isinfectant Rotation - A@, .

, -,,,-A

Microbiologist's View
- \n xamination of the ongoin discwrsim of the valid
rntntion of disinfectants in a p armaceu~calcleanronr a SCOTT V. W. SUTTOr

I HAVE MODERATED THE PMFLIST, an email cliscussion list o n the Internet dedicatee1 t o topics
o f intercst t o microl>iologists in the pharnlaceutical anel personal care inclustrics; a list that 1x1sheen active
sinc,e 1996 (http:/iwww.microI~ioIIorg/p~~~listi~fo.ht~-r-r). I mention this only I>cc:~usein that time I have h:~cl
the opportunity t o clcvclop ;I pcrspcsctive o n issues that interest thc working microbiologist. Occasionally,
the oclcl topic u d l really catch fire in the cliscussion group. This happenccl recently in response t o an inter-
in the March 2005 issue ofcUC.2 iVI~guzine111 dealing with the advisability of
esting :irticlc t h a ~;~ppc%arccl
disinfectant rotation. In this thoughtful article. the author argued for the ncccl to "rotate" a disinfectant with
a s~mriciclc.The interest in this topic initially cr-une as a surprise to me, as I hacl thought the issue long sincc
resolvecl in the p11armaccutic:tl anel personal cart inclustries.

As the clisc~ssioncontinuecl on the PklFList, the T h e next question is o n e of significance. Is this

points of contention l~ecan-rcmore clear. A great deal
:)f discussion revolveel around t h e conccpt that a
nicroorganism coulel I>econ-reresistant to a disinfcc-
.ant. Here is \vhcrc the first hit of clarification is
.equirecl. A microorg:~nism u,ill not hecome resist-
t ~nuc.11o f anything. IL either is o r it is not affcct-
. ~ nto
cd by the compound. Within a v e ~ ylarge population
of microorganisms. there is a c.hancc (normally a
chance o f a p p r o x i m ~ t ~ lLO y 6) that a cell within the.
population will Il;~vc;I mut:~tion at :I specific gene.
1 his might proviclc somc compctitiw aclvantage under
r.
somc environments, pcrllaps s u ~ ~ i vin a lthe presence
of a n elevated level o f a c h c m i ~ ~'The l . mutation that
promotes survival under these conditions could, ovcr
thc course of a few generations. 1)ecome the clon-ri-
nant genotype, in that popul;~tion.This is! of cowsc,
:~ssun-ringthat the ch:~llcngcis not too great. For esam-
ple, it cloes not matter h o w aciclotolerant a particu-
lar mutant is, grcnvth in 6s hyclrocholoric acid is just
plain unlil<ely-the, c.onditions :ire 100inhospitablr t o
life.
Can a low level ofexposurc to I>iocitlessc-lect vari-
ants in a popi11:ttion that are more tolerant t h m the
previous clomin:lnt type! Can 1 0 Ievcl ~
select "resistant" ~ n i c r o o ~ . g ; c ~ lAlxoli~tely.
exposure
i s ~ ~ ~ s ? 'I'he phe-
nomenon o f biocide rcsistancc is well Itnown and has
I x e n extensively reviewed in thc literature 12-51.
Extensive work o n the ~ncchanismof :letion allowing
previously susceptilde microolg:~nis~ns to survivebcxIe-
vatccl levels of the I>ioc.iclc 11ave llighlightecl cftlux
p u m p s a s a major contributor to the bociclc rcsist-
ancc 16,71, as wcll :IS physiologicxl aclaptation 181.
p h e n o m e n o n of any consequence t o t h e p h a r ~ m -
ceutical cleanroom sanitization program? Well, that is
what I hope LO ans\vcr in this short cssay.
The Development of Resistance in
Bacterial Populations
Genetic Resistance
The literature proviclc.~nxmy esarnplcs o f microor-
ganisn-rs able t o survive in disinfectants. This can b e
either in 1ahoratol-y experiments using :In i n c r c ~ s i n g
level o f hiociclc t o select vari:~nts in the population,
o r I>y csamin:~tion of I~iociclalsolutions for the prcls-
vnce of resistant microorganisms. The, gram-ncga-
tive I,acilli are the most frequent isolates from this
type o f evaluation [9-151. This may hc d u e to a com-
Iination of causes inclucling alterations in outer mem-
I m n e perlncalility d u e to changcs in porin diameters
110-191. In adclition, it is not c l e ~ tr h t the outcr-mcm-
I m n e mediated resistance is in ktct d u e to selection
of a mutant genotype from the population, o r rather
phenotypic aclaptation, as this trait has been report-
eel to h e rapiclly lost once thc sclectivc pressure is
remc )vccl.
The other type of experiment pc~rformeclto clemon-
I
strate clevelopn-rent of genetic resistance is o n e in
which a lal>oratory researcher takes I: microorganism
in culture anel esposcs it to incseasing levels of bio-
ciclcs, selecting resist:lncc wriants at cach stage. Thew
is o n e such set o f expc~rimcntsof particular rclev;~nce
to he pharmac~euticalmic.robiologist that w e will
examine in some detail a s a n example.

Controlled Environments www.cemog.us

 In 1992, Connei-m c l Eckm:~npul>- :I resi
lisllcd a study purporting to show the espos
need for rotation of ;I low pH phe-
A great deal of discussion IW of
nolic ;md ;I high pH phenolic t o prc- revolved around the CFU)
vent the grner;rtion of sc.sistant che~n
t S e ~ ~ d o m o nucrugit/o.w
us [20].Tl~is concept that a I ~ r snc
study w:~s:I rrprtiti\.e zone of inhi- microorganism could ture fi
lition design, \\.here, :in :~lk:~linc.
(131I facturi
10.4) and ;In ;rciclic (121%1.6)p h c m - become resistant to this h;
lic disinfectant u w c placed in paper hospit
discs : ~ the
t center of a Ixictcrial lawn.
a disinfectant.
levels
As tllc h n n grcu to visil~lcturl%clity, highel
the clisinfect;~ntdiffusing out f m n the ing :I "seist;rn" colon! . creating a nition
clisc cre~rtcda concentration g1-adicnt. lann using this nV\\ iso1:rtc. :rncl then 331. 1'11
Conner anel Eckman tllen picked loolting for :rnorhc~.'rc4st:rnt" colon! tI1:1t a r
colonies t h t grcu closest to the disc. fronl the first \.:ri.i;rnt. tlisinfc
tI~c~.cforc in the highest concentration R7hat the :ruthors found na.; that 1q>pe1
o f disinfect in the diffusion gradient. the alkaline phrnolic treatment c\-en- ;ItLlre r
for the next cycle. Four treatments t ~ ~ a lrrsultrd
lp in :I \.xiant of I?UCI-LI,(C- Ie\t+i 2
\vere used: water; high pH phenolic: itzosa th:rt producrd 110 zone o f the sun
lo\\. 1211 phenolic; and alternating inhihition ;rrounci the :rlkaline phe- in cont
(rotating) the two phenolics. The nolic-imprrgn;~trcIclisc, n4iile the Io\v
clullenge \?;as over 40 cycles of pick- pH phrnolic :rnd the '.rot;~tecl"phe- Physi
\Y;hile
:rd:rpr:~
nihm f c
,srction
I>iofilm
micnxx
s~1cch:ls
llll:~r stsr
nutrient
COIII111L1
tection f
impede:
to the cc
ty of bic
CIS o f di:
[35-371.
speak to
rants, as
tection a
treatmcn
lier I,y Cm
There
clisc~~ss
aforemer
correctly
of vegeta
PI-o\.ide:
nate spo
Although
among cli
thcir sc.11
A Circle No. 8 on Free Product Info. Card thesc. diff

10 , b July 2005 Controlled Environments + www.cemog.us Controlled En\

:I resistant \,ari:~nt \ \ . o L I ~ c ~ re(1~1ire sistent Ix~cteri:~l load under s o m e ind~1stri:d pl-actice of alternating the
exposure of a n extremely I:1rgc num- conditions. these differences pale daily use of 21 clisinfect:rnt \\,it11 the
I x r of' cells (in excess of 1,000,000 Ixsicle tlie resistance of spores to periodic use of :I sporicicle in a m:u-
C F I I ) to a lo\\. le\.el of the toxic en\.ironment:ll insult. The spore form i h c t i ~ r i n gk~cility'ss:mitization pro-
chemical. I( is not surprising t h t this is nxti~lxllymore resistant to chemi- gr;~ni.The o h i o i ~ s:rppr";cli to this
1 ~ 1nots heen reporteel in lhc. 1iter:l- cal treatments a n d lixrsher agents prol,lem might seem to he the exclu-
tilre from a pliarm:rcci~ticxlmanil- must be used to comlxt t l i ~ s eorgan- si\re use of the sporicicle. l-lo\vever.
h c t ~ ~ r i ncleanroom
g Irlcilit>. In f x t . isms. 'l'liis is tlie 1)asis of tlie conlnlon as the author points out, the
this h ; ~ snor I)een reporteel e\.erl (or
Iiospiral s i ( i ~ : ~ t i o n\ \sh e r e Ix)th tlie
le\ els of 11iic.1-oorg:~nis~iis are mi~cli
higher :~nclthe potenti:~l for recog-
nition of rhe e\ ent is niore liliel!. 1.32.
331. Put simply, selection 01' 11ir1t;tiits
tli:~t are resis(a11t to i n - i ~ s ele\.els ol.
disinfecrants has not I x e n silo\\ n to
Iiaplwn in cle:r~lroo~n settings. Liter-
ature reports of resist:lnce to i n - L I S ~
le\ els are restricted to clescriptions of
tlw si~n.i\ :11 o S slpecific ~ i i i c r o o r ~ ~ ~ i i s t i i s
in cont:lmin:lted solutions 19. 1i.341.

Physiological Adaptation
R'liile \\ e li;~\-ecliscussctl genctic
acl:~pt:~tion,tliere is another 11iecI1:l-
nism for resista~lce.In the pre\ i o r ~ s
section \\ c toi~cliedo n I>iof'ilnis. .A
I>iofilm is :I cotlipleu co~iinii~tiit!.of
microorganisllls suspenclecl in a poly-
s:~ccliaritleglj.coc;~l)u. The e x t ~ ~ c e l -
1ul:lr structilre l>ro\icles :I foilncl:~tion.
nurrients for sollie meliilxw of tlie
co~iuiiunit!. ;1tic1 ;11so pIi!.sic;~I pro-
tection from chemical treatlnellt :IS il
impedes tlie cliffusion o f clle~ilicals
to tlie cells in the interior. The alili-
ty of hiofilm lo \\ it1lst:lncl I ~ ~ r gle\e -
els of disinfect:lnts is \\ell estaldisliecl
135-.3-1. 'Tliis d o e s not. ho\\ e \ er.
speak to llle neeel to rot:lte clisinfec-
t:lnts. :IS tlie I>iol'ilm\\.ill pro\icle pro-
tection against \\.Iiiche\.er cliemic;~l
treatliient !.oi~attempt. ;IS slio\\m w r -
lier ?I.! Canner and l<cl<man.
There is o n e o t l i c ~;~spcctof tliis
disci~ssionI slioi~lclmcntion. In tlie
;~forementioneclarticle 111. tlie ; ~ ~ ~ t l i o r
correctl!. s e p l x t e c l tlie elisinfection
of \cgct:rti\,e cells fro111the need to
pro\ icle sporicicl:~lacti\ it! to eli~iii-
n:tte spores 01' bacteria :~nclI'ungi.
Altlioi~glithere :Ire clear clifkrences
among clift'erent Iwcterial species in
their sensiti\,ities to elisinfectants and
these differences c;ln res~lltin per- A Circle No. 9 on Free Product Info. Card

Controlled Environments <) www.cemag.us ,1 1

July 2005 :
consistent use of common sporicides ;I true measuse 01' the efficacy o f a
(frequently. strong oxidizing agents) particular ctiemical agent ag:~instthat
ing what we clo as "disinfec,tant rotrtion"
is grossly im~ccuratc.We. in f'act. are
phrase-
does nd
i
will result in corrosion of equipment
in a re1;rtively short periocl of t i i w and
Ix~cterialspecies. This measure has lit- not discussing rotating disinfectants at
tle meaning in clisinfrctmcy \\-liere all. 12ather w c are urging tlic roi~tinc prog 1
of an e

pose safety issues for tlie technici:rns the true test is t h r ability of the agent
applying them to the cleanroom. 11 t o kill Ix~cteria.not prevent them from
is far prefesalic to usc. the gentler dis- grou.ing. S o w e start off u.itli tlie
use of :In effecti\,e disinfectant \\-it11
tlic perioclic use of :I sporicicle 130.
401. Hlock 14 11 clefines :I clisinfect;~nt
the 1
infect;~ntfor a s much of the time a s wrong test. Froni this poor heginning AS: " . . .an xgcnt that frees from infec-
possil,le, reserving the sporicicle for w e then argue that a slight l ~ ~ tn c x + tion. . . .that clestroys cliseae o r other
periodic cleaning. response t o an i ~ r a h l eincrease in the al3ility of the l i ; ~ r ~ nmic:roorganism,s
f~~l 1 ~ 1 ma!.t not
event, e.g. po\vcr klilurt.. c~~t:~stropli-organism to grmv in low le\,els of the kill Ixicterial spores. It refc1-s to s u b
ic excess action le\.els; o r bring- cliemic~alagent is proof of resistance, stanct. :lpplied to in:~nini:~te ol>jccts."
ing a f:rcility I x ~ c kon-line after a ignoring the fact that the clilution of 1 Ie goes o n to clvf'ine :I sporicicle :IS
shut-clown. tlie :]gent in a facility mav h e thou- " . . . a n agent tliat destroys microl%al
smcls of times more ~wncentr;~tecl spores, cspeci;~lly:I c1lcmic;rl s u b
On the Need for Clarity ttian the concentration used in the s t m c e tliat kills bacterial spores."
in Terms study 1361. Finall). we ignorc the hasic Wh:~t \\,e are cliscussing is a p n c -
A final aspect of this discussion is the mechanism of action of clisinfectants. ticc more ;rcci~ratelyclescril~cclas A
sen~:~ntics of the suhject 1n;ittcs. A r e d incorrectly applying the moclel of anitiz:~tion program. hut cc11;rinly not
problem is the use o f the term "rt.ist- antibiotic resisunce ~~~~~~~e
a nil~tant "elisinfectant relation"-a term that
ance." This term originateel in the clin- develops resistance to a "magic h u - c o n t i n ~ ~ to
e s colifuse ~ x ~ c t i t i o n e;~ncl
rs
ical niicrohiology arena n.liere t h e let" by altering the specific target of segirl:~tors alike.
inhibition of hc~terialg l r l n ~ hpro\kles the :~ntihiotic)to tlie mode of action
o f disinfectants Summary
(most of which '['he need for tlie rotation o f clisinfec-
Considerinu Cleanroom Garment act ;rt a basic tants in a pharm:rc'e~~tic:dcleanroom
cliernistry level: s:~nitization progl-am is not support-
Rental, cease or Purchase? complc,tely clis- : ~ h l e from a sc.ientific. hasis. T h e
supting tlie cell assi~mptionst h ~ proponentst o f tlie
Consider... memlmne or fun- 1Xrcticc assell as hcts. e.g. generation
clamentally dtcr- of resist:~ntorg:~nisins.greater effic;~-
ing entire cl;~sses c!, of alternating :~gcnts.:!re not s u p
of cell compo- portccl hy the literature. Ho\ve\.cr.
nents). A resist- c\,cn \\-hen ~ l s i n gL: \,aliclatecl clisin-
ance that can be fect:rnt as p;rrt of a \\ell-manageel
me:~silred only in cleanroom sanitiz;~tionprograln. peri-
tlie la1 ). not in tlie odic ~ l s cof~ a sporiciclc is :I pruclent-
Since 1960, Prudential Cleanroom Services fielcl. is of little even an essential-compor~ent of tlic
has remained First in Cleanroom laundry Processing
Services for critically controlled environments. pncticd concern. sanitization psogl-am. It is necdecl t o
A seconcl prol3- acldress tlie occasional appc;u-ance of
la in Building Relatianships 1* in Accountability lem is the term spore-forming osg:~nism,\in the en\+
1" in Commitment 1'' in Experience i~seclto clcscribe roninental monitol-ing program xicl
I* in Availability 1' in Capacity the p l i a r r n a c ~ ~ ~ t i therefore
- cnsure the cltxnest 1x)ssihle
1" in Sterility Assurance & Capabilities cal practice. Given en\,ironnlent for nlanuhcturing. Wc
our cuirent uncler- need to clcarly clesc.rihe oilr 13r.1 ..
' ct~c'es
stancling. clescril,- anel leave Ixliincl the inaccur:~tc~

Strain of
Mesa AZ Los Angeles CA Milpitas CA The need for rotation of disinfectants in a mercially
Denver CO Austin TX Richmond VA Tijuana MX Appl. Eni
pharmaceutical cleanroom sanitization 3598.
IB R.E.W. Hj
brane Per
program is unsupportable from a Vol. 38, (1
H H. Nikaid
scientific basis.
m Circle No. 10 on Free Pmduct Info. Card

Controlled Environments .+www.cemag.us

phrase "disinfectant sorarion," :IS i t
does not descril,~the cursent practice
of an cffcctivc clcansoom sanitization
psog';~m ancl only confuses cliscussion
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Technol., Vol. 6, No. 1, (1993) pp. 94-104.

Reterences
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reliable and rugged
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high chemical tolerance
ratis marcescens In Chlorhexidine," J. Appl.
Environ. Microbiol., Vol. 42, No. 6, (1981) pp. EXi approved transmitters
1093-1102.
R.L. Sautter, et al. "Serratia marcescens available
Meningitis Associated with a Contaminated
Benzalkonium Chloride Solution," Infect.
Control," Vo1.5, (1984) pp. 223-225. Call or e-mail for more information. IVrde rnngr ofhurnrdrt~v
R.L. Anderson, et al. "Investigations into the ~rrsfrurnrtrtsovarlable
Or access our products online at
Survival of Pseudomonas aeruginosa in
poloxamer-lod~ne,"Appl. Environ. Mlcrobiol., www.vaisala.com/instruments/HM70
VOI 47, NO.4, (1984) pp. 757-762.
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brane Permeability," Ann. Rev. Microbiol., 1-888-VAISA1.A (82'1-7252)
Vol. 38, (1984) pp. 237-264. inslrurnrnls@vaiaala.com Reliable.
m H. Nikaido, M. Vaara. "Molecular Basis of
Outer Membrane Permeability," Microbiol. --

Rev., Vol. 49, (1985) pp. 1-32. A Circle No. 11 on Free Product Info. Card

Controlled Env~ronments? www cemag us July 2005 > 13

 Against Adherent Pseudomonas aeruginosa,"
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www.micronova-rnfg.com
888-81 MICRO
3431 West Lornita Boulevard
Torrance, CA 90505-5010
14 b July 2005
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Biofilms," J. Appl. Microbiol. Syrnpos.
Suppl., Vol. 92, (2002) pp. 163-170s.
Detergent concentrate. Filtered to 0.1 microns.
For general cleaning in cleanrooms.
NovaHol
Ready to use cleaner with alcohol. Filtered to
0.1 microns. Decreases bioburden.
Megaclean
Removes heavy soils and adhesive residues.
A Circle No. 12 on Free Product Info. Card
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cherichia coliGrowing As Biofilms to Dis~n-
fectants," Vet. Res., (1997) pp 353-363.
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