi-drug resistance cannot be ignored. Small
molecules will always have a place in infection control; however, effec-
tive candidate development may be more intelligently pursued based
on biological inspiration. Drug development tools necessary to overcome
the pitfalls of biologics, including limited in vitro stability, restricted de-
livery options, limited high-throughput, discovery and development
screening tools, imperfect pharmacokinetics and relatively unexplored
pharmacodynamics, are not as advanced as those available for small
molecule development. Fortunately, limitless potential exists in the
combinations of biologics, biologically inspired molecules, and drug
delivery technologies. Thus, a paradigm shift akin to that necessary for
complex viruses and cancers is essential to design a targeted attack
that eradicates susceptible microbes, contains and squelches microbial
resistance, and protects the host flora from the therapeutic. Such a strat-
egy may arise from combinations of traditional antibiotics, new adju-
vants, and sustainable localized delivery approaches. Using advanced
bioinformatics to predict successful combination delivery and novel tar-
gets may pose significant advantages over current costly development
models that often fail in late phase trials [189].
Solutions to antibiotic resistance are not trivial to implement, with
consequences affecting everyone. While solutions have been proposed,
with some even being launched to address the problem, action taken to
date is merely token. Antibiotics remain indispensable in all health sys-
tems, and the consequences of a lack of a coordinated effort medically,
socially, and economically will be dire [190]. Simple antibiotic steward-
ship is no longer an option in the face of rising drug resistance. Clinical
treatments and practices for infection control must evolve in response
to epidemiological trends in multi-drug resistant bacteria and the devel-
opment of new treatment strategies. Hopefully, repeated emphasis will
promote adoption of new research strategies for infection treatments,
including adherence to three criteria: (1) invention of efficacious new
drugs, (2) prevention of resistance, and (3) protection of the natural
host microbiome (Fig. 2). The best strategy to meet these criteria includes
the development of new combination approaches coupled with local and
smart delivery technologies (e.g. targeted liposomes and nanoparticles
and infection-responsive polymer controlled delivery [191,192]). This
paradigm shift requires a significantly more sophisticated approach to
antibiotic discovery and development. Even with this paradigm shift,
humans and microbes are likely deadlocked in an evolutionary arms
race; without this paradigm shift, the results are more tenuous.
Conflict of interest statement
AEB discloses a financial interest in a corporate entity, Elute Inc., that
has licensed technology related to that discussed in this publication
from the University of Utah for commercial use. Elute Inc. partially
funded this work although they had no input in the design or analysis
of that presented in this work.

Table 2
New combination antimicrobial therapies currently in phase trials. Other additional combination therapies not captured here are currently in preclinical development.

New antibiotic combinatory delivery pipeline [195–197]

Phase I Phase II Phase III

Candidate (company) Family Candidate (company) Family Candidate (company) Family

ATM-AVI aztreonam & Monobactam/ CXL Ceftaroline & Cephalosporin/ CXA-201—ceftolozane Cephalosporin/
avibactam (AstraZeneca) β-lactamase inhibitor avibactam (AstraZeneca) β-lactamase inhibitor & tazobactam (Cubist) β-lactamase inhibitor
Carbavance biapenem Carbapenem/ Imipenem cilastatin Carbapenem/ CAZ104 ceftazidime Cephalosporin/
&RPX7009 (Rempex) β-lactamase inhibitor & MK-7655 (Merck) β-lactamase inhibitor & avibactam (AstraZeneca) β-lactamase inhibitor
24 B.D. Brooks, A.E. Brooks / Advanced Drug Delivery Reviews 78 (2014) 14–27
Acknowledgments
This is a vast and expanding field and we apologize to those whose
work may have been overlooked in preparing this manuscript. Thank
you to Dr. David Grainger (University of Utah) for technical editing.
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