A PERSPECTIVE
ON HEXACHLOROPHENE
Louis Gluck, M.D.
From the School ofMedicine University ofCalifornia San Diego, L.a Jolla, California
ABSTRACT. Hexachlorophene is highly effective in the control of colonization and disease with Staphylococcus
aureus in both normal and high risk nurseries, when properly used, including correct cord and skin care.
However, much more about this compound needs to be known, particularly more about the metabolism inthe human, absorption, excretion, body storage, tissue distri-bution, and so forth. Pediatrics, 51:400, 1973.
S
INCE its synthesis in 1939 and first com-mercial use in 1945, hexachlorophene has become one of the most widely used antisep-tic substances. It is found in products ranging from anti-perspirants and toothpastes to fur-nace filters. It’s most common use in home and hospitals is in 3% concentration in a de-tergent compound (pHisoHex,) in wide public usage since 1949.Hexachlorophene is a chlorinated bisphe-no!, 2,2’ - methylenebis
(3,4,6-thchlorophe-nol), prepared by condensing two molecules of 2,4,5-trichlorophenol with formaldehyde in the presence of sulfuric acid or other strong catalyst.’ It is a white powder, insoluble in water, glycerine or mineral oil, but very solu-ble in propylene glycol and ethyl alcohol and
extremely soluble in acetone.
Hexachlorophene is a highly effective anti-bacterial agent against gram-positive orga-nisms, especially staphylococci and
strepto-cocci, although it also has some effectiveness against gram-negative organisms, such as E. coil.2 Inhibition of growth of S. aureus has been reported at dilutions of 1:8,000,00G3 and even 1: l0,000,000. Partial inhibition of growth of E. coil is seen at 1:1,000,000 dilu-tion,3 but 1:100,000 is the reputed inhibitory
concentration.5
Hexachiorophene is bactericidal as well as bacteriostatic, although concentrations one
thousandfold as great are required to kill or-ganisms. Dilutions of 1:5000 kill S. aureus or
E. coil in 20 to 30 minutes.6 The effectiveness of hexachiorophene can be impaired by low pH and inhibited by serum (and others)
pro-teins and by the nonionic surfactant Tween 80.
It is important to note that bacterial resis-tance by S. aureus to hexachlorophene is
al-most unknown, even when 10 strains were transferred daily for 150 days on agar and broth containing hexachlorophene.8 However, one report by Tanaka9 after 150 successive
transfers described two strains of S. aureus
resistant to hexach!orophene which required a sixteenfold increase in concentration to in-hibit growth. Interestingly these two strains resistant to hexachiorophene had increased sensitivity to penicillin.’0
Prior to recent questions about the safety of hexachlorophene, hexachlorophene had
undergone extensive animal tests to establish
its toxicity. Representative median lethal doses (LD-50)” included 150 to 200 mg/kg in mice, 250 mg/kg in guinea pigs, and 140 mg/ kg in dogs. Various reports of local and acute
toxicity also have been published. Recent hu-man studies will be described below.
Radioactive hexachiorophene fed to rats and rabbits’s appeared both unchanged in the feces and as an unidentified metabolite. Pitt-man’3 identified the metabolite as a glucuro-nide conjugate.
I. EFFECTIVENESS OF HEXACHLORO.
PHENE AS AN ANTI-STAPHYLOCOCCAL
(AND ANTI-STREPTOCOCCAL) AGENT
The first uses of
hexachlorophene-contain-ing compounds on the skin of newborn in-fants as prophylaxis against infection with
Staphylococcus aureus were reported by
Far-quharson et aL,’ Hardyment et al.,’ and Shaffer, et al.,16 who reported reduction and elimination of pyoderma in newborn infants. Gluck and Wood,’7”8 Simon, et al.,’9 and
SUPPLEMENT
zon, et aI., in controlled studies, demon-strated the high degree of effectiveness of a total skin and cord care regimen with 3% hexachiorophene in the reduction of nasal colonization by S. aureus and in the preven-tion, compound thus, of staphylococcal infec-tion.
In 11 years’ usgage of 3% hexachiorophene for infant bathing in the maternity wing of the Geelong Hospital in Australia,
Plueck-hahn and Banks2’ reported outstanding
suc-cess in controlling staphylococcal infection in 26,000 deliveries. Gluck, Wood, and Fousekn
reported 25,000 consecutive deliveries with a
bathing regimen without a single lesion of any sort due to S. aureus. Williams and
Oh-vera described 6- years experience with a
sldn and cord care regimen with 3% hexa-chiorophene compound which showed that a low incidence of colonization and very low incidence of disease was maintained despite
eliminating time-honored restrictions such as caps, masks, gowns, and limitation on person-ne! who enter nurseries. Many other newborn services have had similar successful
experi-ences.
The question whether there is increased acquisition of gram-negative organisms by
in-fants being bathed with a 3%
hexachloro-phene product as compared to infants on dry skin care is moot. Light and Suther1and and Sarkany and Arnold reported increased
colo-nization by gram-negative organisms follow-ing elimination of staphylococci with hexa-chiorophene. Plueckham and Banks,2’ in 11
years’ usgae of 3% hexachlorophene com-pound in a maternity wing found no increase in infection with gram-negative organisms as well as no cross infection with staphylococci
in their 26,000 infants studied.
Gluck, Wood, and Fousek found a defi-nite decrease in total incidence of infection; elimination of gram-positive organisms in-creased the relative proportions of infection with gram-negative organisms.
In this connection, in 1933 Ethel Durham, in her original descriptions of 39 cases of neonatal sepsis, found that 26% of the invad-ing organisms were E. coli 39% were
fl-he-molytic streptococci, and 28% were S.aureus.
The problem of the gram-negative organisms,
in short, have always been with us.
Although it is frequently alleged that mci-dence of colonization and incidence of infec-tion with Staphylococcus aureus are not cor-related, this appears to be not true where
comparative studies have been made. Thus Gillespie, et al.p showed that skin infections developed in approximately 20% of infants colonized by S. aureus whereas only about 1.5% of infants with negative cultures
devel-oped staphylococcal infections.
A major objection in most assessments of incidence of infection in newborn popula-tions is that they look only at the hospital
population with a decided lack of follow up
studies out into the community. In the study reported by Payne,et al. where 180 families were followed for 1 year following newborn infants’ discharges, it was clear that there was
1 1 times as much chance for infants and their
families to develop significant clinical infec-tions with staphylococci when an infant’s nose was colonized upon his discharge from
the hospital as compared to infants who re-turned home with their noses not colonized with S. aureus.
In hospital population with careful antisep-tic skin and cord care, there may be unex-planed cycles; for example, Williams and Oliver’ observed minor transient elevations
of the staphylococcal nasal colonization rate but with a very low incidence of actual dis-ease.
The key aspect in nasal colonization seems to be that the infant himself becomes a “cul-ture medium.”8 The prime site for initial colonization appears to be the cord area, and from there spreading to the adjacent skin. Nasal colonization follows direct handling of
the infant, changing clothes, movements of his own hands, and so forth, which transfer organisms into his nose.’8 The nasal carrier of pathogenic S. aureus becomes a potential menace to himself and to his family.n
402
England clearly showed the value of caring for the umbilical cord with compounds which inhibit the colonization of the cord. This de-lays or prevents nasal colonization. Predilec-tion for cord growth is found not only with
Staphylococcus aureus but also with
fl-he-molytic streptococcus.8’ Where one bathes
the total body of the baby with pHisoHex but
uses alcohol on the cord, nasal colonization may be in the range of 50%. Cord care with careful 3% hexachlorophene compound wash-ing together with the bathing of the baby
assures minimal levels of nasal colonization
and prevention of disease.1&2
Various studies have demonstrated fag-ments of the epidemiologic picture. For ex-ample, the major importance of careful hand-washing was shown by Wolinsky, et al.3’ and
Mortimer, et al. However, this is but one piece of the whole story. In the past it has
been demonstrated amply many times that dry skin care, cohort techniques, and so forth, may have little effect on preventing either colonization or disease. It therefore was
sur-prising to see a return to dry skin care
recom-mended by Food and Drug Admiistration#{176}
and the American Academy of Pediathcs.’ Shortly after cessation of washing with 3% hexachiorophine compound as reported in the bulletin of the Center for Disease Control,n there was an upsurge in outbreaks of infec-tions with Staphylococcus. Our office re-ceived a large number of calls and sugges-tions were being sought for control of several
relatively serious outbreaks. From previous work we suggested return to scrupulous
anti-septic skin and cord care techniques and in each instance, of the several hospitals with whom we consulted, almost immediately upon instituting strict antiseptic skin and cord techniques, the “epidemic” was broken.
In the past it has been alleged that antisep-tic skin and cord care with 3% hexachloro-phene compound is not effective in interrupt-ing epidemics. This certainly is not true based on our previous experiences plus the experi-ences during the recent outbreaks, when in each instance cessation of colonization and termination of disease occurred. It is clear that careful scrupulous skin and cord care
with 3% hexachlorophene compound will end
an outbreak promptly. Other efforts said not to work in all instances were related to poor technique, nearly always to paying no atten-tion to the antiseptic care of the umbilical cord. Unfortunately even the recommenda-tions for nursery procedures following ap-pearance of staphylococcal disease by the Center for Disease Control fail to mention
importance of or specific enough measures
(
using 3% hexachiorophene compound for proper cord care.An outbreak of bullous impetigo due to Group II S. aureus was reported by Albert, et aI.,7 which showed that .75%
hexachloro-phene bath soap was inadequate to control staphylococcal colonization and disease. Pre-vious antiseptic skin care with 3%
hexachloro-phene compound had been given for a long period of time (although no special care was given the umbilicus) with little infection and low levels of colonization until this regimen was discontinued in favor of the .75
hexachlo-rophene soap washing. With the change the epidemic of bullous impetigo occurred in the nursery. A number of alterations in
techni-ques were made (including the return to 3% hexachiorophene bathing) followed by a prompt drop in incidence of colonization to levels prior to the change when 3%
hexachlo-rophene compound had been used. Shortly after this all infants in the nursery were cob-nized “prophylactically” with S. aureus 502A
strain.
Unbelievably, critics of antiseptic skin and cord care have used this study, which,
al-though equivocal, points more toward the
successful use of 3% hexachborophene, as an example of hexachborophene failure! It should
be emphasized that from all evidence ob-tained from controlled studies there is clear value to proper antiseptic skin and cord care with hexachiorophene for the prevention of staphylococcal coboinization and disease.
centers today, including our own, have par-ents visiting in their Special Care nurseries, handling sick infants and premature infants, medical students participating in premature and sick newborn care, caps and masks have disappeared, and in many places even gowns no longer are used. Antiseptic skin and
cord care has replaced many of the rituals which in the past prevented neither
coboniza-tion nor infection, such as the cohort system,
hand washing alone, isolation procedures, dry skin care, and so forth.
It is unrealistic to expect, with the turnover of personnel in nurseries and the variations in
technique from shift to shift and person to
person, that there can be a constant level of
care and adequate control. The more the turn over of personnel and the larger the service, the more difficult it is to control. Unless one has a relatively tiny service under rigid con-trol where one knows exactly what is being done at all times, some sort of universally effective technique is necessary to safeguard infants against staphybococcal disease. The use of 3% hexachlorophene compound gives the most effective antiseptic care for skin and cord.
Upon discontinuance of 3% hexachboro-phene compound and the subsequent wide-spread outbreaks in nurseries of
staphybococ-cab disease,n a number of “explanations” were offered, no one of which was tenable.
The most popular was that personnel had now also stopped washing hands as well as
babies. Without a means of preventing the
baby from becoming a culture medium, hand washing has limited effectiveness. Another explanation was that closer observation was
practiced and with more attention, lesions were being seen. This is, of course, sheer
nonsense; in nurseries providing intensive
care such as the Newborn Special Care Unit in New Haven there has been careful obser-vation for many years. It is not possible that large bullous impetiginous lesions would have gone unnoticed. These lesions appeared with the cessation of 3% hexachlorophene com-pound skin and cord care and disappeared upon the reintroduction of 3% hexachboro-phene compound, as was observed from coast
to coast. To date no better alternative pre-ventive measure has been offered; the risks of
other procedures#{176} or of failing to prevent staphybococcal disease may result in serious unnecessary morbidity and mortality.
II. THE QUESTION OF TOXICITY OF
HEXACHLOROPHENE IN INFANTS
With its widespread acceptance as an anti-septic agent and with no obvious toxicity noted with hexachborophene as ordinarily used, its action was assumed to be known and understood. The insolubility of hexachboro-phene also may have helped to quiet fears about its potential toxicity. However, by
cur-rent pharmacological criteria, very little actu-ally was known about its effects in humans. Perhaps the greatest deterrent toward finding
out more about hexachborophene lay in the problem that no valid analytic technique was
available until very recently capable of de-tecting the scant parts per million or parts per billion found in blood, for example.
The several cases of human poisoning in the past decade and a half almost invariably were due to the ingestion of hexachloro-phene. One case was reported in 1959,’ how-ever, of a 5-day-old infant whose mother mis-understood and used 3% hexachborophene
compound as a lotion. After 4 days of liberal applications, excoriations appeared and the child demonstrated seizure activity. When admitted to the hospital she was found to have twitching, nostagmus, CNS irritability,
and extensive excoriations. On treatment
with fluids she showed improvement and the child was discharged from the hospital after the 16th day, recovered. In 1968 Larsond reported a group of six children, at the Shri-ners Burn Hospital in Galveston, who
devel-oped convulsions during the course of topical
treatment with 3% hexachlorophene
com-pound for their burns. The blood levels of hexachborophene were measured and these were shown to be elevated. Experimental
burns were produced in rats and the absorp-tion of hexachlorophene was shown to occur in this abnormal skin. Blood levels of
from children treated were extraordinarily high but recently have been shown to be erroneous, due to their analytic techniques.
In December, 1968, a valid, highly sensi-live new analytic technique to measure
hexa-chborophene was reported by Browning, et
al.
Bloods were drawn on 50 infants in our institution early in 1970 and blood levelsmeasured of newborn infants who had been
washed with 3% hexachborophene corn-pound.’ A report of these levels (including levels in mothers at delivery and cord bloods of newborn infants) was sent to the FDA.
Kimbrough and Gaines’ studied the toxic effects of hexachiorophene in rats fed a diet containing 500 ppm hexachlorophene. They found an intermyelinic edema of white mat-ter in the central nervous system, which was reversible when hexachborophene feeding was stopped. If continued, the rats developed pa-ralysis and died. Subsequently, Curley, et al.
compared blood levels in rats made toxic by being fed hexachiorophene with levels of hexachiorophene in bloods of infants who were washed by total body bathing and found
that levels in infants ranged as high as 50% those in rats.
A report by Winthrop Laboratories7 of
brain lesions (mntermyelinic edema) in mon-keys washed with 3% hexachborophene com-pound led to the suggested restrictions on the use of 3% hexachborophene compound for the total body bathing of infants.
Described elsewhere in this symposium are
the basic lesions, the interrnyelinic edema which appears to be reversible, in experimen-tal animals.5 There appears to be no change in brain composition other than an increase in the amount of water following experimental feeding of hexachlorophene.
Several investigators currently are examin-ing carefully, both retrospectively and pros-pectively, the brains of babies who have died, particularly in institutions where hexachboro-phene washing has been used. Studies49”#{176}indi-cate that lesions resembling those seen in experimental animals under light microscopy also may be seen in brains of very small pre-mature infants (less than 1400 gm) especially in those subjected to unusual stress-long
term mechanical respiratory assistance,
infec-tions, anoxia, and so forth. The only lesions seen in older infants were secondary to pro-longed hexachborophene usage with abnormal
and excoriated skin. There is no evidence that any full-term baby washed in the usual man-ner in a hospital ever has had untoward
effects. In a followup study reported by Cun-ningham and Tsoulis’ in which 80 infants who had been washed with 3%
hexachboro-phene compound for varying periods from 3 to 82 days, 10 of these for 13 to 82 days, showed no apparent ill effect in their neuro-logic status or developmental patterns. Thus,
current data suggests that the normal use of
hexachlorophene for bathing of term
new-born infants is safe.
III. WHERE WE MIGHT LOOK FURTHER
The problem of toxicity is, of course,
para-mount, and we must recognize what we do not know and how we might go about gaining the kinds of knowledge necessary to make
future rational judgements in this area.
We know that in its metabolism hexachlo-rophene is conjugated to the glucuronide con-jugate which is excreted in the bile.’3 Studies
are needed not on simple blood levels but on bevels of conjugated and unconjugated hexa-chborophene in the blood with usage. Every autopsy done should have tissues taken from infants washed in hexachborophene and blood levels and tissue levels done on vital organs including brain, lungs, heart, kidneys, and intestines. Animal (preferably primate) stud-ies should be done on the toxicity of the glucuronide conjugate.
Valid studies are needed to get an idea whether the entrohepatic shunt mechanisms
are involved in excretion and whether the increased blood levels that one might see in an infant might be due to diminished bowel function and increased reabsorption and
split-ting of the conjugate.
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DISCUSSION ON THE USE OF
HEXACHLOROPHENE IN THE NURSERY
Discussion-following papers by Kimbrough, Mullick and Gluck
Richard Davis, USC: We have been examin-ing brain sections from infants who have died in our nursery. So far we have found five cases similar to those described by Dr. Lampert. However, they occurred both during the period when hexachloro-phene was being used as well as after its
use had been discontinued.
Dr. Shinefield: What was the concentration of hexachlorophene used?
Dr. Davis: One teaspoon of 3% hexachloro-phene in a quart of water.
Moderator: With such a dilute solution, the amount of hexachborophene actually ad-ministered must have been very small. This raises the question as to whether the treated infants form a suitable study group.
Dr. Alan Hodson: We have 10 cases showing striking bilateral and symmetrical vacuo-bation in myelinated areas; six were new-born infants and four were
dermatobogi-cal cases. The newborn infants were all immature (27 to 34 weeks’ gestation) and received daily baths of 3% hexachioro-phene for approximately 8 days. They were selected from 40 infants who died
between 1967 and 1971. None of the infants was asphyxiated at birth and none
required artificial ventilation. These are
preliminary data and we do not yet know what the incidence of these lesions might
have been before hexachlorophene bath-ing was introduced.
Dr. Finberg: I would bike to report an obser-vation recently made in Peru which
