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Silver has been used for centuries. Today, silver and silver nanoparticles (AgNPs) are used in a wide range of healthcare, food industry, domiciliary applications, and are commonly found in hard surface materials and textiles. Such an extensive use raises questions about its safety, environmental toxicity and the risks associated with microbial resistance and cross-resistance. If the mechanisms of antimicrobial action of ionic silver (Ag(+)) have been studied, there is little understanding of AgNPs interactions with microorganisms. There have been excellent reviews on the bacterial resistance mechanisms to silver, but there is a paucity of information on resistance to AgNPs. Silver toxicity and accumulation in the environment has been studied and there is a better understanding of silver concentration and species in different environmental compartments. However, owing to the increased applications of silver and AgNPs, questions remain about the presence and consequences of AgNPs in the environment. This review provides an historical perspective of silver usage, an overview of applications, and combined information of microbial resistance and toxicity. Owing the evidence provided in this review, a call for a better understanding and control of silver usage, and for tighter regulations of silver and AgNPs usage is proposed.
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1
Brief historic and medical use
e use of silver can be traced back in history. Silver
was used in ancient time to preserve water (use of silver
vessels, use of silver coins) (Silver et al. 2006). Its use
for medicinal purposes has been rst documented in
750AD, although it may have occurred before that. In
the 17th century, silver was described as an essential
multipurpose medicinal product and was used to treat
epilepsy and cholera (Edwards-Jones 2009). e rst
scientic paper describing the medical use of silver has
been attributed to F. Crédé in the late nineteen century
who used one-percent silver nitrate solution as eye drops
in newborns, eliminating blindness caused by postpar-
tum eye infections, and in 1901 for internal antisepsis
(Russell & Hugo 1994). At the beginning of the 20th
century the use of silver foil dressing was introduced by
W.D. Halstead a surgeon; the dressing was listed on the
Physician’s Desk Reference until 1955 (Silver et al. 2006).
e U.S. Food and Drug Administration (FDA) approved
charged silver solutions (i.e. electrocolloidals) in the
1920s for use as antibacterial agents. At the same period,
A.C. Barnes in Philadelphia invented Argyrol as a local
antiseptic to prevent eye infections in particular. He rec-
ognized that silver nitrate eye-drops often were caustic
to human tissues and that a more benign and eective
silver product could be produced by absorption of Ag+ on
the surface of colloidal proteins such as gelatin.
e use of silver nitrate (0.5%) in compresses for
the treatment of burn wounds was rst explored by
Moyer and colleagues (1965). Such application worked
well at the time to control Pseudomonas aeruginosa
infection, but the development of bacterial resistance
to silver nitrate (Cason et al. 1966; Cason & Lowbury
1968) prompted a change in formulation and the use
of silver sulphadiazine – a combination of silver and
sulphonamide (Fox 1968; Modak & Fox 1974; Modak et al.
1988). It was proposed that such a combination functions
with the slow release of Ag+ as the primary microbicide
while sulfadiazine serves mostly to keep Ag+ in solution
and to prevent the light-sensitive formation of black
REVIEW ARTICLE
Silver as an antimicrobial: Facts and gaps in knowledge
Jean-Yves Maillard1 and Philippe Hartemann2
1Cardi School of Pharmacy and Pharmaceutical Sciences, Cardi University, Cardi, UK and 2lorraine University,
Faculty of Medicine Nancy, Nancy, France
Abstract
Silver has been used for centuries. Today, silver and silver nanoparticles (AgNPs) are used in a wide range of
healthcare, food industry, domiciliary applications, and are commonly found in hard surface materials and textiles.
Such an extensive use raises questions about its safety, environmental toxicity and the risks associated with microbial
resistance and cross-resistance. If the mechanisms of antimicrobial action of ionic silver (Ag+) have been studied,
there is little understanding of AgNPs interactions with microorganisms. There have been excellent reviews on the
bacterial resistance mechanisms to silver, but there is a paucity of information on resistance to AgNPs. Silver toxicity
and accumulation in the environment has been studied and there is a better understanding of silver concentration
and species in different environmental compartments. However, owing to the increased applications of silver and
AgNPs, questions remain about the presence and consequences of AgNPs in the environment. This review provides an
historical perspective of silver usage, an overview of applications, and combined information of microbial resistance
and toxicity. Owing the evidence provided in this review, a call for a better understanding and control of silver usage,
and for tighter regulations of silver and AgNPs usage is proposed.
Keywords: ionic silver, nanosilver, resistance, toxicity, activity
Address for Correspondence: Jean-Yves Maillard, Cardi University, Cardi School of Pharmacy and Pharmaceutical Sciences, Redwood
Building, King Edward VII Avenue, Cardi, CF10 3NB, UK. E-mail: maillardj@cardi.ac.uk
(Received 20 March 2012; revised 13 July 2012; accepted 16 July 2012)
Critical Reviews in Microbiology, 2012; Early Online: 1–11
© 2012 Informa Healthcare USA, Inc.
ISSN 1040-841X print/ISSN 1549-7828 online
DOI: 10.3109/1040841X.2012.713323
Critical Reviews in Microbiology
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11
20March2012
13July2012
16July2012
1040-841X
1549-7828
© 2012 Informa Healthcare USA, Inc.
10.3109/1040841X.2012.713323
2012
Silver as an antimicrobial
J.-Y. Maillard and P. Hartemann
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2 J.-Y. Maillard and P. Hartemann
Critical Reviews in Microbiology
colloidal Ag0 on the skin surface, again a serious cosmetic
problem with AgNO3-based products, since patients
object to skin blackening (Klasen 2000). However, it
has been suggested that bacterial resistance to silver
sulphadiazine developed rapidly mainly because of the
antibiotic component (Klasen 2000). Other combinations
have then been explored such as combination of
silver sulphadiazine with chlorhexidine (Fraser et
al. 2004), silver sulphadiazine and cerium nitrate
(Flammacerium) (Garner & Heppell 2005a, 2005b).
Today the British National Formulary (2011) authorizes
the use of silver nitrate (40–95%) for external use on
warts, verruca, umbilical granulomas, over-granulating
tissue, cauterization and silver sulphadiazine (1%) for
the “prophylaxis and treatment of burn wounds, as an
adjunct to short-term treatment of infection in leg ulcers
and pressure sores, adjunct to prophylaxis of infection
in skin graft donor sites and extensive abrasions” (BNF
2011). Other medical preparations are listed in Table 1.
During the second half of the 20th century silver was
also used as a disinfectant especially in conjunction with
hydrogen peroxide. e ecacy of numerous commercial
products for the food industry, private swimming pools,
surface and equipment disinfection were based on claims
evidencing a synergistic eect. In fact it has been demon-
strated (Hartemann et al. 1995) that silver acts as a catalyst
in the Fenton reaction for producing free hydroxyl radicals.
e use of silver for healthcare applications has been
briey reviewed by Edwards-Jones (2009) who pointed
out that its use should be justied nancially by an evi-
dence of cost benet as illustrated by the use of nanocrys-
talline silver dressing or the potential use of silver-coated
urinary catheters (Silver et al. 2006; Hsu et al. 2010; Apirag
et al. 2011). It should be noted that the use of silver in cath-
eters is still a matter of debate (Leone et al. 2004). Silver
and especially nanosilver/silver nanoparticles (AgNPs)
is now used in a number of dressings and evidence for
activity has been reviewed by Silver et al. (2006) and more
recently by Toy and Macera (2011). Silver has also been
heavily used in dentistry in silver amalgams (Silver 2003)
and silver containing products are used in medicine in
an expanding range of applications. e most important
current use is undoubtedly as a microbicide to prevent
infections associated with long-term and recurrent sites
including burns, traumatic wounds and diabetic ulcers.
Additional uses include coating of catheters and other
devices implanted on or within the body. Non-medical
uses include home consumer products and disinfection
of water and equipment, which expand tremendously
the range of products containing silver and AgNPs.
e renewed interest in silver can be attributed to
its bactericidal ecacy at a low concentration, relative
limited toxicity of ionic silver to human cells, and recent
advances in the production of nanoparticles and impreg-
nation techniques and polymer technologies (Maillard &
Denyer 2006a; Marambio-Jones & Hoek 2010). e com-
bination of ionic silver and other forms of silver with other
molecules and especially with polymers in dressings aim
to increase the overall antimicrobial eect of silver and its
sustainability, to decrease silver toxicity and interference
with the dressing, and to improve wound healing and uid
handling (Maillard & Denyer 2006a, 2006b). ere are now
a number of silver-based dressings on the market and they
dier widely in their structure, formulation and silver con-
centration (Kostenko et al. 2010; Toy & Macera 2011).
Silver applications
ere has been a tremendous increase in applications
using silver and AgNPs (Silver et al. 2006; Gottschalk
et al. 2010) (Table 2). AgNPs might be the most commonly
used nanomaterials in consumer products (300/1317
listed products contained AgNPs) (Project on Emerging
Nanotechonologies 2011). AgNPs are usually dened as
particles with at least one dimension measuring less that
100 nm. e interest in AgNPs rests with an improved
microbicidal activity (Marambio-Jones & Hoek 2010), a
perceived reduced overall toxicity and an ease of incor-
poration in a number of polymer or biomaterials. Some
of the common attributes of AgNPs rest on a greater
surface area, an improved bioavailability and greater
chemicals and biological reactivity. At least two main
methods are used to provide antimicrobial properties to
polymers: (i) the introduction of silver nanoparticles at
dene concentrations into ready-made items and (ii) the
introduction of silver nanoparticles into raw materials for
subsequent manufacture of polymeric items. e meth-
ods to incorporate silver particle into polymers and other
materials are often proprietary and are the source of the
technology intellectual property.
e use of silver (50 ppm) in personal care products
has been explored as early as 1996 with great success in
terms of controlling skin ora without associated toxicity
or hypersensitivity (Corbett 1996). e use of AgNPs is
more recent with demonstration of microbial ora con-
trol for 24 h (Nakane et al. 2006).
Silver nanoparticles have been used in a wide range of
matrices and formulations such as composites, colloids,
Table 1. List of preparations using silver according to the
Martindale (2002).
Silver acetate, silver borate,
silver allantoinate, silver zinc
allantoinate, silver carbonate,
silver chloride, silver
chromate, silver glycerolate,
colloidal silver iodide, silver
lactate, silver manganite, silver
nylon polymers
Antiseptic
(similar use to silver nitrate)
Silver nitrate (1%) Prophylaxis of gonococcaloph-
thalmianeonatorum (neonatal
conjunctivitis)
Silver protein Antisepsis; eye drops and
mucous membrane
Colloidal silver
Silver sulphadiazine (1%) Prevention and treatment of
infection in severe burns
Eye treatment of Aspergillus
infections
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Silver as an antimicrobial 3
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bers, gels, coatings, membranes and thin lms (Porel
et al. 2011). Silver is also used in food packaging. For exam-
ple, the ecacy of silver (-zeolite) to prevent Pseudomonas
putida at low temperature was observed to be marginal
over 2 days when compared from a silver-free packaging,
but signicant (>3 log) over 4 days (Lee et al. 2011). e use
of AgNPs for liquid packaging has also been reported, with
some very modest eect (1 log reduction of Lactobacillus
plantarum) in 112 days (Emamifar et al. 2011).
Mechanisms of action of ionic silver
Efficacy of silver as an antimicrobial
Silver has a broad spectrum of antimicrobial activity
against planktonic and sessile bacteria (Edwards-Jones
2009; Percival et al. 2011), although bacterial spores, pro-
tozoal cysts and mycobacteria are less aected. e activ-
ity of silver resides in ionic silver at a concentration of 10−9
to 10−6 mol/L, while Ag0 is inactive. Silver ions activity can
be enhanced with combination with other antimicrobial
agents, antibiotics (e.g. sulphonamide; silver sulphadi-
azine), chlorhexidine (Silvazine), cerium nitrate
(Flammacerium). e bactericidal activity of AgNPs has
been reported (Su et al. 2011) including against bacterial
biolms (Kostenko et al. 2010; Huang et al. 2011). AgNPs
is thought to have a better activity than ionic silver (Rhim
et al. 2006; Fernández et al. 2010a, 2010b; Marambio-
Jones & Hoek 2010). AgNPs are thought to have the ability
to generate more ionic silver, to increase the production
of reactive oxygen species, notably when combined to
halides, and to deliver more eciently ionic silver to
small surfaces (Wijnhoven et al. 2009). e bactericidal
activity of AgNPs can be improved with combination
with polymers such as chitosan and cationic polysaccha-
ride (Banerjee et al. 2010). e production of free radicals
in combination with H2O2 is also another way to enhance
the “cidal” activity for disinfecting inanimate surfaces or
water (Hartemann et al. 1995).
e activity of silver depends upon its bioavailability
and the type of target microorganisms. It has been recog-
nized that the activity of silver used for the treatment of
burn wounds is limited and silver is unlikely to eliminate
bacteria already colonizing the wound because of the lack
of penetration of ionic silver and its rapid neutralization
with organic matter. It has been estimated that the maxi-
mum concentration of available ionic sliver attainable in
wound is 1 µg/mL (Maillard & Denyer 2006b). e bio-
availability of silver is aected by silver concentration,
although its concentration exponent is low, its poor solu-
bility in water, its rapid adsorption to surfaces, its rapid
precipitation when combined with chloride, sulphite
and phosphate and its rapid neutralization by organic
matter (mainly protein). In particular, the concentration
of halides has been shown to have an eect on silver
bioavailability, since high halide concentrations bring
silver back into solution, improving antimicrobial activity
against silver-susceptible and -resistant bacteria (Gupta
et al. 1999a). In silver-impregnated dressing, the release of
ionic silver is linked to the level of hydration (Lansdown
et al. 2005). e amount of ionic silver release, the rate of
release and long-term release are also parameters that
may play an important role in the ecacy of silver dress-
ings (Kostenko et al. 2010). e release of ionic silver also
depends upon the nature of the silver antimicrobial and
the polymer matrix used (Monteiro et al. 2009).
Silver activity is modestly aected by temperature or
a change in pH (notably alkaline pH) (Maillard & Denyer
2006b). Duration of exposure is also an important param-
eter to consider for long-term usage devices. e use of
silver in endotracheal tube was shown to prevent biolm
formation for a few days (Berra et al. 2008; Roe et al. 2008)
but not in longer use (Olson et al. 2002).
Table 2. Examples of silver and AgNPs applications.
Healthcare Wounds dressings, antiseptics, hospital beds and furniture
Home consumer products Fabric conditioners, baby bottles, food storage containers and salad bowls, kitchen cutting boards, bed
mattress, vacuum cleaner, disposable curtains and blinds, tableware, independent Living Aids – bathroom
products, furniture (chairs), kitchen gadgets and bath accessories, dishwashers, refrigerators and washing
machines, toilet tank levers to sink stoppers, toilet seat, pillows, and mattresses, food storers, containers, ice
trays, and other plastic kitchenware, hair brush, hair straightener, combs, brushes, rollers, shower caps
Toothpaste, cosmetic deodorants, toothbrushes, tissue paper, epilator, electric shaver
Pet shampoos, feeders and waters, litter pans, pet bedding and shelter, paper, pens and pencils, ATM buttons,
remote control, handrails (buses), computer keyboards, hand dryers, wireless voice communicators with badge
and the sleeves, yoga mat, coatings for use on laptop computers, calculators, sheet protectors, name badges
and holders, shop ticket holders, media storage products, laminating lm, report covers and project folders,
photo holders, memory Book, oce accessories, transparency lm, collapsible coolers
Clothing and fabrics Baby clothes, underwear, socks, footwear, various fabrics and vinyls, bath towels, quilts, sleeping bags, bed
linens, pillows, quilts, mattress protectors and towels
Food Packaging, nanobiotic poultry production
Construction Powder coating (door knobs), wall paints, air conditioning, epoxy resin oor, PVC wall cladding, antimicrobial
ooring, metal suspended ceiling systems, window blinds and shading systems, shelving systems, decorative
wood laminates, electrical wiring accessories, notile panels (alternative to standard tiling), hygienic laminated
surfaces, wallpaper, borders and murals, carpet and carpet underlay, seals (door for cooler doors and freezer
cells, tank lids, mixers and kneading machines, hospital doors, for vibrating screens /vibrosieves in the phar-
maceutical industry)
Disinfectants Agricultural disinfectants, industrial disinfectants, aquaculture disinfectants, pool disinfectants
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4 J.-Y. Maillard and P. Hartemann
Critical Reviews in Microbiology
Water hardness and notably the presence of divalent
cations aect the bactericidal ecacy of AgNPs against
Gram-positive in a liquid environment possibly through
an increase size of nanoparticle aggregates and possibly
a reduced binding to the bacterial surface (Jin et al. 2010).
However, the presence of divalent cations seem to increase
the ecacy of AgNPs against Gram-negative bacteria, pos-
sibly by increasing the interaction and ‘local concentration’
of the negatively charged silver-nanoparticle and the nega-
tively charge lipopolysaccharide layer (Jin et al. 2010). e
size and morphology of nanoparticles aect microbicidal
ecacy (Lok et al. 2007; Pal et al. 2007; Samberg et al. 2011).
Mechanisms of action of silver
It has been proposed that ionic silver while inside the cell,
interact with multiple target sites (Russell & Hugo 1994). Its
antimicrobial activity results from its combination with, and
alteration of, microbial proteins, with eventually structural
and metabolic disruption (Maillard & Denyer 2006a; Silver
et al. 2006). It has been suggested that once sucient ionic
silver has penetrated within the bacterial cell, recovery is
improbable. It can be noted that the presence of moisture
is required for the penetration of ionic silver within the cell.
At the cell membrane level, ionic silver has been observed
to inhibit the proton motive force, the respiratory electron
transport chain, and to aect membrane permeability
resulting in cell death (Percival et al. 2005; Silver et al. 2006;
Edwards-Jones 2009). e virucidal eect of ionic silver is
thought to occur through an interaction with viral proteins
and or viral nucleic acid (Maillard 2001).
A number of studies have proposed both intracellu-
lar and extracellular explanations to explain the activ-
ity of AgNPs (Morones et al. 2005; Gogoi et al. 2006; Lok
et al. 2006; Banerjee et al. 2010). Silver nanoparticles
up to 80 nm have been shown to be able to penetrate
the inner and outer bacterial cell membrane (Xu et al.
2004). AgNPs of less than 10 nm diameter were observed
to cause cytoplasmic leakage by forming pores on the
bacterial cell wall without aecting extracellular pro-
teins and bacterial nucleic acid (Gogoi et al. 2006). e
release of ionic silver from AgNPs (when it occurs) does
not appear to be responsible for the observed “cidal”
activity of AgNPs (Lok et al. 2006; Su et al. 2009; Miyoshi
et al. 2010). Su et al. (2009) demonstrated that bacte-
ricidal eect of silver nanoparticles immobilized on
a surface was caused by the loss of membrane integ-
rity due to reactive oxygen species, while the energy-
dependent metabolism was inhibited. A combination
of nanosilver and iodine as shown to damage bacterial
cell wall and produced reactive oxygen species causing
oxidation damage in the cell cytoplasm leading to cell
death (Banerjee et al. 2010).
Bacterial resistance to ionic silver
Occurrence of resistance to silver
Silver resistance in bacteria following the use of silver
has been well documented. Probably the rst report of
documented resistance in practice follows the use of
silver nitrate and silver sulphadiazine for burn wound
treatment. Cason et al. (1966) rst reported silver resis-
tance in Pseudomonas aeruginosa associated with burn
wounds. A number of reports highlighting outbreaks of
burn wound infection or colonization by Gram-negative
isolates resistant to ionic silver and silver sulphadiazine
have since emerged; in Enterobacter cloacae (Gayle
et al. 1978), Providencia stuartii (Wenzel et al. 1976),
Pseudomonas aeruginosa (Bridges et al. 1979), Salmonella
Typhimurium (Mchugh et al. 1975) emerged soon after.
Silver-resistance from environmental bacterial isolates
has since been well documented in Enterobacteriaceae
(Hendry & Stewart 1979; Kaur & Vadehra 1986; Starodub
& Trevors 1989, 1990) and in Acinetobacter baumanii
(Deshpande & Chopade 1994).
It has been suggested that exposure to silver might
contribute to the selection of bacteria that are intrinsi-
cally resistant to silver (Wenzel et al. 1976; Bridges &
Lowbury 1977; Haefeli et al. 1984; Silver 2003; Davis et al.
2005).
In the laboratory, high-resistance to silver (>1024
ppm) in Escherichia coli has been produced following
step-wise training (i.e. repeated exposure to increasing
concentration) (Li et al. 1997).
It is interesting that the available reports on the
development of bacterial resistance to silver concern
Gram-negative bacteria. ere is a lack of evidence in
emerging silver resistance in Gram-positive bacteria,
possibly because Gram-positive bacteria are, at least for
some genera, less susceptible to silver (Cason et al. 1966;
Spacciapoli et al. 2001).
Mechanisms of resistance to silver
Since it appears that the lethal eect of ionic silver fol-
lows its penetration into the cell cytoplasm, the main
mechanisms conferring silver resistance involve reduc-
ing ionic silver penetration via a non-specic transporter
(Nies 1999), reducing accumulation (i.e. increasing in
silver eux) (Silver 2003) and reducing its concentration
by increased neutralization and reduction of Ag+ to the
inactive metallic form (Nies 1999).
For example, in a silver-resistant Escherichia coli
produced by stepwise training, active eux and outer
membrane protein changes accounted for the high resis-
tance of the strain to ionic silver (Li et al. 1997). Kaur and
Vadehra (1986) observed a similar silver uptake between
a Klebsiella strain resistant to silver (70 µg/mL) com-
pared to a silver-sensitive parent strain (10 µg/mL). Since
the ionic silver uptake of spheroplasts of both strains was
also similar, the dierence in susceptibility was attributed
to a change in cell membrane composition. e activ-
ity of succinate dehydrogenase was also reduced in the
silver-resistant strain (Kaur & Vadehra 1986). However,
Starodub and Trevors (1989, 1990) observed dierences
in silver binding to and accumulation in Escherichia coli,
between a silver-resistant isolates (1 mM silver nitrate)
and a silver-sensitive construct derived from the isolate
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Silver as an antimicrobial 5
© 2012 Informa Healthcare USA, Inc.
cured of its plasmid conferring silver resistance. e
formation of an inactive, insoluble silver sulphide fol-
lowing the chelation of silver by the sulfhydryl groups
of metal-binding proteins has also been described (Liau
et al. 1997), while exopolysaccharide could be involved
in reducing the concentration of ionic silver (Miao et al.
2009).
Bacterial resistance to AgNPs has been described (Lok
et al. 2007; Samberg et al. 2011; Hsu et al.2010). e exact
mechanisms conferring resistance to AgNPs are likely
to dier in part from mechanisms conferring resistance
to ionic silver since AgNPs has been shown to be eec-
tive against silver-resistant bacteria. Overexpression of
detoxication enzymes and membrane repair related
proteins have been suggested as mechanisms involved
in AgNPs resistance (Simon-Deckers et al. 2009). A
reduction of AgNPs penetration or accumulation might
be explained partly by the interaction of AgNPs with the
outer membrane of Gram-negative bacteria. e pres-
ence of lipopolysaccharide might induce electrostatic
repulsion with negatively charged silver nanoparticles
(Costerton et al. 1974) while phosphomonoester func-
tion group and carboxyl groups could complex with ionic
silver (Guiné et al. 2006).
Transfer of resistance
Silver resistance in bacteria has been found to be
often encoded on plasmid (McHugh et al. 1975; Gupta
et al. 2001; Davis et al. 2005) and has been described in a
number of Gram-negative bacteria such as P. aeruginosa,
Pseudomonas stutzeri, Citrobacter spp., Serratia marc-
escens and Salmonella enterica serovar Typhimurium has
been documented (Silver et al. 2006). It has also on occa-
sions been described on bacterial chromosome (Silver &
Phung 1996, 2005; Gupta et al. 2001).
In silver-resistant S. enterica Typhimurium isolated
from a burns unit, silver resistance was encoded on the
plasmid pMG101, also conferring multi-drug resistance
(Silver 2003). e plasmid contained silCBA that encodes
a resistance nodulation division (RND) eux pump with
homologues to that of AcrB in E. coli (Silver 2003), silE
encoding for periplasmic silver-binding protein, SilE
which bind ionic silver (Silver et al. 2006). SilA is an inner
membrane cation pump protein while SilC an outer
membrane protein (Silver et al. 2006). e silver resis-
tance determinant has been described as unique among
resistance system since it encodes for two energetically
distinct eux pump (Figure 1) (Silver et al. 2006). e sil
genes have been found to occur only on IncH incompa-
bility group plasmids (Silver et al. 2006). e occurrence
of silver encoded plasmid in enteric bacterial isolates
from a hospital was found to exceed 10% (Silver 2003).
In A. baumanii silver-resistance encoded on a 54 kb plas-
mid was transferred successfully to E. coli by conjuga-
tion. e transformed E. coli cells were shown to be more
ecient to eux accumulated silver ions (Deshpande &
Chopade 1994).
Loh et al. (2009) reported that the presence of silver-
resistance genes in methicillin-resistant Staphylococcus
aureus (MRSA; 33 isolates) and methicillin-resistant
coagulase-negative S aureus (MR-CNS; 8 isolates) iso-
lated from wounds and nasal cavities in human and
animals was low (2 /33 MRSA and 1/8 MR-CNS) and
restricted to a single gene (silE). In addition isolates with
the silE genes remain susceptible to a silver-containing
hydrober wound dressing (Loh et al. 2009). Another
study investigating the presence of silver-resistance genes
in 172 isolates from human (112) and equine chronic
wounds (60) reported that only 6 isolates, all Enterobacter
cloacae (2 from human and 4 from horses), possessed
the resistant sil gene cassette (Woods et al. 2009). All the
silver-resistant genes were present extrachromosomally.
e sil gene cassette in these isolates conferred a resis-
tance of > 5 mg/L MIC, compared to a 1.25 mg/L in the
sil-negative strains. It was further reported that a silver-
containing dressing killed the sil-positive and -negative
strains within 30 min, although the sil-positive strains
were overall more resilient to the silver dressing (Woods
et al. 2009).
Plasmid encoded silver resistance is of a particular
concern since plasmid mediated metallic salt resistance
is associated with co-resistance to chemotherapeutic
antibiotics (Mchugh et al. 1975; Gupta et al. 1999b) and
that silver resistance might persist in the clinical setting
(Gupta et al. 2001). is is particularly pertinent follow-
ing the widespread use of silver in hospital products,
devices and environmental surfaces.
Toxicity of silver
Cell and human toxicity
e rst well-known and well-described complication
of silver ingestion or application in human is argyria.
Argyria occurs when subdermal Ag deposits results in
an irreversible gray to blue-black coloring of the skin.
It is the rare result of ingesting large amounts of silver
preparations usually as health stimulants (Russel & Hugo
1994). Argyria is permanent but not physically harmful;
it is however an inherent serious cosmetic problem. e
most familiar human exposure to Ag is from dental amal-
gams that contain 35% Ag (0) and 50% Hg (0) (Dunne
et al. 1997).
e use of ionic silver and silver derivatives for treat-
ment and prevention of infection of burn wounds or
skin grafting has been associated with a number of side
eects such cytotoxicity, staining, methaemoglobinae-
mia and electrolyte disturbance, longer slough separa-
tion time, retardation of wound healing and the possible
inactivation of enzyme debriding agents. e develop-
ment of new dressings that allow the slow but sustained
release of ionic silver while enhancing wound healing
and uid handling is contributing to a decrease in side
eect together with an increase in antimicrobial activity
(Maillard & Denyer 2006b).
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6 J.-Y. Maillard and P. Hartemann
Critical Reviews in Microbiology
Investigations on the toxicity of metal particulates,
including AgNPs, are still in their infancy at this time and
have concentrated on revealing the toxicity and tissue
distribution of silver. Consequently, more comprehensive
studies are required to fully understand the toxicity associ-
ated with metal particulate exposure. AgNPs might present
a potential hazard to human health since they can become
systemically available following exposure as evidenced
by their preferential accumulation within the liver. Silver
accumulates within the liver and this may be associated
with toxicity and inammatory responses. However, the
contribution of the liver to the elimination of silver notably
through the bile and the reticuloendothelial system needs
further investigating. e appearance of argyria, which is
reliant on the accumulation of silver within the skin, has
transpired following silver ingestion, further emphasiz-
ing the propensity of silver to become systemically avail-
able (Johnston et al. 2010). According to these authors it
is apparent that the toxicity of silver particulates depends
on their internalization and oxidative nature, which drives
inammatory, genotoxicity, and cytotoxic events. e tox-
icity of AgNPs might be better controlled by the prevention
of ionic silver leaching and a better design of the AgNPs
impeding penetration into mammalian cells, thus avoid-
ing deposition of silver in the body (Su et al. 2011).
Concentrations of AgNPs (5 µg/mL and 10 µg/mL)
have been shown to induce necrosis and apoptosis of
mouse spermatogonial stem cells (Braydich-Stolle et al.
2005). e toxicity of AgNPs might be mediated by the
concentration of ionic silver released (Miao et al. 2009),
although complexation with cysteine (a strong ionic sil-
ver ligand) may enhance overall toxicity (Navarro et al.
2008). Kim et al. (2009) suggested that oxidative-stress
might be a mechanism involved in the cell toxicity of
AgNPs. e size and morphology of nanoparticles aect
toxicity (Liu et al. 2010).
Environmental toxicity
Accumulation of heavy metal in the environment has
been mentioned by the Agency for Toxic Substances
and Disease Registry (ATSDR 2012) and the European
Commission (1998). Silver may also accumulate in the
environment although to a lesser extent than other heavy
metals.
ere is a general agreement that dissolved silver ions
are responsible for the biological toxic action that is espe-
cially pronounced against microorganisms (Navarro et al.
2008; Choi et al. 2008; Hwang et al. 2008). Silver is present
in the environment primarily as silver suldes and silver
chloride (AgCl1
n
−n) complexes (Cowan et al. 1985; Kramer
1995). Dissolved organic carbon (DOC) and colloid com-
plexes with silver are probably also prevalent (Sujari
& Bowen 1986; Wen et al. 1997). While silver sulde
dominates under reducing conditions, the other silver
Figure 1. Protein products of bacterial plasmid silver resistance genes (from Silver 2003). Reproduced with permission of FEMS Microbiology
Reviews. (See colour version of this gure online at www.informahealthcare.com/mby)
Critical Reviews in Microbiology Downloaded from informahealthcare.com by Cardiff University on 09/03/12
For personal use only.
Silver as an antimicrobial 7
© 2012 Informa Healthcare USA, Inc.
species are more important in oxidizing waters where
sh are likely to reside. e free silver ion (Ag+), which
is undoubtedly the most toxic species of silver, is present
at concentrations worth consideration only in freshwater,
not in brackish water or seawater (Hoogstrand & Wood
1998). e existence of various silver species depends on
physicochemical environmental conditions.
e silver ion is one of the most toxic forms of a heavy
metal, surpassed only by mercury and thus has been
assigned to the highest toxicity class, together with cad-
mium, chromium (VI), copper, and mercury (Doudoro
& Katz 1953). Annual silver released to the environment
from industrial wastes and emissions has been estimated
at approx. 2,500 tonnes, of which 150 tonnes gets into
the sludge of wastewater treatment plants and 80 tonnes
is released into surface waters (Smith & Carson 1977;
Petering 1984).
Obviously, the perception of high silver toxicity has
long been due to the fact that most laboratory toxic-
ity experiments tested AgNO3, which readily dissolves,
releasing the highly toxic free Ag+ ion (Ratte 1999).
Because of enhanced heavy metal analyses and experi-
mental techniques (e.g. the ultraclean technique) (Benoit
et al. 1994; Cutter & Radford-Knoery 1994; Willie et al.
1994; Shafer et al. 1998; Schildkraut et al. 1998), a better
understanding of total silver concentrations in various
environmental compartments and, in particular, of silver
speciation has emerged.
Silver sulde, silver thiosulfate complex and silver
chloride complexes were tested and compared with
free silver ion for their toxic against fathead minnow
(Pimephales promelas) (Le blanc et al. 1984). Silver chlo-
ride complexes, silver sulphide and silver thiosulfate
complex were about 300 times, at least 15,000 times, and
more than 17,500 times less acutely toxic, respectively,
than free silver ion. e estimated maximum acceptable
toxicant concentrations (MATCs) determined from the
embryo larval tests with silver sulde thiosulfate complex
were greater than 11 mg/L (as total silver). e MATC
previously reported for free silver ion from tests with
rainbow trout (Salmo gairdneri) was greater than 0.00009
but less than 0.00017 mg/L. ese dierences in acute
toxicities and the dierences of ve orders of magnitude
in the MATC values are attributed to the inuence of
chemical speciation on the eects of silver in the aquatic
environment. us, the speciation of silver is an essential
factor in its potential to aect sh and, presumably, other
aquatic life, and therefore should be considered in envi-
ronmental risk assessment.
Research evidence demonstrates that apparent toxic-
ity is related to individual silver species rather than total
silver concentration. In natural waters, where silver con-
tamination can be of concern, evidence of toxicity from
the dissolved silver ion is generally less than in laboratory
tests because of the rich opportunities for possible cova-
lent, complexing, or colloidal hinding silver encounters
with a variety of reactant (Adams & Kramer 1998; Shafer
et al. 1998; Schildkraut et al. 1998).
e majority (>94%) (Shafer et al. 1998) of the silver
released into the environment will remain in the soil or
wastewater sludge at the emission site. A portion, the
toxicity of which should not be underestimated, will be
transported for long distances by air. Silver from indus-
trial and public wastewater is bound to the activated
sludge of wastewater treatment plants. e remaining
portion of the silver enters the aquatic environment
and, under freshwater conditions, it will be immediately
adsorbed to sediments or suspended particles. Silver is
kept in solution by colloidal and complex material will
be transported downstream and enter lakes, estuaries
or the sea. However, there is no evidence of substantial
biomagnications of silver in aquatic organisms to date
(Bard et al. 1976; Terhaar et al. 1977; Biddinger & Gloss
1984; Forsythe et al. 1996; Galvez et al. 1996).
Gaps in knowledge
Testing the efficacy of silver-containing products
ere are many products that incorporate, or are impreg-
nated or coated with silver or AgNPs (Table 2). e meth-
odologies to test the antimicrobial ecacy of fabrics and
surfaces are based on the principle of diusion from the
coated/impregnated surface through liquid or moisture
by immersion of the material in a broth, or by placing the
material onto a nutrient surface conducive for micro-
organisms and antimicrobials. Most environmental
surfaces or textile would contain very little moisture and
with this in mind, the current standard ecacy tests such
as the ISO 22196 (2011) or JIS Z 2801 (2000) do not reect
the usage of the materials in conditions that reect the
practice and may provide an overestimation of their anti-
microbial ecacy.
e parameters used for testing the antimicrobial
ecacy of antimicrobial surfaces are paramount. For
example, in a number of studies investigating the activity
of silver dressings against bacterial biolms, results from
in vitro experiments (Percival et al. 2008; Shahverdi et al.
2007; omas & McCubbin 2003; Yin et al. 1999) diered
dramatically the results obtained from in vivo studies
(Heggers et al. 2005). However, experimental param-
eters do not explain all the dierences in results between
in vitro and in vivo studies. An in vitro study mimicking
conditions found in situ observed dierences in anti-
microbial ecacy of a number of silver dressing against
bacterial biolm (Kostenko et al. 2010). Nevertheless, the
use of a test reective of the usage conditions of the anti-
microbial products would be a huge improvement from
the current situation.
Silver resistance
e distinction between silver-sensitive and silver-
resistant bacteria needs to be better claried notably in
relation with experimental parameters such as concen-
trations of halides. e clinical implication of silver-resis-
tant bacteria and the presence of silver-resistance genes
in environmental isolates need to be established.
Critical Reviews in Microbiology Downloaded from informahealthcare.com by Cardiff University on 09/03/12
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8 J.-Y. Maillard and P. Hartemann
Critical Reviews in Microbiology
e presence of plasmid mediated silver resistance is
of concern (Gupta & Silver 1998). Such transferable resis-
tance has been associated with the emergence of multi-
drug resistant microorganisms, although the extent of such
transfer, and the subsequent associated risks, has not been
appropriately assessed in the healthcare environment.
e bulk of evidence of emerging silver-resistance in
bacteria concerns Gram-negative species. We are not
aware of publications on the development of silver–resis-
tance in gram-positive. is could be a serious omission
owing the importance of Gram-positive bacteria, notably
staphylococci, in human diseases.
Overall the mechanisms involved in silver resistance
and their occurrence have been little studied; the gap
in knowledge is particularly apparent with resistance to
AgNPs. is is particularly pertinent when one considers
the number of products containing AgNPs.
Silver mechanisms of action and toxicity
It is clear that AgNPs applications will increase in the
future as the demand for applications is there. ere is a
need for a better understanding of these parameters on
the ecacy and toxicity of AgNPs because of the wide
variety in size, concentration, shape, materials, polymer
and surfaces used.
Further work is needed to understand better the
interactions of AgNPs with dierent bacterial cell types
and other microorganisms. Bactericidal eect is likely to
be multifactorial and the eect of external factors such
as the presence divalent cations may play an important
role in the ecacy of silver. More evidence of the mecha-
nisms of action of AgNPs attached on a surface, without
the leaching of ionic silver is needed together with a bet-
ter understanding of the generation of reactive oxidative
species in the mechanisms of action of AgNPs.
e bioavailability of AgNPs in the environment is
paramount to understand potential toxicity, unfortu-
nately this information is lacking.
Further considerations
Silver has been used for its antimicrobial activity for
centuries. Advances in polymeric sciences has provided
a renewed interest of silver for some medical applica-
tions such as dressings for which tangible benets such
as increased activity and reduced side eect have been
observed. e AgNPs market is a buoyant one and is
expected to expand rapidly (Gottschalk et al. 2010). It has
been estimated that the market size for AgNPs was 320 T/
year in 2009, which far exceeds (×10000) the volume of
bulk silver (Gottschalk et al. 2010).
e wide use of silver and AgNPs (at a low concen-
tration) in other applications such as fabrics, textiles
and other surfaces may appear controversial and will
remain controversial as long as the benets have not
been addressed, measured and justied appropriately.
A recently published report on AgNPs usage highlighted
the concern that the over use of AgNPs might lead to
emerging silver-resistance but also resistance to anti-
biotics. A panel of experts agrees that the use of AgNPs
should be better regulated (Crocetti & Miller 2012).
While the benets of silver are widely recognized, little
attention has been paid to the potential risks of continu-
ous use of silver and its possible contribution to microbi-
cide and antibiotic resistance needs to be evaluated.
Very few countries have a framework in place to regu-
late the sale of treated articles. In the EU, the issues or arti-
cles with internal and external eect are very complicated.
It has been agreed that if an article has an external eect,
it should be regarded as a biocidal product, but precisely
how to do this is not agreed. e preferred answer seems
to be to regulate the active substance, or formulation used
and to view the article as a delivery system.
e US EPA classied silver ions and colloidal silver as
a microbicide. Colloidal silver is on the unapproved EFSA
list of food supplement and as such it cannot longer be
legally sold as food supplement in the EU. Manufacturers
have thus relabeled their colloidal silver-based product
as “water disinfectants.
Declaration of interest
e authors report no conicts of interest.
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... Before the discovery of antibiotics, silver nitrate solution was used as eye drops for new born children to avoid conjunctivitis [12,13]. Also, silver compounds were used as an antibiotic coat for medical devices [14][15][16][17]. Ag and its compounds have promising applications in wound dressing and as cream to treat external infections [14][15][16]. ...
... Also, silver compounds were used as an antibiotic coat for medical devices [14][15][16][17]. Ag and its compounds have promising applications in wound dressing and as cream to treat external infections [14][15][16]. For example silver sulfadiazine (SSD) and nanosilver compounds have great interest in wound dressing to treat external infections [11,17,18]. ...
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The new homoleptic [Ag(5-nitroquinoline)2]ClO4 centrosymmetric complex was synthesized and its structure aspects were investigated. It crystallized in the monoclinic space group C2/c with a = 10.0279(2) Å, b = 13.2295(3) Å, c = 14.7552(3) Å and β = 102.1050(10)° while V = 1913.96(7) Å3 and half molecule as asymmetric formula. The Ag(I) is coordinated with two symmetrically related 5-nitroquinoline ligand units via the heterocyclic nitrogen atom with Ag-N distance of 2.146(6) Å and N1-Ag-N1 angle of 173.0(3)°. The two coordinated 5-nitroquinoline have anti configuration to one another and the perchlorate anion is set freely uncoordinated. The only Ag…O interactions are Ag1…O2 (3.110 Å) and Ag1…O1 (3.189 Å) which occur between the Ag(I) in one complex unit and the O-atoms from the NO2 groups in the neighbouring complex units. Hence, Ag(I) has coordination number 2 and its coordination geometry is slightly bent. Hirshfeld analysis indicated that the O…H (51.1%), C…H (11.8%), H…H (10.8%) and C…C (8.9%) contacts are the most common. Exclusively, the O…H, C…O, N…O, O…O and Ag…O contacts are the only shorter contacts than the vdWs radii sum of the interacting atoms. The studied Ag(I) complex showed good antimicrobial activity. It has comparable antibacterial activity against P. vulgaris (MIC = 9.7 μg/mL) and S. aureus (39.1 μg/mL) to Gentamycin (4.8 and 9.7 μg/mL, respectively) while better antifungal activity against A. fumigatus (MIC = 39.1 μg/mL) than Ketoconazole (156.2 μg/mL).
... Silver is known to be an effective antibacterial agent and has been used in surgical procedures for many centuries [28]. Silver-based materials provide increased resistance toward bacteria, which results in low bacterial susceptibility, and therefore Ag ions can be integrated into several biomaterials to improve their antibacterial efficacy [29][30][31]. Recent reports show that the addition of Ag 2 O in BAGs results in the reduction of microbial contamination and promotes rapid antibacterial mechanism [32][33][34]. ...
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This article discusses the effect of silver oxide (Ag2O) on structural changes, apatite-forming ability, and bioactivity during addition onto the fluorophosphate glass (FPG) network. The foremost objective of silver incorporation on to fluorophosphate glass is to enhance the antibacterial efficacy of glass material which can be widely used as implants to minimize the post-surgical infections. Silver-added fluorophosphate glasses (AFPGs) with composition of 48P2O5–29CaO−(20−x)Na2O–3CaF2−xAg2O (x = 0, 0.3, 0.6, 0.9, and 1.2 mol%) were prepared using conventional glass-melting method followed by rapid quenching technique. The in vitro apatite-forming ability of AFPG was evaluated by immersing the samples in simulated body fluid (SBF) for 21 days. The pH variations of the SBF solution were noted throughout the in vitro study and plotted to estimate dissolution mechanism. The structural properties and compositional estimation of AFPG samples before and after in vitro study were analyzed using X-ray diffractometer, Fourier transform infrared spectroscopy, scanning electron microscopy, energy-dispersive X-ray spectroscopy, and X-ray photoelectron spectroscopy. Cytotoxicity of the prepared AFPG samples was evaluated using MTT assay. The bacteriostatic effect of AFPG samples were studied using different strains of bacteria such as Escherichia coli, Pseudomonas aeruginosa, Klebsiella pneumonia, Staphylococcus aureus, S. epidermidis, and S. mutans. The obtained peaks from XRD analysis at 28.12°, 31.73°, 46.71°, 29.11°, 32.25°, 51.59°, and 67.49° confirm crystalline nature and apatite formation on the glass surface. The attained characteristic FTIR peaks at 560 and 600 cm ⁻¹ shows the presence of apatite groups of vibration. The SEM image infers the spherical structure on the glass surface representing the presence of apatite layer and the EDAX graph shows the elemental composition of the prepared glass surface. From the present study, it was noted that glass sample containing 0.9 mol % of Ag2O enhanced apatite formation, was less cytotoxic and showed better antibacterial activity. Thus it can be inferred that AFPG0.9 sample can play a significant role in biomedical applications.
... Another mechanism of inhibitory action is the induction of oxidative stress due to the generation of reactive oxygen species (ROS), including free radicals. These can damage the cell membrane, make it porous, denature proteins, and inhibit cellular respiratory enzymes, leading to cell death [60][61][62]. EuNPs may employ one or more of these mechanisms to inhibit microbial growth. ...
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... There have also been reports on the safety of silver in humans. Medical applications of silver include wound dressings, creams, and antibiotic coatings for medical devices [28][29][30]. Wound dressings containing silver sulfadiazine or silver nanomaterials are sometimes used to treat external infections [31][32][33]. Silver coatings on endotracheal tubes have been used to reduce the incidence of ventilator-associated pneumonia [34]. ...
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... The SPR peak at 422nm, which is comparable to earlier consulted research, was used to confirm AgNPs synthesis in this work (11). Ag+ ions and silver-based compounds, such as AgNPs, exhibit apparent antibacterial properties against multidrug-resistant organisms (12). Four distinct bacteria were chosen as representative species to test the antibacterial impact of AgNPs. ...
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Silver is generally solubilized as the tightly bound thiosulfate complex during processing of photographic paper and film. Data are presented showing that this silver thiosulfate complex is not harmful to secondary waste treatment plants and is much less toxic than ionic silver to other aquatic organisms. The data show that silver thiosulfate in secondary biological waste treatment plants is degraded to insoluble silver sulfide, which is removed in the sludge. Thus, essentially all of the silver from photoprocessing is compatible with biological treatment. Analyses have shown that silver concentrations are not excessive in the Genesee River or Lake Ontario near Rochester, N. Y., despite a concentration of photographic manufacturing and processing facilities in the area.
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AFTER thermal burns local and systemic infection, especially with Pseudomonas aeruginosa , is a major cause of death. The use of soluble sodium sulfonamides in wounds and burns was investigated during World War II, 1 and in studies of extensive burns, 2 topical antibacterial therapy was combined with treatment for the burn wound by using a neutralized mixture of tannic acid and sodium sulfadiazine. Although the results were good, emphasis shifted to the role of sodium salts in systemic therapy in an era of disbelief in the efficacy of local antibacterial therapy. As predicted in 1952 by Meleney, 3 there is now a renaissance of topical antibacterial therapy with the introduction of dilute silver nitrate solutions 4 and mafenide-containing ointments. 5 Both agents are effective in burn wound sepsis, especially that caused by P aeruginosa , but both also produce characteristic fluid and electrolyte alterations. The hypotonic (29.4 millimol/liter) silver nitrate solution
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Enterobacter cloacae sepsis was found in 15 burn center patients in 1976, of whom 13 died. Nine of the deaths occurred in the first 60 days. The Burn Center isolates were resistant to silver sulfadiazine (AgSD) in agar cup-plate tests and confirmed by tube dilution tests. Hospital, non-burn isolates of E. cloacae were sensitive to AgSD. All E. cloacae isolates were sensitive to mafenide acetate (MA) in the agar cup-plate tests, but this was not confirmed by the tube dilution tests. The agar cup-plate susceptibility test is a simple, rapid and effective technique for determining resistant and sensitive isolates of E. cloacae. Patients who were changed from AgSD to MA because of resistant E. cloacae infection did not have improved survival. An animal study showed that AgSD was ineffective against this strain of E. cloacae and that MA was more effective than AgSD when applied 24 hr postburn but neither were effective at 48 hr postburn. MA was bacteriostatic but not bactericidal with this E. cloacae strain.
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WITHIN THE LAST 30 years the mortality from burns and scalds has fallen. However, this change is largely relatable to the reduction of the death rate from burns and scalds covering 60% or less of the body's surface, and the more especially from those covering less than 50% (Table 1). Although burns covering more than 65% of the body are still regularly but not always fatal, the fact that, on a graph, the relationship of mortality to the size of burn is ogival is reason to believe that ultimately even burns covering 90% to 100% of the body will not always be lethal. Traumatic shock is no longer a significant contributing factor to the mortality rate. Even the shock attending thermal injuries covering 50% to 85% of the body is successfully treated by the provision of a sufficient quantity of a balanced solution of sodium salts, such as Hartmann's solution.*