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ANTIMICROBIAL AGENTS AND CHEMOTHERAPY, Dec. 2004, p. 4898–4902 Vol. 48, No. 12
0066-4804/04/$08.00⫹0 DOI: 10.1128/AAC.48.12.4898–4902.2004
Copyright © 2004, American Society for Microbiology. All Rights Reserved.
In Vitro Activities of OPT-80 and Comparator Drugs against
Intestinal Bacteria
Sydney M. Finegold,
1,2,3,4
* Denise Molitoris,
2
Marja-Liisa Vaisanen,
2
Yuli Song,
2
Chengxu Liu,
2
and Mauricio Bolan˜os
2
Medical
1
and Research
2
Services, VA Greater Los Angeles Healthcare System, and Departments of Medicine
3
and Microbiology, Immunology and Molecular Genetics,
4
UCLA School of Medicine,
Los Angeles, California
Received 4 July 2004/Returned for modification 28 July 2004/Accepted 31 August 2004
The activities of OPT-80 against 453 intestinal bacteria were compared with those of seven other drugs.
OPT-80 showed good activity against most clostridia, staphylococci, and enterococci, but streptococci, aerobic
and facultative gram-negative rods, anaerobic gram-negative rods, and Clostridium ramosum were resistant.
Poor activity against anaerobic gram-negative rods may maintain colonization resistance.
Drugs that are poorly absorbed orally may have a place in
therapy for intestinal infections and in certain other situations
in which intestinal bacteria may play a role (7). It is also
important to note the activity of such drugs against members of
the bowel flora that might confer colonization resistance (19).
Vancomycin is used systemically for therapy of severe or mul-
tiresistant gram-positive infections and orally for Clostridium
difficile infections. Although the drug is highly effective against
those infections, vancomycin resistance has been observed in
various organisms, including enterococci, Lactobacillus spp.,
Leuconostoc spp., Pediococcus spp., and staphylococci (4, 9, 15,
17). Such gram-positive organisms are often resistant to other
agents as well (8).
OPT-80 is an 18-membered macrocyclic antibiotic, also
known as tiacumicin B, that, like vancomycin, targets gram-
positive organisms (16, 18). It is currently under development
as a new, narrow-spectrum antibacterial agent to treat C. dif-
ficile-associated diarrhea (CDAD) and colitis. Toxigenic C.
difficile is the causative agent in 20% of cases of antibiotic-
associated diarrhea (2) and is the principal cause of antibiotic-
associated colitis. Current treatments for this disease include
oral vancomycin and metronidazole, but both of these drugs
have a relatively broad spectrum and may exacerbate disrup-
tion of gut flora that led to CDAD originally. Indeed, a major
drawback to both treatments is the incidence of recurrence of
CDAD, which is approximately 20% (5). A unique feature of
OPT-80 is its selectivity for Clostridium, particularly C. difficile
and Clostridium perfringens; previous work has shown that the
MIC for C. difficile is approximately 10- to 100-fold lower than
those for other organisms, including other gram-positive or-
ganisms (1, 16, 18). OPT-80 is also primarily retained in the
gut, with low levels in serum following oral administration in
hamsters (16), rats, monkeys, and humans (Optimer Pharma-
ceuticals, personal communication).
This study was designed to evaluate the in vitro activity of
OPT-80 and comparator agents against intestinal bacteria. An-
timicrobial concentration ranges were selected to encompass
or surpass the levels that would be achieved in the gut (to the
extent that this information is available), subject to the limita-
tions of solubility of the drugs in the testing medium. Table 1
is a summary of the range of concentrations of antimicrobial
agents used during testing and the levels achieved in the bowel
or feces (6, 11, 12).
The bacteria included in this study were mostly recent iso-
lates representative of the indigenous bowel flora. Bacteria
were identified according to established procedures (10), sup-
plemented in a number of cases by 16S rRNA sequence anal-
ysis. Drug MICs for anaerobes were determined by the NCCLS-
approved Wadsworth agar dilution technique (14). Aerobic
and facultative bacteria were tested according to NCCLS
guidelines (13), using Mueller-Hinton (Sigma, St. Louis, Mo.)
agar without blood except for Streptococcus mitis and Strepto-
coccus sanguinis, for which 5% fresh sheep blood was added.
The antimicrobial agents tested were obtained as powders
from the following companies: amoxicillin, clindamycin, met-
ronidazole, tobramycin, and vancomycin from Sigma; lithium
clavulanate from GlaxoSmithKline (King of Prussia, Pa.); lin-
ezolid from Pfizer (Groton, Conn.); ciprofloxacin from ICN
Biomedicals (Irvine, Calif.); and OPT-80 from Optimer Phar-
maceuticals, Inc. (San Diego, Calif.).
* Corresponding author. Mailing address: Infectious Diseases Sec-
tion (111 F), VA Medical Center West Los Angeles, 11301 Wilshire
Blvd., Los Angeles, CA 90073. Phone: (310) 268-3678. Fax: (310)
268-4928. E-mail: sidfinegol@aol.com.
TABLE 1. Summary of drug concentrations tested and fecal drug
levels reported previously
a
Drug Fecal drug levels (g/g)
b
Range of conc
tested
Amoxicillin-clavulanate 25–250 (?) 0.03–128
Ciprofloxacin 890 0.03–512
Clindamycin ⬎200 (increases up to day 5 of
therapy) 0.03–512
Linezolid 9% of dose excreted in feces as
inactive metabolites 0.25–128
Metronidazole 0–23; 2–3 0.25–128
OPT-80 3,000 on 450-mg/day dose
c
;
dosage not yet finalized 0.03–1,024
Tobramycin 1,000–3,000 (?) 0.25–1,024
Vancomycin 1,000–8,000 0.5–1,024
a
See references 3, 8, and 11.
b
?, data not solid.
c
Optimer Pharmaceuticals, Inc., personal communication.
4898
TABLE 2. In vitro activity of Optimer-80 and six comparative agents against 453 bacterial isolates
Bacterial group (n
a
)Antimicrobial agent MIC
c
Range
50% 90%
Bacteroides fragilis group spp.
b
(50) Amoxicillin-clavulanate 1 16 0.50–32
Ciprofloxacin 16 128 8–256
Clindamycin 4 ⬎128 0.50–⬎128
Linezolid 4 8 2.0–8
Metronidazole 1 4 0.25–16
Optimer-80 256 ⬎1,024 256–⬎1,024
Tobramycin 256 ⬎1,024 256–⬎1,024
Vancomycin 64 128 16–256
Veillonella spp. (10) Amoxicillin-clavulanate 0.5 1 0.25–1
Clindamycin 0.5 0.5 0.5
Linezolid 2 2 1.0–2
Metronidazole 2 2 2
Optimer-80 32 128 16–128
Tobramycin 16 64 8.0–64
Vancomycin 512 512 128–⬎1,024
Other anaerobic gram-negative rods
d
(51) Amoxicillin-clavulanate 1 2 0.12–16
Ciprofloxacin 1 8 0.25–32
Clindamycin 0.5 8 0.5–⬎128
Linezolid 1 2 0.5–4
Metronidazole 0.25 4 0.25–⬎128
Optimer-80 1,024 ⬎1,024 0.06–⬎1,024
Tobramycin 128 ⬎1,024 1–⬎1,024
Vancomycin 512 ⬎1,024 0.5–⬎1,024
All anaerobic gram-negative species (111) Amoxicillin-clavulanate 1 8 0.12–32
Ciprofloxacin 1 32 0.25–256
Clindamycin 0.5 ⬎128 0.5–⬎128
Linezolid 4 4 0.5–8
Metronidazole 1 4 0.25–⬎128
Optimer-80 256 ⬎1,024 0.06–⬎1,024
Tobramycin 256 ⬎1,024 1–⬎1,024
Vancomycin 128 ⬎1,024 0.5–⬎1,024
Clostridium bifermentans (9) Amoxicillin-clavulanate 0.25–0.5
Ciprofloxacin 2.0–8
Clindamycin 0.5
Linezolid 1.0
Metronidazole 0.25–1
Optimer-80 0.06
Tobramycin 4–256
Vancomycin 1.0
Clostridium bolteae (7) Amoxicillin-clavulanate 0.5–32
Ciprofloxacin 8.0–64
Clindamycin 0.5–2
Linezolid 4.0
Metronidazole 0.25–1
Optimer-80 1–64
Tobramycin 8–128
Vancomycin 1.0–16
Clostridium clostridioforme (4) Amoxicillin-clavulanate 1.0–16
Ciprofloxacin 32
Clindamycin 0.5
Linezolid 4.0
Metronidazole 0.25
Optimer-80 4.0–128
Tobramycin 16–1,024
Vancomycin 1.0–8
Clostridium difficile (23) Amoxicillin-clavulanate 2 4 0.5–8
Ciprofloxacin 8 32 1.0–64
Clindamycin 2 ⬎128 0.5–⬎128
Linezolid 4 32 1.0–32
Metronidazole 0.25 0.5 0.25–1
Optimer-80 0.12 0.25 0.06–2
Tobramycin 512 ⬎1,024 64–⬎1,024
Vancomycin 1 2 0.5–4
Clostridium glycolicum (9) Amoxicillin-clavulanate 0.25–1
Ciprofloxacin 1.0–16
Clindamycin 0.5
Linezolid 1.0
Metronidazole 0.25–0.5
Optimer-80 0.06–1
Tobramycin 16–256
Vancomycin 0.5–1
Continued on following page
VOL. 48, 2004 NOTES 4899
TABLE 2—Continued
Bacterial group (n
a
)Antimicrobial agent MIC
c
Range
50% 90%
Clostridium innocuum (9) Amoxicillin-clavulanate 0.5–1
Ciprofloxacin 2.0–8
Clindamycin 0.5–⬎128
Linezolid 2.0–4
Metronidazole 0.25–1
Optimer-80 32–128
Tobramycin ⬎1,024
Vancomycin 8.0–16
Clostridium paraputrificum (8) Amoxicillin-clavulanate 0.25–2
Ciprofloxacin 1.0–4
Clindamycin 0.5–4
Linezolid 0.5
Metronidazole 0.25–1
Optimer-80 0.06–8
Tobramycin 32–512
Vancomycin 1–2
Clostridium perfringens (14) Amoxicillin-clavulanate 0.25 0.25 0.25–0.5
Ciprofloxacin 0.5 1 0.25–1
Clindamycin 0.5 2 0.5–2
Linezolid 2 4 1.0–4
Metronidazole 0.5 2 0.25–2
Optimer-80 0.062 0.062 0.06
Tobramycin 256 1,024 1.0–1,024
Vancomycin 1 1 0.5–1
Clostridium ramosum (10) Amoxicillin-clavulanate 0.5 0.5 0.25–0.5
Ciprofloxacin 16 16 4.0–16
Clindamycin 1 4 1.0–8
Linezolid 8 16 8.0–16
Metronidazole 0.5 1 0.5–2
Optimer-80 512 512 256–512
Tobramycin 256 256 128–256
Vancomycin 4 8 4.0–8
Clostridium sordellii (5) Amoxicillin-clavulanate 0.25
Ciprofloxacin 0.25
Clindamycin 0.5–2
Linezolid 1.0
Metronidazole 0.5
Optimer-80 0.06
Tobramycin 2.0–256
Vancomycin 1.0
Other clostridial species
e
(9) Amoxicillin-clavulanate 0.25–2
Ciprofloxacin 0.25–32
Clindamycin 0.5–2
Linezolid 1.0–4
Metronidazole 0.25–⬎128
Optimer-80 0.06–⬎1,024
Tobramycin 0.25–⬎1,024
Vancomycin 1.0–64
All Clostridium species (107) Amoxicillin-clavulanate 0.5 4 0.25–32
Ciprofloxacin 8 32 0.25–64
Clindamycin 0.5 8 0.5–⬎128
Linezolid 2 4 0.5–32
Metronidazole 0.5 1 0.25–⬎128
Optimer-80 0.062 128 0.06–⬎1,024
Tobramycin 256 ⬎1,024 0.25–⬎1,024
Vancomycin 1 16 0.5–64
Anaerobic non-spore-forming gram-
positive rods
f
(63)
Amoxicillin-clavulanate 0.25 1 0.25–4
Ciprofloxacin 2 32 0.25–128
Clindamycin 0.5 4 0.25–⬎128
Linezolid 0.5 2 0.5–4
Metronidazole 4 ⬎128 0.25–⬎128
Optimer-80 1 32 0.06–⬎1,024
Tobramycin 64 512 1.0–⬎1,024
Vancomycin 1 2 0.5–⬎1,024
Anaerobic gram-positive cocci
g
(49) Amoxicillin-clavulanate 0.25 1 0.25–32
Ciprofloxacin 1 32 0.25–64
Clindamycin 0.5 4 0.5–⬎128
Linezolid 1 4 0.5–4
Metronidazole 0.25 1 0.25–2
Optimer-80 0.5 2 0.06–1,024
Tobramycin 16 256 1.0–1,024
Vancomycin 1 1 0.5–8
Continued on following page
4900 NOTES ANTIMICROB.AGENTS CHEMOTHER.
For analysis, the bacteria tested were generally placed into
genus, species, or other groups with at least 10 isolates. The
ranges and the MICs at which 50 and 90% of isolates were
inhibited were determined except for organisms with fewer
than 10 strains tested, for which only the ranges are reported
(Table 2).
Although vancomycin showed relatively poor activity against
gram-negative anaerobes, including the Bacteroides fragilis
TABLE 2—Continued
Bacterial group (n
a
)Antimicrobial agent MIC
c
Range
50% 90%
All anaerobic gram-positive species (219) Amoxicillin-clavulanate 0.5 2 0.25–32
Ciprofloxacin 4 32 0.25–128
Clindamycin 0.5 4 0.25–⬎128
Linezolid 1 4 0.5–32
Metronidazole 0.5 128 0.25–⬎128
Optimer-80 0.12 64 0.06–⬎1,024
Tobramycin 128 ⬎1,024 0.25–⬎1,024
Vancomycin 1 8 0.5–⬎1,024
Streptococcus, formerly S. milleri group
h
(14)
Amoxicillin-clavulanate 0.5 1 0.25–1
Ciprofloxacin 0.5 0.5 0.5
Clindamycin 1 4 0.5–4
Metronidazole 64 128 64–128
Optimer-80 32 32 16–64
Tobramycin 128 256 32–256
Vancomycin 1 1 1.0
Other Streptococcus species
i
(9) Amoxicillin-clavulanate 0.03–4
Ciprofloxacin 0.5–4
Clindamycin 0.03–⬎128
Metronidazole 256–⬎256
Optimer-80 16–128
Tobramycin 8.0–16
Vancomycin 0.5–1
Enterococcus species
j
(21) Amoxicillin-clavulanate 1 2 0.5–128
Ciprofloxacin 4 128 2.0–⬎128
Clindamycin 16 512 8.0–⬎512
Metronidazole ⬎1,024 ⬎1,024 ⬎1,024
Optimer-80 8 8 2.0–16
Tobramycin 32 ⬎1,024 16–⬎1,024
Vancomycin 1 4 0.5–4
Staphylococcus aureus and Staphylococcus
epidermidis
k
(19)
Amoxicillin-clavulanate 0.5 2 0.12–16
Ciprofloxacin 0.5 1 0.03–16
Clindamycin 0.25 0.25 0.12–⬎512
Metronidazole 256 ⬎1,024 128–⬎1,024
Optimer-80 0.5 2 0.25–2
Tobramycin 0.5 1 0.25–2
Vancomycin 2 4 1.0–4
Total for all strains (453)
l
Amoxicillin-clavulanate 1 16 0.03–⬎128
Ciprofloxacin 2 32 0.03–512
Clindamycin 0.5 512 0.03–⬎512
Linezolid 2 4 0.5–32
Metronidazole 1 ⬎1,024 0.25–⬎1,024
Optimer-80 8 1,024 0.06–⬎1,024
Tobramycin 64 ⬎1,024 0.25–⬎1,024
Vancomycin 2 ⬎1,024 0.5–⬎1,024
a
n, number of strains tested.
b
Bacteroides distasonis (7), Bacteroides fragilis (13), Bacteroides ovatus (10), Bacteroides thetaiotaomicron (10), Bacteroides vulgatus (10).
c
Minimum inhibitory concentrations (MICs) are listed in micrograms/milliliter. 50%, MIC at which 50% of isolates tested were inhibited; 90%, MIC at which 90%
of isolates tested were inhibited.
d
Bilophila wadsworthia (10), Fusobacterium mortiferum (3), Fusobacterium necrophorum (3), Fusobacterium nucleatum (4), Fusobacterium varium (2), Porphyromonas
spp. (11), Prevotella spp. (8), Sutterella wadsworthensis (10).
e
Clostridium bartlettii (1), Clostridium butyricum (2), Clostridium disporicum (1), Clostridium hypermegas (1), Clostridium orbiscindens (1), Clostridium subterminale (1),
Clostridium species (1), Clostridium tertium (1).
f
Actinomyces meyeri (1), Actinomyces odontolyticus (5), Actinomyces viscosus (2), Atopobium minutum (3), Bifidobacterium adolescentis (3), Bifidobacterium breve (1),
Bifidobacterium dentium (2), Bifidobacterium species (3), Collinsella aerofaciens (7), Eggerthella lenta (5), Eubacterium biforme (1), Eubacterium cylindroides (1),
Eubacterium limosum (5), Eubacterium saburreum (3), Lactobacillus catenaforme (1), Lactobacillus jensenii (4), Lactobactillus fermentum (1), Lactobacillus species (4),
Propionibacterium avidum (1), Propionibacterium acnes (7), Propionibacterium propionicus (1), Propionibacterium species (2).
g
Anaerococcus prevotii (7), Anaerococcus tetradius (6), Finegoldia magna (7), Peptoniphilus asaccharolyticus (6), Peptostreptococcus anaerobius (7), Peptostreptococcus
micros (6), Ruminococcus gnavus (4), Ruminococcus species (5), Ruminococcus torques (1).
h
Streptococcus anginosus (7), Streptococcus constellatus (4), Streptococcus intermedius (3).
i
Streptococcus mitis (3), Streptococcus salivarius (3), Streptococcus sanguinis (3).
j
Enterococcus avium (1), Enterococcus faecalis (14), Enterococcus faecium (6).
k
Staphylococcus aureus (9), Staphylococcus epidermidis (10).
l
Not all data are shown (data for 60 strains of aerobic or facultatively gram-negative bacilli are not shown).
VOL. 48, 2004 NOTES 4901
group, these organisms are usually suppressed in the intestinal
tract by the very high levels achieved in the bowel by oral
administration (Finegold et al., unpublished data).
OPT-80 was distinctly less active against the B. fragilis group
than vancomycin. Vancomycin had good activity against all
clostridia, whereas OPT-80 had fairly good activity against
Clostridium bolteae and Clostridium clostridioforme, fair activity
against Clostridium innocuum, and relatively poor activity
against C. ramosum. It is interesting that among the clostridia
studied, susceptibility or resistance to OPT-80 correlated with
the taxonomic clusters of clostridia (3) to which they belong.
Clostridia that were very sensitive to OPT-80 were all in clos-
tridial clusters I and XI; those that were less susceptible belong
to clusters XIVa, XVI, and XVIII. Both OPT-80 and vanco-
mycin had good activity against most anaerobic gram-positive
non-spore-forming rods and anaerobic gram-positive cocci.
Vancomycin had better activity against streptococci, both
showed good activity against enterococci and staphylococci,
and both had poor activity against nonanaerobic gram-negative
bacilli (data for the latter group not shown).
C. difficile-associated colitis has generally responded well to
therapy with vancomycin, metronidazole, or bacitracin, all ad-
ministered orally; the current data indicate that it should re-
spond well to oral OPT-80 as well, but studies on this are not
available yet. Additional indications for therapy with some or
all of the drugs in this study include neutropenic enterocolitis,
intestinal colonization with vancomycin-resistant enterococci
and staphylococci or antibiotic-resistant viridans group strep-
tococci in an immunocompromised host, preoperative bowel
preparation, D-lactic acidosis, bowel bacterial overgrowth syn-
drome, and investigational use in late-onset autism (7).
Factors that would help determine the relative utility of
these various agents would include such things as usefulness of
the compounds for therapy of serious systemic infections, lev-
els of drug achieved in the gastrointestinal tract, maintenance
of colonization resistance in the bowel, bactericidal activity,
drug allergy, absorbability of the drugs with oral administra-
tion, gastrointestinal and systemic toxicity, frequency with
which resistance develops, cross-resistance with other com-
pounds (particularly those that are used systemically), fre-
quency of dosage required, patient tolerance of the medication
(over prolonged periods in the case of autism), palatability,
ease of administration to young children (liquid preparation
preferred), and cost. Clinical studies are needed to assess the
clinical utility of the various drugs with good activity against
intestinal bacteria in these situations.
This study was funded by Optimer Pharmaceuticals, Inc., San Diego,
Calif., and Veterans Administration Merit Review research funds.
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4902 NOTES ANTIMICROB.AGENTS CHEMOTHER.
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