- Email: [email protected]
In vitro activity of temafloxacin against gram-positive cocci including methicillin-resistant Staphylococcus aureus
In Vitro Activity of Temafloxacin Against GramPositive Cocci Including Methicillin-Resistant Staphylococcus aureus Y PETER C. FUCHS, M.D.,
Port/and
Oregon
Published reports on the in vitro activity of temafloxacin indicate its activity against gram-positive cocci is equal to or slightly greater than that of ciprofloxacin, and generally twofold greater than that of ofloxacin. The few ciprofloxacin-resistant Staphylococcus aureus strains reported were also resistant to temafloxacin. Because temafloxacin achieves higher plasma and tissue levels than ciprofloxacin, greater differences between minimal inhibitory concentrations and tissue levels occur with temafloxacin than with ciprofloxacin, which may provide temafloxacin with greater therapeutic efficiency against gram-positive coccal infections.
From the Department of Pathology, St. Vincent Hospital and Medical Center, Portland, Oregon. Requests for reprints should be addressed to Peter C. Fuchs, M.D., Department of Pathology, St. Vincent Hospital and Medical Center, 9205 SW Barnes Road, Portland, Oregon 97225.
December
ince the introduction in the mid-1980s of the fluoroquinolones into medical practice in the United States, their use has become widespread. Currently, three such compounds are available: norfloxacin, ciprofloxacin, and ofloxacin. Each of these agents exhibits a broad spectrum of antimicrobial activity. The least active is norfloxacin, which, because of its pharmacokinetic profile, has been largely limited to use in urinary tract infections. Of the three, ciprofloxacin exhibits the greatest activity against gram-negative bacteria, including many Pseudomonas aeruginosa strains [l]. The activity of ofloxacin against gram-negative bacteria is less than that of ciprofloxacin [ll, but because of its higher serum and tissue levels, its clinical effectiveness may be comparable. The activity of ciprofloxacin against gram-positive cocci is less than it is against gram-negative bacilli, although the majority of gram-positive cocci are considered susceptible. The in vitro breakpoint for ciprofloxacin susceptibility is a minimal inhibitory concentration (MIC) of 4 pg/mL [2]. In most studies the ciprofloxacin MI&, (concentration at which 90% of isolates are inhibited) for Staphylococcus aureus is 0.5 pg/mL. When first introduced, 4% of S. aureus isolates (including methicillinresistant strains) were resistant to ciprofloxacin. However, since 1985 the number of ciprofloxacinresistant staphylococci (both S. aureus and coagulase-negative species) has progressively increased [3-81. Currently, most of the ciprofloxacin-resistant S. aureus strains are also methicillin resistant. Because of this development-in addition to the fact that the ciprofloxacin MIC& for many streptococcal and enterococcal species is l-2 PgimL-the need for fluoroquinolones with better gram-positive activity has become increasingly apparent. Temafloxacin is a new difluoroquinolone with reported excellent antimicrobial activity, including activity against gram-positive cocci. Further, its pharmacokinetics are favorable: steady state maximum and minimum serum concentrations are 1.0 pg/mL and 0.5 pg/mL per 100 mg of drug per dose administered with a twice daily regimen [9]. The purpose of this article is to review briefly the pubS
30, 1991
The American Journal of Medicine
Volume 91 (suppl 6A)
6A-15s
SYMPOSIUMON FLUOROQUINOLONES /FUCHS TABLE I MICso and M&o
&/ml)
of Temafloxacin Compared with Those of Ciprofloxacin Temafloxacin
Number
Organism
Reference
Tested
MGo
Hardy eta/[101 Chin etal[ll]
Staphylococcus
aureus
and Ofloxacin Against Gram-Positive Cocci
M&o
0.12 0.5 0.25 0.5 0.25
Rotston eta/[121
Ciprofloxacin MI’Go
0.25 0.5 0.5 0.25 0.25 0.25 0.25 0.25 0.5
Mko
0.12 0.5 0.5 0.5 1.0 1.0 0.25 0.25 0.25 0.5 0.39 0.39 0.12 0.25 2.0 0.5 0.25 0.25 0.39 0.5 0.25 0.25
!:;8 0.78 0.25 0.5 0.25 0.5 0.25 0.12 0.39 0.25 0.25 0.12
0.25 1.0 1.0 0.5 0.5 0.5 0.5 0.5 1.0 2.0 3.13 1.56 0.25 2.0 0.5 1.0 0.25 0.25 0.39 0.25 0.25 0.25
Ofloxacin MIGo
M&c
0.5 0.5
0.5 1.0
0.25 0.25 0.5 0.5 0.39 0.39 0.25 0.5 0.5 0.5
0.5 0.5 0.5 1.0 0.78 0.78 0.25 1.0 1.0 1.0
0.5 0.39
0.5 0.78
0.25
0.5
Staphylococcus haemolflicus
Rolston eta/[121 Simor eta/[151
Staphylococcus hominis
Rolston eta/[121
I::2 0.12 0.25 0.25 0.20 0.20 0.12 0.12 0.5 0.5 0.25 0.12 0.39 0.25 0.25 0.12
Staphylococcus saprophyticus
Ralston eta/(121 Nyeefa/[14] Simor eta/[151
0.12 0.25 0.5
0.12 0.5 0.5
0.12 0.25 0.5
0.12 0.5 0.5
1.0 1.0
2.0 1.0
Hardyeta/[lO] Barry and Jones [13] Simor eta/(151
0.12 0.25 0.25 0.12 0.25
0.25 0.5 0.5 0.25 0.25 0.5
0.12 0.12 0.12 0.25 0.12 0.5 0.5 0.5 0.5 0.5 0.5 0.78 0.5 1.0
0.25 0.25 0.25 0.25 0.25 0.5 1.0
i:: 0.25 0.25
i:: 0.5 1.0
1.0
2.0
!:I 1.0 1.0 0.78 0.5 4.0 1.0
1.0 1.0 1.0 1.56 1.0 1.0
;i 210 1.56 1.0 2.0
::i 2.0
2.0 2.0 4.0
1.0 2.0
2.0 2.0 2,o
Barry and Jones [13] Nye eta/[141 Simor eta/[151 Nakanishi eta/[161
Swanson eta/[171 Barry and Fuchs [18] Chin eta/[111
Staphylococcus epidermidis
Ralston eta/[121 Nye eta/[141 Nakanishi eta/[161
Coagulase-negative staphylococci WI
Barry and Fuchs 1181 Hardy etal[IO] Chineta/[ll] Ralston et a/[121 Barry and Jones [13] Nye eta/[141 Simor eta/[151 Nakanishi eta/[161 Swanson eta/(171
Streptococcus pyogenes
i:: A:! 1.0 0.78 0.5 2.0 1.0
Chin eta/[111 Ralston eta/[121 Barry and Jones [13] Nye eta/[141
Streptococcus agaiactiae
Chin eta/[111 Ralston eta/[121 Barry and Jones [13]
Streptococcus groups C, F, G
Streptococcus viridans
Chin eta/[111
Streptococcus pneumoniae
Hardyetai[lO] Chin eta/[111 Ralston eta/[121 Barry and Jones [13] Nye eta/(141 Simor eta/[151 Nakanishi eta/[161 Swanson et a/[171 Mazzulli eta/[191 Hardy efa/[101 Nye eta/[141 Simor eta/[151
Enterococcus species
Enferococcus faecalis
Chin eta/[111 Rolston etai[l2] Nakanishi eta/[161
Enterococcus faecium
Nakanishi eta/[161
December
30,
1991
The American Journal of Medicine
i! 1:o 1.0
A:.! 2.0
2 1.0
;:i 2.0 1.0 0.5 2.0
f:8
2.0 1.0
;:i
2.0
!:i
?i
i::
2.0
i:! 3.13 0.5 1.0
%i 3.13 2.0 1.0
::i 1.56 2.0 1.0
ki 2:o ;:i 1.56 6.25
4.0 2.0 2.0
4.0 4.0 2.0
1.56 6.25
3.13 12.5
::I 1.0
8 210
f,8 1:56 1.0 0.5 1.0 2.0 1.0
!:i 1.56 3.13
i:! 1.56 12.5
!:i 0.78 3.13
j = methiclllin susceptible; MR = methicillin resistant; PS = penicillin susceptible.
6A-16s
i:i 2.0
Volume 91 (suppl 6A)
33 3:13 2.0 2.0
SYMPOSIUM
lished reports on the in vitro activity of temafloxacin against gram-positive cocci and to compare it with the activity of ciprofloxacin and ofloxacin, the two currently available quinolones with respectable gram-positive antimicrobial activity.
STAPHYLOCOCCUS AUREUS Reports comparing the in vitro activity of temafloxacin, ciprofloxacin, and ofloxacin against gram-positive cocci are summarized in Table I [lo181. Most reports demonstrate temafloxacin to be the most active against S. aureus. The median MICSO for temafloxacin was 0.25 pg/mL, compared with 0.5 PglmL for ciprofloxacin and ofloxacin. No perceptible difference in activity was observed against methicillin-resistant (MRSA) and methicillin-susceptible (MSSA) strains in most studies in which they were observed separately. In one study, however, which tested recent clinical bacteremit isolates from 40 medical centers, there were 10 quinolone-resistant isolates among 75 MRSA strains and none among 75 MSSA strains [18]. This probably reflects the recent trend of increasing quinolone resistance mentioned previously. The median MICaO of ofloxacin against S. aureus was 0.5 pg/mL, essentially the same as that for ciprofloxacin. However, ofloxacin achieves considerably higher blood levels and tissue levels than does ciprofloxacin. As a result, the threshold in vitro level for ofloxacin susceptibility has been established as 2 Fg/mL, compared with 1 PgimL for ciprofloxacin [2]. Selection of quinolone-resistant isolates can be accomplished in vitro, and presumably in vivo, by exposing an organism to drug concentrations approximating the MIC. The smaller the ratio of MIC to drug concentration (as occurs in serum and tissue), the less the likelihood of selecting resistance and the better the chance of eradicating the organism. Since the MICs of ofloxacin and ciprofloxacin against S. aureus are similar, and since the plasma and tissue levels of ofloxacin are approximately twice those of ciprofloxacin, one can theoretically expect spontaneous-resistance mutants of S. aureus to occur less frequently with ofloxacin than with ciprofloxacin therapy. Theoretically, then, because the MICSO of temafloxacin is one-half those of the other two, while its tissue and plasma levels are comparable to that of ofloxacin [14], it would be expected that temafloxacin should prove more effective than either ofloxacin or ciprofloxacin against S. aureus. Spontaneous resistance developed in S. aureus at a rate of 3.6 x lo-’ when exposed to two times the temafloxacin MIC and <9 x lo-’ at four times the MIC [16].
ON FLUOROOUINOLONES
/ FUCHS
COAGULASE-NEGATIVE STAPHYLOCOCCI Studies reporting results on coagulase-negative staphylococci, either as a group or individually speciated showed comparable relative activities of the three drugs (Table I). The median MIC&,,s of temafloxacin and ciprofloxacin are 0.25 pg/mL, compared with 1 pg/mL for ofloxacin. Since the in vitro activities of temafloxacin and ciprofloxacin are very similar against coagulase-negative staphylococci, any advantage of temafloxacin over ciprofloxacin would be due to its superior pharmacokinetics.
STREPTOCOCCI In the published studies reviewed, the temafloxacin MICSOs against various species of streptococci were the same or twofold lower than those of ciprofloxacin (Table I). The MIC$,,s of ofloxacin tended to be twofold higher than that of ciprofloxacin. These minor differences in the antibacterial activities of temafloxacin and ciprofloxatin were observed primarily with Streptococcus pneumoniae and Streptococcus pyogenes. No difference in quinolone activity against S. pneumovziae was observed between penicillin-susceptible and moderately susceptible strains [19] or resistant strains [131.
ENTEROCOCCI As a group, the enterococci were the least susceptible of the gram-positive cocci to any of the three quinolones. The MIC&,,s of temafloxacin and ciprofloxacin were 2 PgimL, whereas that of ofloxatin was 2 PgimL in one study [ll] and 4 PgimL in another [14] (Table I). In one study the enterococci were identified to species level, and Enterococcus faecium was fourfold more resistant to any of the three quinolones than E. faecalis [16]. Organisms with ciprofloxacin MICs of 2 pg/mL are not considered susceptible. On the other hand, organisms with a temafloxacin MIC of 2 PgimL would be considered susceptible, albeit right at the susceptibility threshold. Thus, temafloxacin may be more effective against enterococcal infections than either ciprofloxacin or ofloxacin. By determination of minimal bactericidal concentrations (MBCs) and by time-kill studies, temafloxacin, similar to other quinolones, is bactericidal [16,171. The MBCs tend to be zero to two times the MICs for most organisms, including S. aureus. As with other quinolones, the in vitro activity of temafloxacin can be influenced by several factors. These include (a) pH: there is a significant decrease in temafloxacin activity in an acid environment [11,16]; with S. aureus, a fourfold increase in MIC occurred when decreasing the pH from 8.0 to 6.0 [16]. (b) Magnesium ion concentration: the
December 30, 1991
The Amencan Journal of Medicine
Volume 91 (suppl 6A]
6A-17s
SYMPOSIUM
ON FLUOROQUINOLONES
/ FUCHS
temafloxacin MICs increased substantially with increasing Mg2+ concentration [11,16]. The temafloxacin MIC for S. aureus increased eightfold in broth containing 9,s of Mgat, compared with unsupplemented broth [Xl. (c) Inoculum size: there was generally a two- to fourfold increase in temafloxacin MU.3 when the inoculum concentration was increased from lo5 to lo7 colony-forming units/ mL [lo, i6].
COMMENT In summary, the overall in vitro activity of temafloxacin against gram-positive cocci is the same as or slightly superior to that of ciprofloxacin, depending on the species. However, because of its higher plasma levels, temafloxacin offers promise of being more effective therapeutically. Murine protection tests have demonstrated temafloxacin to be eight times more potent against S. aureus, S. pneumonicxe, and S. Fyogenes than ciprofloxacin and two to four times more potent than ofloxacin in this model [10,17]. Further clinical studies will be needed to establish whether these in vitro observations are predictive of clinical differences.
REFERENCES 1. Mitsuhashi S. Comparative a&bacterial activity of new quinolone-carboxyirc acid derivatives. Rev Infect Dis 1988; 10 (Suppl 1): S27-31. 2. National Committee for Clinical Laboratory Standards. Methods for dilution antimrcrobial susceptibility tests for bacteria that grow aerobically. M7-A2 1990. Villanova, Pennsylvania: National Committee for Clinical Laboratory Standards, 1990. 3. Humphreys H, Mulvihill E. Ciprofloxacin-resrstant Staphylococcus aweus [Letter]. Lancet 1985; ii: 383. 4. Oppenheim BA, Hartley JW, Lee W, Burnie JP. Outbreak of coagulase-negative staphylococcus highly resistant to ciprofloxacin In a leukemia unit. Br Med J 1989; 299: 294-7.
6A-18s
December
30, 1991
The American Journal of Medicine
5. Schakffer S. Methicillin-reslstant strains of Staphyiococcus aureus resrstant to qulnolones. J Clin Microbial 1989; 27: 335-6. 6. Shalit I, Berger SA, Gorea A, Frimerman H. Widespread qulnolone resistance among methicillin-resistant Staphyiococcus amus isolates in a general hosprtal. Antimicrob Agents Chemother 1989; 33: 593-4. 7. Kotilainen P, Nikoskelainen J, Huovinen P. Emergence of ciprofloxacrn-resistant coagulase-negative staphylococcai skin flora rn immunocompromrsed patients receivrng crprofloxacin. J infect Dis 1990: 161: 41-4. 8. Trucksis M, Hooper DC, Wolfson JS. Emerging resistance to fluoroquinolones in staphylococci: an alert [Editorial]. Ann Intern Med 1991; 114: 424-6. 9. Granneman RG, Carpentier P, Morrison PJ, Pernet AG. Pharmacokinetics of temafioxacin in humans after multiple oral doses, Antimicrob Agents Chemother 1991; in press. 10. Hardy DJ, Swanson RN, Hensey DM, et a/. Comparative antibacterial actrvrties of temafloxacin hydrochloride (A-62254) and two reference fluoroquinolones. Antimicrob Agents Chemother 1987; 31: 1768-74. 11. Chin NX, Frgueredo VM, Novelli A, Neu HC. In vitro activrty of temafloxacrn, a new difluoro quinolone antimicrobial agent. Eur J Clan Microbial Infect DIS 1989; 7: 58-63. 12. Ralston KVI, Ho DH, LeBlanc B, Gooch G, Bodey GJ. Comparative rn vrtro activIty of the new difluoroquinolone temafloxacin (A-62254) against bacterial isolates from cancer patients. Eur J Clin Microbial Infect Dis 1988; 7: 684-6. 13. Barry AL, Jones RN. In vitro activities of temafloxacin, tosufloxacin (A-61827) and five other fluoroquinolone agents. J Antimicrob Chemother 1989; 23: 527-35. 14. Nye K, Shi YG, Andrews JM, Ashby JP, Wise R. The in vitro activity, pharmacokrnetics and tissue penetration of temafloxacin. J Antimicrob Chemother 1989: 24: 415-24. 15. Simor AE, Fuller SA, Low DE. Comparative in vitro activities of sparfloxacin (Cl-978 AT-4140) and other antimicrobial agents against staphyiococcl, enterococci and respiratory tract pathogens. Antimicrob Agents Chemother 1990; 34: 2283-6. 16. Nakanishi N, lnove M, lnove K, Yamaguchi T, Nitsuhashi S. In vitro acbvity of temafloxacin hydrochlorrde (TA-167 or A-62254), a new fluorinated 4-qurnolone. Chemotherapy 1990; 36: 345-55. 17. Swanson RN, Hardy DJ, Chu OTW, Shipkowitz NL, Clement JJ. Activity of temafloxacin against resprratory pathogens. Antimicrob Agents Chemother 1991; 35: 423-9. 18. Barry AL, Fuchs PC. Antrstaphylococcal activity of temafloxacrn, tosufloxacin and three other fluoroquinolone compounds. Antimrcrob Agents Chemother 1991; in press. 19. Mazzulli T, Simor AE, Jaeger R, Fuller S, Low DE. Comparative In vrtro activities of several new fluoroquinolones and p-lactam antimicrobial agents agarnst community isolates of Streptococcus pneumoniae. Antrmfcrob Agents Chemother 1990: 34: 467-9.
Volume 91 (suppl 6A)
Port/and
Oregon
Published reports on the in vitro activity of temafloxacin indicate its activity against gram-positive cocci is equal to or slightly greater than that of ciprofloxacin, and generally twofold greater than that of ofloxacin. The few ciprofloxacin-resistant Staphylococcus aureus strains reported were also resistant to temafloxacin. Because temafloxacin achieves higher plasma and tissue levels than ciprofloxacin, greater differences between minimal inhibitory concentrations and tissue levels occur with temafloxacin than with ciprofloxacin, which may provide temafloxacin with greater therapeutic efficiency against gram-positive coccal infections.
From the Department of Pathology, St. Vincent Hospital and Medical Center, Portland, Oregon. Requests for reprints should be addressed to Peter C. Fuchs, M.D., Department of Pathology, St. Vincent Hospital and Medical Center, 9205 SW Barnes Road, Portland, Oregon 97225.
December
ince the introduction in the mid-1980s of the fluoroquinolones into medical practice in the United States, their use has become widespread. Currently, three such compounds are available: norfloxacin, ciprofloxacin, and ofloxacin. Each of these agents exhibits a broad spectrum of antimicrobial activity. The least active is norfloxacin, which, because of its pharmacokinetic profile, has been largely limited to use in urinary tract infections. Of the three, ciprofloxacin exhibits the greatest activity against gram-negative bacteria, including many Pseudomonas aeruginosa strains [l]. The activity of ofloxacin against gram-negative bacteria is less than that of ciprofloxacin [ll, but because of its higher serum and tissue levels, its clinical effectiveness may be comparable. The activity of ciprofloxacin against gram-positive cocci is less than it is against gram-negative bacilli, although the majority of gram-positive cocci are considered susceptible. The in vitro breakpoint for ciprofloxacin susceptibility is a minimal inhibitory concentration (MIC) of 4 pg/mL [2]. In most studies the ciprofloxacin MI&, (concentration at which 90% of isolates are inhibited) for Staphylococcus aureus is 0.5 pg/mL. When first introduced, 4% of S. aureus isolates (including methicillinresistant strains) were resistant to ciprofloxacin. However, since 1985 the number of ciprofloxacinresistant staphylococci (both S. aureus and coagulase-negative species) has progressively increased [3-81. Currently, most of the ciprofloxacin-resistant S. aureus strains are also methicillin resistant. Because of this development-in addition to the fact that the ciprofloxacin MIC& for many streptococcal and enterococcal species is l-2 PgimL-the need for fluoroquinolones with better gram-positive activity has become increasingly apparent. Temafloxacin is a new difluoroquinolone with reported excellent antimicrobial activity, including activity against gram-positive cocci. Further, its pharmacokinetics are favorable: steady state maximum and minimum serum concentrations are 1.0 pg/mL and 0.5 pg/mL per 100 mg of drug per dose administered with a twice daily regimen [9]. The purpose of this article is to review briefly the pubS
30, 1991
The American Journal of Medicine
Volume 91 (suppl 6A)
6A-15s
SYMPOSIUMON FLUOROQUINOLONES /FUCHS TABLE I MICso and M&o
&/ml)
of Temafloxacin Compared with Those of Ciprofloxacin Temafloxacin
Number
Organism
Reference
Tested
MGo
Hardy eta/[101 Chin etal[ll]
Staphylococcus
aureus
and Ofloxacin Against Gram-Positive Cocci
M&o
0.12 0.5 0.25 0.5 0.25
Rotston eta/[121
Ciprofloxacin MI’Go
0.25 0.5 0.5 0.25 0.25 0.25 0.25 0.25 0.5
Mko
0.12 0.5 0.5 0.5 1.0 1.0 0.25 0.25 0.25 0.5 0.39 0.39 0.12 0.25 2.0 0.5 0.25 0.25 0.39 0.5 0.25 0.25
!:;8 0.78 0.25 0.5 0.25 0.5 0.25 0.12 0.39 0.25 0.25 0.12
0.25 1.0 1.0 0.5 0.5 0.5 0.5 0.5 1.0 2.0 3.13 1.56 0.25 2.0 0.5 1.0 0.25 0.25 0.39 0.25 0.25 0.25
Ofloxacin MIGo
M&c
0.5 0.5
0.5 1.0
0.25 0.25 0.5 0.5 0.39 0.39 0.25 0.5 0.5 0.5
0.5 0.5 0.5 1.0 0.78 0.78 0.25 1.0 1.0 1.0
0.5 0.39
0.5 0.78
0.25
0.5
Staphylococcus haemolflicus
Rolston eta/[121 Simor eta/[151
Staphylococcus hominis
Rolston eta/[121
I::2 0.12 0.25 0.25 0.20 0.20 0.12 0.12 0.5 0.5 0.25 0.12 0.39 0.25 0.25 0.12
Staphylococcus saprophyticus
Ralston eta/(121 Nyeefa/[14] Simor eta/[151
0.12 0.25 0.5
0.12 0.5 0.5
0.12 0.25 0.5
0.12 0.5 0.5
1.0 1.0
2.0 1.0
Hardyeta/[lO] Barry and Jones [13] Simor eta/(151
0.12 0.25 0.25 0.12 0.25
0.25 0.5 0.5 0.25 0.25 0.5
0.12 0.12 0.12 0.25 0.12 0.5 0.5 0.5 0.5 0.5 0.5 0.78 0.5 1.0
0.25 0.25 0.25 0.25 0.25 0.5 1.0
i:: 0.25 0.25
i:: 0.5 1.0
1.0
2.0
!:I 1.0 1.0 0.78 0.5 4.0 1.0
1.0 1.0 1.0 1.56 1.0 1.0
;i 210 1.56 1.0 2.0
::i 2.0
2.0 2.0 4.0
1.0 2.0
2.0 2.0 2,o
Barry and Jones [13] Nye eta/[141 Simor eta/[151 Nakanishi eta/[161
Swanson eta/[171 Barry and Fuchs [18] Chin eta/[111
Staphylococcus epidermidis
Ralston eta/[121 Nye eta/[141 Nakanishi eta/[161
Coagulase-negative staphylococci WI
Barry and Fuchs 1181 Hardy etal[IO] Chineta/[ll] Ralston et a/[121 Barry and Jones [13] Nye eta/[141 Simor eta/[151 Nakanishi eta/[161 Swanson eta/(171
Streptococcus pyogenes
i:: A:! 1.0 0.78 0.5 2.0 1.0
Chin eta/[111 Ralston eta/[121 Barry and Jones [13] Nye eta/[141
Streptococcus agaiactiae
Chin eta/[111 Ralston eta/[121 Barry and Jones [13]
Streptococcus groups C, F, G
Streptococcus viridans
Chin eta/[111
Streptococcus pneumoniae
Hardyetai[lO] Chin eta/[111 Ralston eta/[121 Barry and Jones [13] Nye eta/(141 Simor eta/[151 Nakanishi eta/[161 Swanson et a/[171 Mazzulli eta/[191 Hardy efa/[101 Nye eta/[141 Simor eta/[151
Enterococcus species
Enferococcus faecalis
Chin eta/[111 Rolston etai[l2] Nakanishi eta/[161
Enterococcus faecium
Nakanishi eta/[161
December
30,
1991
The American Journal of Medicine
i! 1:o 1.0
A:.! 2.0
2 1.0
;:i 2.0 1.0 0.5 2.0
f:8
2.0 1.0
;:i
2.0
!:i
?i
i::
2.0
i:! 3.13 0.5 1.0
%i 3.13 2.0 1.0
::i 1.56 2.0 1.0
ki 2:o ;:i 1.56 6.25
4.0 2.0 2.0
4.0 4.0 2.0
1.56 6.25
3.13 12.5
::I 1.0
8 210
f,8 1:56 1.0 0.5 1.0 2.0 1.0
!:i 1.56 3.13
i:! 1.56 12.5
!:i 0.78 3.13
j = methiclllin susceptible; MR = methicillin resistant; PS = penicillin susceptible.
6A-16s
i:i 2.0
Volume 91 (suppl 6A)
33 3:13 2.0 2.0
SYMPOSIUM
lished reports on the in vitro activity of temafloxacin against gram-positive cocci and to compare it with the activity of ciprofloxacin and ofloxacin, the two currently available quinolones with respectable gram-positive antimicrobial activity.
STAPHYLOCOCCUS AUREUS Reports comparing the in vitro activity of temafloxacin, ciprofloxacin, and ofloxacin against gram-positive cocci are summarized in Table I [lo181. Most reports demonstrate temafloxacin to be the most active against S. aureus. The median MICSO for temafloxacin was 0.25 pg/mL, compared with 0.5 PglmL for ciprofloxacin and ofloxacin. No perceptible difference in activity was observed against methicillin-resistant (MRSA) and methicillin-susceptible (MSSA) strains in most studies in which they were observed separately. In one study, however, which tested recent clinical bacteremit isolates from 40 medical centers, there were 10 quinolone-resistant isolates among 75 MRSA strains and none among 75 MSSA strains [18]. This probably reflects the recent trend of increasing quinolone resistance mentioned previously. The median MICaO of ofloxacin against S. aureus was 0.5 pg/mL, essentially the same as that for ciprofloxacin. However, ofloxacin achieves considerably higher blood levels and tissue levels than does ciprofloxacin. As a result, the threshold in vitro level for ofloxacin susceptibility has been established as 2 Fg/mL, compared with 1 PgimL for ciprofloxacin [2]. Selection of quinolone-resistant isolates can be accomplished in vitro, and presumably in vivo, by exposing an organism to drug concentrations approximating the MIC. The smaller the ratio of MIC to drug concentration (as occurs in serum and tissue), the less the likelihood of selecting resistance and the better the chance of eradicating the organism. Since the MICs of ofloxacin and ciprofloxacin against S. aureus are similar, and since the plasma and tissue levels of ofloxacin are approximately twice those of ciprofloxacin, one can theoretically expect spontaneous-resistance mutants of S. aureus to occur less frequently with ofloxacin than with ciprofloxacin therapy. Theoretically, then, because the MICSO of temafloxacin is one-half those of the other two, while its tissue and plasma levels are comparable to that of ofloxacin [14], it would be expected that temafloxacin should prove more effective than either ofloxacin or ciprofloxacin against S. aureus. Spontaneous resistance developed in S. aureus at a rate of 3.6 x lo-’ when exposed to two times the temafloxacin MIC and <9 x lo-’ at four times the MIC [16].
ON FLUOROOUINOLONES
/ FUCHS
COAGULASE-NEGATIVE STAPHYLOCOCCI Studies reporting results on coagulase-negative staphylococci, either as a group or individually speciated showed comparable relative activities of the three drugs (Table I). The median MIC&,,s of temafloxacin and ciprofloxacin are 0.25 pg/mL, compared with 1 pg/mL for ofloxacin. Since the in vitro activities of temafloxacin and ciprofloxacin are very similar against coagulase-negative staphylococci, any advantage of temafloxacin over ciprofloxacin would be due to its superior pharmacokinetics.
STREPTOCOCCI In the published studies reviewed, the temafloxacin MICSOs against various species of streptococci were the same or twofold lower than those of ciprofloxacin (Table I). The MIC$,,s of ofloxacin tended to be twofold higher than that of ciprofloxacin. These minor differences in the antibacterial activities of temafloxacin and ciprofloxatin were observed primarily with Streptococcus pneumoniae and Streptococcus pyogenes. No difference in quinolone activity against S. pneumovziae was observed between penicillin-susceptible and moderately susceptible strains [19] or resistant strains [131.
ENTEROCOCCI As a group, the enterococci were the least susceptible of the gram-positive cocci to any of the three quinolones. The MIC&,,s of temafloxacin and ciprofloxacin were 2 PgimL, whereas that of ofloxatin was 2 PgimL in one study [ll] and 4 PgimL in another [14] (Table I). In one study the enterococci were identified to species level, and Enterococcus faecium was fourfold more resistant to any of the three quinolones than E. faecalis [16]. Organisms with ciprofloxacin MICs of 2 pg/mL are not considered susceptible. On the other hand, organisms with a temafloxacin MIC of 2 PgimL would be considered susceptible, albeit right at the susceptibility threshold. Thus, temafloxacin may be more effective against enterococcal infections than either ciprofloxacin or ofloxacin. By determination of minimal bactericidal concentrations (MBCs) and by time-kill studies, temafloxacin, similar to other quinolones, is bactericidal [16,171. The MBCs tend to be zero to two times the MICs for most organisms, including S. aureus. As with other quinolones, the in vitro activity of temafloxacin can be influenced by several factors. These include (a) pH: there is a significant decrease in temafloxacin activity in an acid environment [11,16]; with S. aureus, a fourfold increase in MIC occurred when decreasing the pH from 8.0 to 6.0 [16]. (b) Magnesium ion concentration: the
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temafloxacin MICs increased substantially with increasing Mg2+ concentration [11,16]. The temafloxacin MIC for S. aureus increased eightfold in broth containing 9,s of Mgat, compared with unsupplemented broth [Xl. (c) Inoculum size: there was generally a two- to fourfold increase in temafloxacin MU.3 when the inoculum concentration was increased from lo5 to lo7 colony-forming units/ mL [lo, i6].
COMMENT In summary, the overall in vitro activity of temafloxacin against gram-positive cocci is the same as or slightly superior to that of ciprofloxacin, depending on the species. However, because of its higher plasma levels, temafloxacin offers promise of being more effective therapeutically. Murine protection tests have demonstrated temafloxacin to be eight times more potent against S. aureus, S. pneumonicxe, and S. Fyogenes than ciprofloxacin and two to four times more potent than ofloxacin in this model [10,17]. Further clinical studies will be needed to establish whether these in vitro observations are predictive of clinical differences.
REFERENCES 1. Mitsuhashi S. Comparative a&bacterial activity of new quinolone-carboxyirc acid derivatives. Rev Infect Dis 1988; 10 (Suppl 1): S27-31. 2. National Committee for Clinical Laboratory Standards. Methods for dilution antimrcrobial susceptibility tests for bacteria that grow aerobically. M7-A2 1990. Villanova, Pennsylvania: National Committee for Clinical Laboratory Standards, 1990. 3. Humphreys H, Mulvihill E. Ciprofloxacin-resrstant Staphylococcus aweus [Letter]. Lancet 1985; ii: 383. 4. Oppenheim BA, Hartley JW, Lee W, Burnie JP. Outbreak of coagulase-negative staphylococcus highly resistant to ciprofloxacin In a leukemia unit. Br Med J 1989; 299: 294-7.
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5. Schakffer S. Methicillin-reslstant strains of Staphyiococcus aureus resrstant to qulnolones. J Clin Microbial 1989; 27: 335-6. 6. Shalit I, Berger SA, Gorea A, Frimerman H. Widespread qulnolone resistance among methicillin-resistant Staphyiococcus amus isolates in a general hosprtal. Antimicrob Agents Chemother 1989; 33: 593-4. 7. Kotilainen P, Nikoskelainen J, Huovinen P. Emergence of ciprofloxacrn-resistant coagulase-negative staphylococcai skin flora rn immunocompromrsed patients receivrng crprofloxacin. J infect Dis 1990: 161: 41-4. 8. Trucksis M, Hooper DC, Wolfson JS. Emerging resistance to fluoroquinolones in staphylococci: an alert [Editorial]. Ann Intern Med 1991; 114: 424-6. 9. Granneman RG, Carpentier P, Morrison PJ, Pernet AG. Pharmacokinetics of temafioxacin in humans after multiple oral doses, Antimicrob Agents Chemother 1991; in press. 10. Hardy DJ, Swanson RN, Hensey DM, et a/. Comparative antibacterial actrvrties of temafloxacin hydrochloride (A-62254) and two reference fluoroquinolones. Antimicrob Agents Chemother 1987; 31: 1768-74. 11. Chin NX, Frgueredo VM, Novelli A, Neu HC. In vitro activrty of temafloxacrn, a new difluoro quinolone antimicrobial agent. Eur J Clan Microbial Infect DIS 1989; 7: 58-63. 12. Ralston KVI, Ho DH, LeBlanc B, Gooch G, Bodey GJ. Comparative rn vrtro activIty of the new difluoroquinolone temafloxacin (A-62254) against bacterial isolates from cancer patients. Eur J Clin Microbial Infect Dis 1988; 7: 684-6. 13. Barry AL, Jones RN. In vitro activities of temafloxacin, tosufloxacin (A-61827) and five other fluoroquinolone agents. J Antimicrob Chemother 1989; 23: 527-35. 14. Nye K, Shi YG, Andrews JM, Ashby JP, Wise R. The in vitro activity, pharmacokrnetics and tissue penetration of temafloxacin. J Antimicrob Chemother 1989: 24: 415-24. 15. Simor AE, Fuller SA, Low DE. Comparative in vitro activities of sparfloxacin (Cl-978 AT-4140) and other antimicrobial agents against staphyiococcl, enterococci and respiratory tract pathogens. Antimicrob Agents Chemother 1990; 34: 2283-6. 16. Nakanishi N, lnove M, lnove K, Yamaguchi T, Nitsuhashi S. In vitro acbvity of temafloxacin hydrochlorrde (TA-167 or A-62254), a new fluorinated 4-qurnolone. Chemotherapy 1990; 36: 345-55. 17. Swanson RN, Hardy DJ, Chu OTW, Shipkowitz NL, Clement JJ. Activity of temafloxacin against resprratory pathogens. Antimicrob Agents Chemother 1991; 35: 423-9. 18. Barry AL, Fuchs PC. Antrstaphylococcal activity of temafloxacrn, tosufloxacin and three other fluoroquinolone compounds. Antimrcrob Agents Chemother 1991; in press. 19. Mazzulli T, Simor AE, Jaeger R, Fuller S, Low DE. Comparative In vrtro activities of several new fluoroquinolones and p-lactam antimicrobial agents agarnst community isolates of Streptococcus pneumoniae. Antrmfcrob Agents Chemother 1990: 34: 467-9.
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