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www.deroyal.com

Antimicrobial IV Dressings:

Algidex

versus Chlorhexidine Gluconate

ALGIDEX AG

IV PATCH

silver alginate catheter dressing

WHITE PAPER

Approximately 250,000 central line-associated bloodstream infections are acquired each year in US hospitals with death

occurring in 28,000 cases [1], [2]. The average cost to treat each patient is estimated to be $29,156 and places a $2.3 billion

burden on the United States healthcare system each year [1]. Additionally, the Centers for Medicare and Medicaid have

classiﬁed central line-associated blood stream infections as “never events” preventing hospitals from obtaining reimbursement

for treating these infections, further amplifying the burden on the healthcare system [3]. The prevalence and designation of

central line-associated bloodstream infections as “never events” highlights the importance of preventing these nosocomial

infections. To combat these infections, intravenous (IV) dressings have been developed to prevent blood borne infections

originating from intravenous lines.

Chlorhexidine Gluconate (CHG) impregnated dressings and silver alginate dressings represent the two primary classes of

antimicrobial IV dressings. CHG is a common antiseptic used in numerous medical applications for its robust antibiotic effect

on bacteria. Silver alginate dressings obtain their antibiotic properties through the release of silver ions that have been well

documented for antiseptic applications since ancient times. DeRoyal has developed a novel wound dressing called Algidex

that incorporates maltodextrin into the silver alginate matrix. The purpose of this paper is to summarize the antibacterial

mechanisms of action, to compare the potential for antibacterial resistance and to compare the safety of CHG and silver for

use in humans to highlight the advantages of the Algidex

IV patch for patients with catheter access sites.

Mechanisms of Action for Antibacterial Properties of CHG and Algidex

The mechanisms of action for the antibiotic properties of CHG, silver, and maltodextrin are important to the understand of the

beneﬁts and risks associated with each compound in preventing IV line associated infection. Chlorhexidine (CHL), discovered

in 1954, is a strong antiseptic with widespread use in medicine due to its strong bacteriostatic, bactericidal, and fungicidal

activity. Since CHL is insoluble in water, clinical solutions are formulated with gluconic (CHG) or acetic acid (CHA) to disinfect

patient skin, medical equipment, and surfaces in medical centers. The antimicrobial properties of CHL arise from the net

cationic charge of the molecules that permits binding to the negatively charged phospholipids on the bacterial cell disrupting

the cell wall [4]. Once the cell wall has been ruptured, the CHL molecule crosses the cell membrane and lyses the cell body by

binding to negative charges on the intracellular membrane. This action leads to apoptosis of the bacterium. This antibacterial

mechanism acts rapidly causing cell death in 20 seconds [5]. Clinical studies have also shown that the CHL molecule binds to

skin proteins allowing the slow release of bound CHL thus prolonging the duration of the antibacterial environment [6]; however,

this interaction with human cells can lead to individuals develop sensitivities or allergies to CHL that can cause adverse

reactions and affect skin integrity.

Antimicrobial IV Dressings: Algidex

AG ®

versus Chlorhexidine Gluconate

ALGIDEX AG

IV PATCH

silver alginate catheter dressing

Figure 1

Figure 1: Zone of inhibition tests results comparing Algidex IV dressing to CHG IV dressing*

Algidex

combines the antibacterial properties of silver ions and maltodextrin to create a unique multipronged attack on

bacteria. Similar to CHG, silver ions bind to negative charges on the bacteria cell wall to disrupt the wall integrity allowing silver

ions to diffuse across the cell membrane. Once inside the cell, the silver ion binds to intracellular structures interfering with

several bacterial processes that result in cell death of the bacterium. These processes include disruption of the cell membrane,

interfering with organelle function, disrupting organelle membranes, impairing cellular respiration, denaturing intracellular

enzymes, RNA, and DNA, and disrupting metabolic events modulated by other ions [7], [8]. The maltodextrin incorporated into

the Algidex

IV dressing matrix has been demonstrated to create an acidic environment that is not conducive to bacteria

survival, and upsets osmotic gradients which disrupt the cell wall and cell membrane [9], [10]. These properties of maltodextrin

are thought to increase the antibacterial properties of Algidex

IV patch that is designed to act as an anti-bacterial barrier to

bacteria that commonly infect IV access points. Figure 1 demonstrates that Algidex

IV dressing is equivalent at inhibiting

bacterial growth for MRSA and standard Staph aureus compared to a CHG impregnated IV dressing, and that Algidex

superior to the CHG impregnated IV dressing at inhibiting the gram negative bacteria Pseudomona aeruginosa as determined

from standard zone of inhibition tests. A similar independent study demonstrated that the Algidex

IV patch exhibits similar

antibiotic properties to the same CHG impregnated IV dressings and was more effective than other silver dressings compared

in the study [11]. A clinical study in very low birth weight infants demonstrated that the Algidex

IV dressings decreased

infection rates by 45.8% in patients with central lines compared to no antimicrobial dressing, an important ﬁnding considering

CHG is cautioned against use in neonates due to porous fragile skin [12]. Furthermore, Algidex

has been shown to be safe

in neonates as no adverse events were reported for Algidex

IV dressings in two studies involving 114 NICU patients [12],

[13]. The wound healing properties of Algidex

dressings have recently been demonstrated through effective treatment of

chronic tracheostomy ulcers in PICU patients without causing adverse skin reactions [14]. These clinical ﬁndings support the

clinical effectiveness of Algidex

dressings and support Algidex

IV dressings as a viable alternative to CHG impregnated

IV dressings. To fully appreciate the advantages of the Algidex

IV patch over CHG impregnated dressings, a review of

potential bacterial resistance and safety in humans of each dressing is warranted.

Potential bacterial resistance to CHG and Algidex

Microbial resistance to antimicrobial agents has been a major concern for clinicians and scientist since the advent of antibiotics

in 1937. The wide spread use of antibiotics in medicine has led to an explosion of antibiotic resistant strands of bacteria that

led to superbugs immune to powerful antibiotics that thrive in and plague medical centers throughout the world. The resistance

of bacteria to antibiotic agents developed from native genetic elements in bacterium that mutated and rapidly evolved to

survive antibiotic exposure. In fact, several years before penicillin was introduced for clinical use, scientist identiﬁed the ﬁrst

antibiotic resistance enzyme, penicillinase, that neutralized penicillin before damaging and killing the targeted bacteria. Following

the introduction of penicillin to the clinic, antibiotic resistance quickly spread among different species of bacteria leading to

widespread resistance through transmission of genetic material via bacterial plasmids and up-regulation of self-preserving

genes [15]. Scientists have realized that widespread antibacterial resistance is due to a number of contributing factors that

include the inability of antibiotics to kill all individual bacteria cells, through exposure of bacteria to non-lethal levels of antibiotic

molecules, and the unfortunate conglomeration of different bacterial strands that naturally occurs in medical centers transferring

genetic material. These realizations motivated research that led to the development of modern artiﬁcial antiseptics like CHL to

combat resistant bacteria that colonize most modern medical centers; however, scientiﬁc research is starting to indicate that

bacteria are gaining resistance to these agents through similar mechanisms that foster resistance to antibacterial drugs. The

speciﬁc mechanisms of bacterial resistance to CHG, silver, and maltodextrin and potential for clinical relevant resistance will be

brieﬂy discussed.

Potential bacterial resistance to chlorhexidine

Chlorhexidine is the current antiseptic of choice in the clinical community due to its rapid bactericidal mechanisms; however,

this widespread use has led to the identiﬁcation of several genetic markers indicating antibacterial microbes are developing

resistance to CHL. Several studies and review articles have highlighted the presence of resistance mechanisms to CHL in

bacteria strains obtained from clinical isolates and clinical professionals[16]–[19]. Most research on bacterial resistance to CHL

has focused on identifying the presence of efﬂux proteins that remove multiple types of antimicrobial molecules, including CHL,

from the intracellular space of bacteria [17], [18]. In total, 11 known efﬂux proteins have been conﬁrmed to be transport CHL

out of the bacteria causing the minimal inhibitory concentration for CHL to increase in a given strand of bacteria [17]. A review

by Horner et al. cites 18 studies that have identiﬁed presence of multidrug efﬂux genes in bacteria isolates obtained from the

clinical environment and hospital personnel. Each of these studies demonstrated a decrease in susceptibility to CHL compared

to standard wild type bacteria [17]. A study from a single hospital in Taiwan demonstrated a progression of increased resistance

in bacteria isolates and increased prevalence of resistance in individual strands over 15 years (1990 – 2005, every ﬁve years)

[17], [19]. Wang and colleagues hypothesized that the increased resistance and increased prevalence of resistance was due to

increased usage of CHL in hospital units. This hypothesis was supported by identifying an increase in the percentage of MRSA

isolates that had a minimal inhibition concentration > 4 mg/L from 1.7% to 46.7% during the 15 year duration of the study [19]. Vali

et al. performed extensive research to identify the frequency of biocide genes and study the effects of CHL exposure on clinical

strains of MRSA [18]. Experiments designed to simulate conditions associated with surface disinfection demonstrated that CHL

was less effective on clinical strains compared to control strains not previously exposed to CHL. Additionally, minimal effects

of CHL were observed on control and clinical isolates following a CHL residual test designed to simulate residuals that may be

present on surfaces in the hospital. These results demonstrate that clinical isolates have acquired CHL resistance features and

establish a plausible method for bacteria naïve to CHL to develop resistance. This study also identiﬁed an increased resistance

to antibiotics in control strains of bacteria following the CHL residue test suggesting CHL exposure in the hospital environment

may evoke increased antibacterial resistance in bacteria that survives CHL disinfection. Vali and colleagues conclude that

reduced susceptibility to CHL is a serious concern and stresses the importance of continuously assessing the susceptibility

of clinical MRSA to CHL exposure to evaluate the protocols designed to prevent nosocomial infections at individual medical

centers[18].

The review by Horner et al. and the studies by Vali et al. and Wang et al. demonstrate that current well established resistance

mechanisms are being adapted by bacteria to contend with CHL and other antiseptics; however, it was not until recently

that a speciﬁc bacterial protein was identiﬁed that speciﬁcally functions to remove CHL from bacteria. Hassan et al. recently

characterized a family of CHL efﬂux proteins originally identiﬁed in Acinetobacter buamannii clinical isolates that have been shown

to survive exposure to clinically relevant CHL concentrations of at least 1%. The new class of CHL efﬂux proteins was identiﬁed

through a whole-genome microarray that showed an unidentiﬁed protein was overexpressed following CHL exposure. The

researchers transfected the gene to encode for this protein into E. coli and demonstrated that the transfected line had increased

resistance to CHL compared to control E. coli conﬁrming the role of the protein. Additional experiments utilized tryptophan

ﬂuorescence quenching to demonstrate the speciﬁcity of the protein to exclusively bind CHL by comparing ﬂuorescence levels

induced by CHL to 11 additional antimicrobial compounds [16]. While not addressed in the paper, the authors inferred in a press

release that the clinical isolates used in this study originated from medical facilities in Iraq and Afghanistan that treated injured

soldiers where A buamannii was observed to develop superbug antibiotic resistance, and cite its ability to survive exposure to

disinfectants like CHL as the primary reason for developing marked antibiotic resistance [20]. Clearly, these studies summarize

a continuous increase in bacterial resistance to CHL and highlight the risk of widespread use of CHL in the clinic without proper

controls to prevent bacteria from developing effective resistance to CHL.

The clinical relevance of the documented bacterial CHL resistance in clinical isolates is heavily debated in the medical community.

The primary reason for this debate is limited documentation of catheter associated blood infections that resulted from CHL

resistant gram positive bacteria commonly implicated in nosocomial acquired infections; however, there are numerous reports

of nosocomial catheter-associated bloodstream infections resulting from CHL contaminated with gram negative bacteria. The

most commonly cited bacteria associated with contaminated CHL solutions that cause catheter related bloodstream infections is

Burkholderia cepacia (formerly Pseudomonas cepacia) [21]–[24]. In each of these epidemic reports, the outbreak was determined

to be caused by bacteria present in puriﬁed water used to dilute high concentration CHL solutions to concentrations that ranged

between 0.5% to 2.5% that were used to disinfect catheter access sites. Rose et al. showed that the MIC and MBC for CHL to

inhibit B. cepacia was greater than 100 mg/L demonstrating signiﬁcant resistance of this bacteria to CHL [25]. The four epidemic

reports combined with Rose et al. demonstrates that CHL is not an effective antiseptic against all bacteria species.

Archomobacter xylosoxidans have also been shown to cause catheter related bloodstream infection through contamination of

CHL. The ﬁrst report on an outbreak of catheter-related bacteremia due to A.xylosoxidans contamination of CHL occurred in a

hemodialysis unit where the disinfectant was used to clean vascular access point. In this case, the bacteria were localized to an

atomizer used to spray CHL on the skin before placement and during maintenance of dialysis catheters. Testing of the ionized

water used to dilute the CHL from 5 to 2.5% were negative for bacterial growth indicating that the bacteria had colonized

directly into the atomizer that contained the CHL [26]. This report represented the second study to implicate contaminated

CHL in a delivery vessel and the ﬁrst to implicate A xylosoxidans in causing bloodstream infections [26], [27]. An outbreak of

A xylosoxidans infection was also described in a neonatal care unit that was attributed to CHL used to disinfect skin. In this

report, 52 patients were determined to be colonized with CHL resistant bacteria and 8 developed an infection. Five of the eight

had positive blood culture samples and the other three had positive cerebral spinal ﬂuid cultures. All infections resolved with

appropriate antibiotic treatment and no deaths were attributed to the infection. The bacteria was found to be colonized in all

vessels containing the antiseptic and on one faucet in the unit leading the authors to hypothesize that the contamination of CHL

occurred when staff washed the exterior of the CHL vessels [28]. This report highlights the importance of a multitier approach

to infection control. The report indicates that CHL was heavily used in the NICU but not in other areas of the hospital which was

offered as a reason why the infection epidemic was contained in the NICU.

Gram-positive bacteria have yet to be positively identiﬁed to have clinically relevant resistance to CHL, yet concern in the

medical community is increasing that these bacteria will lose their CHL susceptibility. A recent study in a pediatric oncology unit

investigated the increased resistance and tolerance of Staphylococcus aures to antimicrobials and antiseptics. An epidemiology

study was conducted on all patients with S aures infections from 2001 to 2011 to determine trends associated with infection and

disease type. Additionally, all isolates obtained during this period were analyzed for the presence of qacA/B genes that encode

for efﬂux channels associated with CHL removal. The study found that the most common infection type was bloodstream

associated (85/213) with 84.7% involving a catheter (72/85). Prevalence of the qacA/B gene was initially found to be present

in 7.6% of 156 isolates tested at qacA/B emergence in 2007; however, by the end of the study in 2011, 22.2% of the isolates

had obtained the qacA/B gene. The authors indicate that the percent increase in qacA/B positive isolates signiﬁcantly increased

each year, and found that the increase in CHL resistance was correlated with increased infection in patients that received

hematopoietic stem cell transplant (HSCT) or had acute myelogenous leukemia (AML). Additionally, isolates that obtained

the qacA/B were found to gain resistance to ciproﬂoxacin commonly used to treat infections in the unit. Interestingly, the

qacA/B gene was not detected until two years after the unit adopted CHL as the antiseptic of choice for disinfecting the skin

prior to placement of a central venous line or peripheral arterial catheter. Although qacA/B prevalence occurred only after the

introduction of CHL to the unit, overall infections from S. aures did decreased during the study suggesting CHL had a positive

impact; however, the authors note that increased resistance to CHL is concerning and state that the full clinical signiﬁcance is

not understood. A major concern raised by the authors was the increase in proportion of infections in AML and HSCT patients,

the patients with the highest exposure to CHL[29]. While heavy CHL usage in these patients could not be directly implicated, this

study is the ﬁrst to provide statistically relevant evidence that supports CHL resistance as a causality of S aures blood stream

infections.

The history that describes the development of bacterial resistance to CHL is disconcerting and is similar to the development

of antibacterial resistance that has become widespread. At the discovery of CHL, there was no known resistance to the

molecule; however, 61 years later, scientists are discovering that bacteria are slowly developing resistance to CHL through

similar mechanisms that gave rise to the antibacterial resistant superbugs. Alarmingly, the majority of these studies reporting on

CHL resistance have been published in the last 10 years and corresponds with the increased adoption of CHL for clinical use.

Bacterial resistance to CHL will continue to increase with heavy application of CHL in the clinic, especially if medical centers do

not adopt additional antimicrobial strategies to combat infection.

Potential bacterial resistance to silver

Silver is the primary antimicrobial component of the Algidex

IV patch. Silver has been employed as an antimicrobial agent

in infection control since ancient times as a method to disinfect water and to treat infections [30]. As with any biocide, bacteria

exposed to silver can develop resistance mechanisms against future exposure due to selective pressure placed on the bacteria

population through similar mechanisms discussed for CHL. The increased use of silver in the medical environment has raised

concerns of bacteria developing a resistance to silver. Similarly to CHL, a number of studies have identiﬁed strands of bacteria

that have developed a resistance to silver [31]–[36]; however, other studies have demonstrated that bacterial silver resistance is

rare and transmission of genetic information for resistant mechanism is difﬁcult [30], [37]–[41].

There are two known primary mechanisms through which bacteria can gain resistance to silver, active efﬂux and non-active

periplasmic proteins. Active efﬂux proteins are encoded by qac genes similar to the qacA/B gene associated with increased

resistance to CHL, and have been documented in several studies [36], [41], [42]. The active efﬂux protein is embedded in the

cell wall of the bacteria and functions to remove silver before it can cross the cell membrane. Efﬂux proteins actively transport

silver ions out of the cell either through an energy dependent ATPase mechanism or a chemiosmotic cation/proton antiporter

[42]. Non-active periplasmic proteins are mediated by genes found in bacterial plasmids and functions by binding ionic silver

rendering it inactive [36], [41], [42]. The only conﬁrmed plasmid to contain genes that encode proteins that bind silver is pMG101

[36]. Plasmid pMG101 was originally isolated from bacteria that caused an outbreak of antibiotic/silver resistant Salmonella

typhimurium and contains nine genes in three transcription units speciﬁc to silver resistance [31], [36]. A separate study has

shown that the pMG 101 plasmid can be transferred to E. coli in laboratory conditions, increasing bacterial resistance to silver

via periplasmic proteins [43]. Besides the studies summarized here, the exact mechanisms responsible for bacterial silver

resistance are unknown and require additional research before the full scope of bacterial resistance to silver is fully understood.

Bacterial resistance to silver has been reported sporadically since the advent of silver nitrate products applied to burns in the

1970’s. Despite these isolated reports of silver resistant bacteria; there is little clinical evidence that support emerging clinically

relevant bacterial silver resistance that is similar to the resistance seen for antibiotics and the emerging resistance to other

antiseptics like CHL. Recent studies aimed at identifying silver resistant genes in clinical isolates have demonstrated the rarity

of silver resistant genes in antibiotic resistant bacteria [37], [39]. Percival et al. screened 112 bacterial isolates obtained from

diabetic foot ulcers in one clinic for silver resistance genes. The study found that only two isolates of Enterobacter cloacae

contained silver resistant genes, but noted this bacteria species is rarely implicated in wound infections. Furthermore, application

of a silver-containing dressing to the isolated E cloacae exhibiting silver resistance genes killed all strains following 48 hours of

exposure. All other isolates, including known wound pathogens (24 isolates of S aureus and 9 isolates of P aeruginosa), did

not contain genes that encode for silver resistance [37]. Loh et al. investigated the prevalence of silver resistant genes in MRSA

(n=33) and methicillin-resistant coagulase-negative staphylococci (MR-CNS, n=8) isolates obtained from nasal and wound

sources in both humans and animals. Only three isolates in the study were found to contain a silver resistance gene and all three

isolates were found to be susceptible to clinically relevant levels of silver exposure [39]. Both of These studies demonstrate that

the prevalence of silver resistance genes is low and that the presence of silver resistant genes does not necessarily translate to

protection from silver when the resistant bacteria is exposed to therapeutic levels of silver ions.

The use of silver in modern medicine has steadily increased since the original application of silver nitrates in burns. Silver is used

to control and prevent infection in a variety of applications that includes burns, chronic wounds, and acute wounds (i.e. surgical

incision and IV sites). Resistance to silver has been studied since the 1970’s; however, reported cases of silver resistance are

rare and there is little evidence indicating an emerging bacterial resistance to silver as has been seen with CHL [38], [41]. As

with any antiseptic, the increased use of silver in the clinic will increase exposure of antibacterial resistant bacteria to silver

raising the potential for signiﬁcant silver resistance to develop. Clinical researchers should continue to monitor the prevalence

of silver resistant genes and bacteria; however, the risk of clinical bacteria isolates developing a clinically relevant resistance

is minimal. The low potential for bacterial resistance to silver is best illustrated by comparing the history of silver to the history

of modern antiseptics and antibiotics. Bacteria have been exposed to sub-clinical levels of silver ions for over 4 billion years

and applied at clinically relevant levels for “modern” medical purposes for over 200 years without bacteria developing clinically

relevant silver resistance [30], [41]. Scientists speculate that the primary reason why bacteria have not developed an effective

resistance against silver is due to the multiple mechanisms through which silver damages and kills individual bacteria compared

to the single killing mechanism of antibiotics and antiseptics associated with bacterial resistance developed within the 70 years

of clinical use [8].

Potential bacterial resistance to maltodextrin

Maltodextrin is a high molecular weight polysaccharide. Application of polysaccharide (i.e. sugar) in wound healing dates back

to ancient times, and sugar was ﬁrst documented as a method for treating ulcers in 1714 [44]. Simple granulated sugar [45],

honey [46], and high molecular weight polysaccharides (i.e. maltodextrin) [47] have all been utilized in wound care and have

been characterized to have excellent antimicrobial activity due to high glucose content. The antimicrobial properties from high

glucose content arise from the acidic environment and high osmotic gradients that disrupts normal bacterial function [9], [10],

[48]. To date, no bacterial resistance to sugar mediated wound care products has been documented. Two recent studies have

demonstrated that bacteria resistance could not be evoked following stepwise exposure to honey in S. aureus, P auruginosa,

E. Coli, and S. epidermidis strands [49], [50]. The acidic environment and osmotic gradients established by the high glucose

content of the honey were cited as the primary reasons why the tested bacteria did not develop resistance mechanisms to the

honey. The failure of these experiments to create resistance in bacteria strands known to rapidly develop antibiotic resistance

demonstrates the low likelihood of bacteria developing a resistance to glucose based antimicrobial agents. The unique addition

of maltodextrin into DeRoyal’s silver alginate wound dressing gives Algidex

an advantage over traditional silver alginates

as the beneﬁcial antimicrobial actions of silver and polysaccharides are combined for synergistic antimicrobial activity, and

minimizes the potential for bacteria to develop resistance to Algidex

wound dressing when applied in the clinic.

Safety of CHG impregnated and Algidex

IV Dressings

Safety of CHG impregnated dressings

Chlorhexidine is generally considered safe by the clinical community and is the antiseptic of choice due to the prolonged

antibacterial action from CHL binding to human cells; however, in some instances, CHL interaction with cells can lead

individuals to develop sensitivities or allergies that can cause serious adverse events. Studies have estimated the incidence

of allergies or sensitization to CHL range between 0.5 to 13.1% [51]; however, these rates increase for patients that are very

sick, immunocompromised, have venous insufﬁciency, or have received chronic or repetitive treatment with CHL products

[4], [51]–[53]. In addition to patients, healthcare workers that are continuously exposed to CHL have been shown to be at an

increased risk for developing an occupational allergy to CHL [54], [55]. Allergic reactions to CHL are typically manifested as

contact dermatitis; however, case reports also indicate that CHL can cause immediate uticaria, immediate anaphylactic shock,

or anaphylactic shock after repeated exposure.

Initial manifestation of CHL sensitization is typically seen as contact dermatitis characterized by local inﬂammation and reddening

of the skin accompanied by burning and itching sensations. Contact dermatitis onset can be delayed up to 24 to 48 hours and

can take 14 to 28 days to resolve [56]. Since CHL is an underappreciated allergen in the medical community, contact dermatitis

induced by CHL is often misdiagnosed inadvertently increasing the risk that a patient will experience a more severe allergic reaction

in future exposures to CHL [53]. In rare cases, patients may experience immediate urticarial and/or anaphylaxis shock [4]. Urticaria,

commonly referred to as hives, is characterized by red, itchy, raised areas of skin that vary in size and can appear anywhere on

the body following exposure to CHL or other allergen. Urticaria can resolve within hours of allergen removal or last for several days

or weeks [56]. Anaphylactic reactions represent a serious whole body allergic reaction that is characterized by a rapid onset of

symptoms. Symptoms of anaphylaxis include urticarial, ﬂushing, and itchiness of the skin, soft tissue swelling, shortness of breath,

nausea, and arrhythmia. Anaphylactic shock is life threatening if symptoms are not treated immediately. While anaphylaxis can

develop acutely due to CHL exposure, most cases of anaphylactic shock occur after repeated CHL exposure and following an

associated mild allergic reaction that went undiagnosed [51]–[53]. Repetitive exposure to CHL is clearly a concern in the medical

community as CHL usage continues to increase in the clinic. Clinical researchers now recommend allergic testing for CHL allergies

prior to hospitalization in an effort to prevent severe anaphylactic reactions [4], [51]–[53].

Despite the documented increase incidence of CHL allergic reactions, the usage of CHL continues to increase in the clinic

and multiple companies have developed CHL impregnated devices in an attempt to prevent nosocomial infections, including

the CHG impregnated IV dressings Biopatch

and Tegaderm

CHG. These dressings are designed to continuously expose

the IV site to CHG to prevent nosocomial catheter related infections for up to seven days. Both dressings are secured with an

occlusive dressing as is standard for IV dressings. Safety and efﬁcacy studies that compared each CHG dressing to a standard

non-antimicrobial dressing revealed contact dermatitis occurred in 1.49% (Biopatch

) and 2.3%(Tegaderm

CHG) of dressing

changes [57], [58]; however the rates of contact dermatitis are likely greater than these ﬁgures as the authors indicate that

“contact dermatitis usually occurred for a single catheter per patient” indicating patient contact dermatitis prevalence is likely

greater. Clinical studies have reported that CHG IV dressings can cause pressure necrosis, scarring or severe sponge-associated

contact dermatitis at a rate of 5.6% in pediatric patients and up to 15% in neonates [52], [59]–[61]. These complications and

associated complication rates indicate that CHG IV dressings may not be ideal for use in pediatric patients. In all cases reporting

adverse skin events related to the CHG IV dressing, very critically ill patients were identiﬁed to have an increased risk of

developing skin lesions associated with the CHG dressing [52], [57]–[61]. With prevalence of CHL sensitization estimated to be

as high as 13.1% in adults, more research is needed to fully understand the risks of CHL sensitization or allergy and to further

investigate the safety of CHG impregnated IV dressings [51].

The neurotoxicity of CHL represents another safety concern in application of CHG impregnated dressings for protecting

neuraxial anesthesia access catheters from infection. A study in 1955 demonstrated that CHG caused meningeal adhesions

and neural cell death when the chemical was injected into the cerebral spinal ﬂuid of monkeys [62], and a separate study in 1984

conﬁrmed the neurotoxicity of CHL through direct injection of the chemical in the anterior chamber of the eye causing marked

and dose-dependent degeneration of adrenergic nerves in rodents [63]. These studies prompted the US Physician’s Desk

Reference Manual to warn that “CHG is for external use only. Keep out of eyes and ears and avoid contact with meninges”,

and led to many manufacturers to contraindicate the application of CHL products for spinal procedures including neuraxial

anesthesia [64]; however, despite these warning, clinicians have used CHL products off label for antisepsis to prevent bacterial

infection in neuraxial procedures. While studies have shown CHG antisepsis have a low complication rate in these procedures

[65], there are at least three conﬁrmed cases of CHG evoked adhesive arachnoiditis and six additional potential cases with

similar symptom progressions [66], [67]. The ﬁrst case that received wide publicity occurred in 2001. A woman received epidural

anesthesia to prevent pain during an elective caesarean section. The patient debilitated rapidly progressing to a paraplegic

with limited use of her arms in the following weeks. In 2007, a judge awarded civil damages due to “a measurable quantity of

CHL (deﬁned as 0.1 mL)” contaminating the anesthesia [68]. In 2012, a medical expert that testiﬁed in the original case and

disagreed with the judgment released an editorial, admitting he was wrong in claiming CHL was not responsible for the adhesive

arachnoiditis during the litigation. His opinion changed due to a similar case in a patient where a known quantity (8 mL) of CHG

was injected in the subdural space. In both cases, the deterioration of the patient was very similar including the time course of

presenting symptoms, rapid neurological deterioration, need for ventricular shunting to treat hydrocephalous, and progressing

to paraplegia with upper limb involvement. The similarities between the two cases forced Bogod to change his opinion; however,

he notes the amount injected in the 2001 case was signiﬁcantly less and likely only a residual amount [66]. Killeen et al. reported

on an additional case that occurred in 2011 and compiled a list of six additional cases with similar deterioration noted in patient

without a conﬁrmed cause of adhesive arachnoiditis. In this case, the authors report that the applied CHL was allowed to air

dry for three minutes according to standard operating procedures before the epidural procedure was performed, and that there

was no indication of CHL pooling prior to inserting the epidural catheter. While no direct evidence of CHL contamination was

obtained, the authors concluded through a process of elimination that CHL contamination was the likely cause of the neurologic

complications suffered by the patient [67]. Killen et al also suggested the additional identiﬁed cases were also caused by CHL

contamination due to similarities between the present case and the prior cases with conﬁrmed CHL exposure described by

Bogod [66], [67].

Despite documented evidence that CHL can cause neurologic complications, most anesthesiologist discount these cases due

to the belief that trace amounts of CHL cannot cause adhesive arachnoiditis or other neurologic complications. A recent study

investigated the effects of diluted CHL on plated neurons and Schwann cells to determine the potency of trace CHL. The researchers

applied serial dilutions of 2% CHG and 10% povidone-iodine to investigate cytotoxicity of these antiseptics on human neuronal

and rat Schwann cells. The investigation found that CHL was cytotoxic for neurons and Schwann cells at all concentrations tested

including a 200x dilution that is well below concentration used in the clinic [69]. This ﬁnding provides supporting evidence that trace

amounts of CHL can cause cell death of neurons as well as the myelin producing Schwann cells giving credence to the conclusion

that trace CHL could have caused the debilitating adhesive arachnoiditis in the documented cases.

Absorption of CHG through the skin into the bloodstream is the major reason why the CDC recommends against using the

chemical on infants less than 2 months of age. The implications of the absorption into the bloodstream are not well understood;

however, the neurotoxicity of CHL chemicals is a major concern. Chapman et al. recently reported CHG in the blood stream

in 10 of 20 preterm infants that ranged between 1.6 and 206 ng/ml following cleansing of skin with CHG prior to placement

of a PICC line. Seven of these infants experienced their highest concentration of CHG 2 to 3 days after exposure to CHG

suggesting that the binding of CHG to skin cells can lead to further absorption in infants [70]. Milstone et al recently tested

these concentrations of CHG on cerebellar granule neurons and found that these trace amounts of CHG causes inhibition

of L1 cell adhesion molecule preventing proper development of the neurons. Such effects of CHG in vivo could potentially

have devastating developmental consequences in neonates and more research is needed to understand if CHG can cross

the blood brain barrier to damage neural tissue [71]. These studies demonstrate that CHL concentrations signiﬁcantly below

clinical concentrations can cause substantial damage to neurological tissue. Further research is needed to fully understand the

potential risks of neurological damage associated with CHL in at risk populations.

Safety of the Algidex

IV dressing

Silver, in the ionic form, is an emerging antimicrobial material that is receiving increased interest from the medical community to

ﬁght infection. As previously discussed, ionic silver prevents infection through a multitier approach that disrupts the cell wall and

membrane, interferes with organelle function, impairs cellular respiration, denatures intracellular enzymes, RNA, and DNA, and

disrupts metabolic events modulated by other ions [7], [8]. These multiple mechanisms of ionic silver decrease the likelihood

that bacteria will develop a resistance to silver treatment. In addition to silver, the DeRoyal

Algidex

IV patch includes

maltodextrin which has been shown to have antibacterial and wound healing properties [10], [47]. Together, ionic silver and

maltodextrin create an optimal antimicrobial environment that is effective at preventing infection. The safety of the Algidex

IV patch in humans will be brieﬂy discussed.

Silver is generally considered non-toxic unless silver is absorbed in great amounts (2000 ng/ml). At 2000 ng/ml, Argyria, a

syndrome characterized by deposition of silver in tissue leading to graying of skin, and can cause growth retardation, disturbed

hemopoiesis, and cardiac, hepatic, and renal dysfunction. No clinical symptoms have been reported in adults with moderately

elevated concentrations of silver (<1000 ng/ml) [72]; however, toxicity may occur below these levels in infants as indicated

by one case report where the infant was reported to have a silver concentration of 323 ng/ml [73]. In terms of Algidex

patches, patients are not expected to absorb silver in amounts that exceed safe clinical values. In the study by Khattak et al., the

highest reported silver absorption value in 25 patients was 103 ng/ml, three times below the silver serum reported in the case

report; however, the reported average serum silver was 7.6±20.93 ng/ml for all infants and 22.5±40.4 ng/ml for infants below

750 g (n=6)[12]. Estimated daily exposure to silver in these patients was between 62 and 124 μg/day which is approximately

100 times less than the parenteral dosages required to cause toxicity in animals and enteral dosages reported to cause toxicity

in humans [12]. If the CDC assumption of 20% dermal absorption is correct, then potential silver exposure from an Algidex

IV patch is almost 1000 times less than doses expected to cause silver toxicity [74]. These estimates by Khattak and colleagues

are supported by the fact that no infant included in the study experienced an adverse event related to silver despite being more

susceptible to absorbing silver than older patients [12]. Absorption of silver from an Algidex

IV patch signiﬁcantly decreases

for the patient population at age 2 years, as skin is more permeable during the ﬁrst two years of life, increasing the safety factor

of the Algidex

IV patch with patient age [75].

Silver allergic reaction exists; however, they are very rare in a clinical setting. Delayed contact hypersensitivity most often occurs

in people exposed to silver on a daily basis due to occupation. Clinically, silver allergy is most likely to develop in burn patients

treated with silver products. These patients develop a silver allergy due to prolonged silver exposure and increased absorption

of silver through damaged skin [76]. The risks of patients developing an allergy to silver in the Algidex

IV patch are

considered to be very low. Maltodextrin is considered generally non allergenic since the molecule is constructed from glucose

units linked together by glycosidic bonds. The only allergic concern associated with maltodextrin is residual gluten proteins

sometimes present following manufacturing of maltodextrin. A report released by the European food safety authority found

that maltodextrins may contain low levels of proteins and peptides capable of causing an allergic reaction; however the levels

of protein needed to cause an allergic reaction is not known and concluded that residual proteins in maltodextrin are likely not

sufﬁcient to cause a severe allergic reaction in susceptible individuals [77]. These observations for silver and maltodextrin clearly

support the safety of the Algidex

IV patch for use in humans.

FDA MAUDE Database CHG IV Patches versus Algidex

IV Patch

The clinical literature reports a wide range of adverse event prevalence associated with CHG impregnated IV dressings. Large

clinical evaluations by a French group reported a low adverse event rates of 1.49% for Biopatch

and 2.3% for Tegaderm

CHG

for individual dressing changes, but did not report the adverse event rates on per patient basis [57], [58]. Other studies have

reported chlorhexidine sensitivities in the general population as high as 13.1% in adults [51] and 15% in neonates [52]. Most of

the adverse events associated with CHG impregnated IV dressings are likely considered minor and typically are only reported

in a clinical journal when the adverse event had a profound impact on a patient’s care. One of the best qualitative measures

to assess a device’s safety in the clinic is the MAUDE database that reports malfunctions and adverse events attributed to the

device while utilized in a patient’s care. The MAUDE database was quarried to identify the number of records reporting adverse

events for the Biopatch

, Tegaderm

CHG, and Algidex

IV patch to better understand prevalence of adverse events for

these antimicrobial IV dressings.

A MAUDE database search for the term “Biopatch” returned 183 records dating back to 1994; however, one hundred eighty

of these records were reported after January 2000 [78]. The MAUDE records were categorized as adverse skin reactions,

infection, device malfunction, anaphylaxis reaction, unknown events, and events not related to the Biopatch

dressing. Adverse

skin reactions were reported in 122 records or 67% of all records. In most records reporting a skin reaction, patients often

experienced redness of the skin and itching sensations at the dressing location indicating sensitivity to the dressing material. A

large cohort of patients experienced skin breakdown under the Biopatch

leading to ulcer formation commonly associated with

grade 2 or 3 burns. At least 28 of the patients that developed full thickness ulcers where CHL products were used to prep the

skin for catheter placement. One of these reports described a case of toxic epidermal necrolysis that led to eventual death of

a patient that had a serious adverse reaction attributed to the CHG in the Biopatch

. In 36 reports (20%), the Biopatch

was

implicated in causing an infection in the treated patient. In one case, the end user reported a 40% increase in infection rate

following a trial of the Biopatch

. Additionally, 22% of these cases were reported for patients undergoing dialysis. There are 19

reports of device malfunction; however 12 of these reports were attributed to the Biopatch

adversely affecting the patient’s

care. In most of the 12 cases, the Biopatch

was implicated in sticking to catheter causing the catheter to be removed from

the patient. Additionally, the Biopatch

dressing was implicated in three cases of anaphylaxis shock following treatment of CHL

sensitive patients with multiple CHL products. The Biopatch

was used in 16 or 9% (2 unknown, 14 not related) events that did

not directly implicate the dressing in causing the reported adverse event [78].

The search term “Tegaderm

CHG” was used to identify adverse events in the MAUDE database that were attributed to

the Tegaderm

CHG IV dressing [79]. One hundred twenty ﬁve records were returned that dated back to 2008, and were

categorized as adverse skin reactions, infection, device malfunction, and events not related to the Tegaderm

CHG IV dressing.

Adverse skin reactions were reported in 118 of the 125 records (94%). The majority of adverse skin reactions reported the

formation of full thickness ulcers caused by the Tegaderm

CHG dressing. A small number of the reports described minor skin

reactions similar to contact dermatitis. In 17 of the reports, a CHL based antiseptic was used to clean the skin before placing

the catheter implicating repeated exposure to CHL in the observed skin reaction. Infection attributed to the Tegaderm

CHG

dressing was reported in 17 cases (14%). There were only two reports of device malfunction, but in each case, the patient was

adversely affected through the removal of the catheter stuck to the Tegaderm

dressing. The Tegaderm

CHG IV dressing was

mentioned in three reports reporting on failure of a second device (catheter) that was covered by the dressing. In these cases,

the Tegaderm

CHG dressing was not implicated in the reported adverse event [79].

The MAUDE database was quarried with the search term “Algidex” and returned only one record; however the record did not

report on an adverse event that directly involved the Algidex

IV dressing [80]. The returned record reported on the inﬁltration

of ﬁve catheters into the body involving four patients. An Algidex

IV patch was used to dress the catheter insertion points,

but the adverse event report did not implicate the dressing. The Algidex

IV patch was approved for use by the FDA in 2004

and in ten years of use, no adverse events reported to MAUDE database have been attributed to the Algidex

IV patch

demonstrating the exemplary safety record of the product [80].

MAUDE database searches for the Biopatch

, Tegaderm

CHG, and Algidex

IV dressings revealed signiﬁcant qualitative

trends that can be used to assess the safety of CHG impregnated IV dressings compared to the Algidex

IV dressing. Over

100 reported serious adverse events exist for both the Biopatch

and Tegaderm

CHG IV dressings with the majority of these

events involving injury to the skin. Within each dataset, most patients suffered an adverse skin injury following continuous

exposure to CHG over a signiﬁcant period of time (typically greater than seven days) and received multiple CHG dressings

before symptoms of the injury developed. In some cases, CHG antiseptic skin cleanser was used to disinfect the skin before

placing the catheter and the CHG impregnated dressing around or over IV. This action increased the patient’s exposure to

the CHG and likely contributed to the adverse event. In most of the patients with skin injuries, the patients were very ill, had

compromised or fragile skin, were receiving chemotherapy or dialysis, suffered organ failure, were immunocompromised or

had a surgery that utilized multiple CHG impregnated devices. These categories of susceptible patients match patient types

cited in the literature as susceptible to CHG reactions; however, most patients that are admitted for continuous or critical care

ﬁt within one or more of these categories at some point during their hospitalization. Blood stream infections were identiﬁed as

adverse events for both CHG impregnated dressings supporting the ﬁndings in the literature that suggests CHL is not effective

against all strands of bacteria. In most of these cases, the infection was preceded by skin ulceration or breakdown caused by

overexposure to CHG creating an ideal environment for bacteria proliferation. Interestingly, only 3 of the 183 adverse events

associated with the Biopatch

were reported from 1994 until 2000. This six year period most likely represents inconsistent

reporting of adverse events to the MAUDE database; however this period could also be representative of increased incidence

of CHL sensitization referenced in the literature. If the former, then approximately 77 cases (12 per year) were likely not reported

during this time frame for the Biopatch

. In total, 305 reports involved one of the two leading CHG impregnated IV dressings

compared to 1 the unrelated report involving the Algidex

IV dressing. This profound difference in number of MAUDE reports

for CHG impregnated dressings compared to the reports for the Algidex

IV dressing qualitatively supports superior safety

of the Algidex

IV dressing compared to CHG IV dressings.

This review highlighted the strengths and closely examined the weaknesses of both CHL and ionic silver as antiseptic agents

for the prevention of central-line associated bloodstream infections. Chlorhexidine is a proven antiseptic that has seen a rapid

increase in clinical utilization due to the emergence of antibacterial resistant bacteria strands. The mechanism of action for

CHL kills most bacteria within 20 seconds and exerts a prolonged effect; however, there are emerging safety concerns due to

a documented increase in bacterial resistance and increased prevalence of CHL sensitivities and allergies that is attributed to

overreliance and indiscriminate use of CHL in medical clinics worldwide. Adverse skin reactions are the most commonly cited

complication associated with CHL and is consistently attributed to repeated and continuous exposure to CHL from impregnated

medical devices. These concerns surrounding CHL clinical usage have led researchers to investigate new antiseptic techniques

and agents to help maintain safe and clean clinical environments, especially in maintaining clean environments surrounding

catheters placed in the body.

Ionic silver as an antiseptic has seen a reemergence in modern medicine due to its effective multifaceted antimicrobial mechanism

of action and safety in humans. Silver allergies are documented to be very rare often requiring large amounts of silver absorption

before humans develop a silver sensitivity. Additionally, silver wound dressings have not caused serious ulceration of skin as

has been documented for CHG impregnated dressings. While bacterial mechanisms to resist silver antisepsis exists, research

has shown that these mechanisms are rare, not easily transferrable, and do not necessarily provide effective resistance against

silver ions. Potential for bacteria to develop effective resistance to silver is considered to be minimal as no signiﬁcant resistance

mechanism has developed despite bacterial exposure to silver for over 4 million years and over a thousand year history of

human antiseptic use. The innovation of adding maltodextrin into the silver matrix of the Algidex

IV dressing creates a

synergistic antimicrobial medical device combining the antibacterial properties of a polysaccharide and silver. Maltodextrin is

considered safe and generally non-allergenic. Like silver, the bacterial resistance to maltodextrin is unlikely as the antibacterial

properties of polysaccharides have been maintained since ancient times.

Both chlorhexidine and silver products like the Algidex

IV patch have a place in clinical antisepsis protocols; however,

the beneﬁts and risks must be considered. In the clinic, the goal is to prevent nosocomial infection without endangering the

patient to other risks. The widespread usage of CHL products threatens to increase CHL bacteria resistance similarly to the

documented rapid rise of bacterial resistance to antibiotics. Medical clinics should adopt a multifaceted antisepsis protocol that

includes more than one antiseptic to effectively ﬁght bacteria with antibiotic resistance. Additionally, there is a growing trend of

patients developing sensitivity or allergies to CHL from prolonged or repetitive exposure to the chemical. Reducing exposure

of patients to CHL should be a priority in medical centers that exclusively use CHL for antisepsis. The Algidex

IV patch

represents one method to signiﬁcantly reduce patient exposure to CHL in medical facilities that use CHG impregnated dressings

to manage inserted catheters. The safety record of the Algidex

IV dressing compared to CHG impregnated IV dressings is

outstanding as indicated by clinical reports and records in the MAUDE database. The Algidex

IV dressing has been shown

to have similar efﬁcacy CHG dressings at inhibiting bacteria growth and combined with a superior safety record make it the ideal

antimicrobial barrier dressing for inclusion in CLABSI prevention bundles designed to reduce the risk of nosocomial catheter

related bloodstream infections in the clinic.

Conclusion

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cfm?MDRFOI__ID=3037395

DeRoyal, DeRoyal logo, Improving Care. Improving Business., and Algidex Ag

are registered trademarks of DeRoyal Industries, Inc.

BioPatch is a registered trademark of Johnson & Johnson Corporation.

Tegaderm is a registered trademark of 3M Corporation.

DeRoyal Industries, Inc. | 200 DeBusk Lane, Powell, TN 37849 USA

888.938.7828 or 865.938.7828 | Customer Service: 800.251.9864 | www.deroyal.com

Reprint # 0-2426 | Rev. 1/18

Product # Size Qty/Bx Qty/Cs HCPC

46-IV20 ¾” Disc w/2 mm opening 5 50 A6209

46-IV22 1” Disc w/4 mm opening 5 50 A6209

46-IV25 1” Disc w/7 mm opening 5 50 A6209

46-IV32

1” Disc w/4 mm opening (w/insert)

5 50 A6209

46-IV34

¾” Disc 5 50 A6209

46-IV375 1½” Disc w/7 mm opening 5 50 A6209

ALGIDEX AG

I.V. PATCH

silver alginate catheter dressing

• Absorbs moisture around the catheter insertion site

• Sterile patch of polyurethane foam coated with an ionic silver

alginate and maltodextrin matrix

• Ionic silver contacts wound pathogens

• Does NOT require activation or the use of sterile distilled water

• Up to seven days wear time*

Dialysis catheters

Central venous lines

Arterial catheters

External ﬁxator pins

Epidural catheters

Peripheral IV catheters

Gastrostomy feeding tubes

Non-vascular percutaneous devices

INDICATIONS:

CONTRAINDICATIONS:

Do not surgically implant.

Do not use on:

third degree burns, ulcers resulting

from infections, lesions in patients

with active vasculitis, patients

with sensitivity to silver, silver

compounds, or alginates.

scan here for more

information about

Algidex AG

I.V. Patch