Relationship of biocide use to antibiotic resistance

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Relationship of biocide use to antibiotic
resistance
Stuart B. Levy, M.D. Tufts University School of
Medicine Alliance for the Prudent Use of
Antibiotics
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Its A Question of Residues
?
Residues
Triclosan QACs Triclocarban
Non-residues
Bleach Peroxides Alcohols
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Cross- and Co- Resistance (Biocides and
antibiotics)

• Target mutations
• Multidrug efflux systems
• Plasmids transposons

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C
l
H
O
O
C
l
C
l
Triclosan
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Triclosan Resistance


MIC

Fold

Mutated


(µg/ml)

Change

Gene





AG100

0.05

1.0

---

AG100 (low)

0.2

4.0

fabI
(F203L)

AG100 (medium)

1.9

40

fabI
(M159T)

AG100 (high)

25

500

(G93V)

fabI

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Inhibitors of Enoyl reductase (fabI, inhA)
Isoniazid
Triclosan
Diazaborine
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Mutations in InhA confer triclosan resistance in
Mycobacterium smegmatis

• Strain Selected InhA Relative
  MIC
• on mutation (in 7H9
  medium)
• Triclosan Isoniazid
• mc2155 (wt) -- none 1.0
  1.0
• MT 1 TRC M161V 6.3 8.5
• MT 9 TRC M103T 6.3 1.2
• MT 17 TRC A124V 5.8
  2.0
• mc2651 INH S94A 6.3 22.0
• mc2155 -- none 6.3
  gt64
• (pinhA)

• TRC triclosan, INH isoniazid
  McMurry et al, AAC 43711, 1999.

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Efflux as a Common Mechanism of Biocide and
Antibiotic Resistance
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bile salts triclosan chloroxylenol quaternary
amines chlorhexidine
pine oils
organic solvents
antibiotics
acrAB
mar
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Biocide resistance and antibiotic resistance
Regulators and efflux pumps
Biocide Inducer/Substrate Affected proteins Drugs
QACs, chlorhexidine, triclosan Morita et al JAC 51991 (2003) NfxB MexCD-OprJ (P. aeruginosa) Multiple antibiotics
Triclosan Schweizer et al AAC 42394 (1998) Schweizer FEMS Microb Lett 2021 (2001) MexAB-OprM MexJK (P. aeruginosa) Multiple antibiotics
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Genetic linkage of resistance to QACs and to
ß-lactam antibiotics in staphylococci
Sidhu et al AAC 462797 (2002)
Sidhu et al MDR 7363 (2001)
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DECREASED DRUG SUSCEPTIBILITY
DRUG RESISTANCE
Penicillin resistant S. pneumoniae Fluoroquinolon
e resistant E.coli Vancomycin resistant S. aureus
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Triclosan Susceptibility (Staphylococcus)
60
50
S. aureus N43
40
S. capitis N42
of total isolates
30
S. epidermidis N73
20
S. warneri N155
10
0
1.0
2.0
4.0
0.0312
0.0625
0.1250
0.2500
0.5000
Triclosan MIC (ug/ml)
Household hand isolates
A. Aiello et al. Antimicrob. Agnts. Chemother.
482973-2979, 2004.
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Triclosan Susceptibility Klebsiella pneumoniae
(N 69)
35
30
25
20
of total isolates
15
10
5
0
1.0
2.0
4.0
8.0
16.0
32.0
0.0312
0.0625
0.1250
0.2500
0.5000
Triclosan MIC (ug/ml)
Household hand isolates
A. Aiello et al. Antimicrob. Agnts. Chemother.
482973-2979, 2004.
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Antibiotic susceptibility of MRSA
andbenzalkonium chloride resistant derivatives

• MIC (?g/ml)
• Antibiotic MRSA
• Parent BZ-R-1 BZ-R-2
• Oxacillin 16 512 512
• Cloxacillin 0.5 256 512
• Moxalactam 64 256 1024
• Flomoxef 8 128 128
• Cefmetazole 8 128 64
• Cephalothin 64 128 128
• Ampicillin 16 32 32
• Chloramphenicol 4 4 4
• Ofloxacin 8 32 32
• Tetracycline 128 128 128
• Benzalkonium chloride 5 10 10

• Akimitsu et al, AAC 433042, 1999.

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Antibiotic Susceptibility of Benzalkonium
Chloride selected mutants
S. Langsrud et al. Appl. Microb. 140321 (2003)
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Antibiotic Resistance and Hand Soaps
Figure 2. Proportion of study participants with
gt1 bacterial species resistant to an
antimicrobial agent on their hands. In the group
that used antibacterial products, 82 and 105 hand
samples were available at baseline and at
year-end, respectively. In the group that used
nonantibacterial products (i.e., plain soap), 82
and 96 hand samples were available at baseline
and at year-end, respectively.
Aiello, et al. Emerg Inf Dis 111565, 2005.
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Resistance evolves in time and volume of drug
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Evolution of MDR in S. aureus
Penicillin
Methacillin
MRSA
PenRSA
VISA
Vancomycin
VRSA
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Contributors to Drug Resistance
TODAY
ANTIBIOTICS (people, animals, agriculture)
BIOCIDES
DRUG RESISTANT MICROBES
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Contributors to Drug Resistance
TOMORROW?
ANTIBIOTICS (people, animals, agriculture)
BIOCIDES
DRUG RESISTANT MICROBES