Previous Article | Next Article 
Antimicrobial Agents and Chemotherapy, May 1998, p. 1253-1255, Vol. 42, No. 5
Departments of Pathology (Clinical
Microbiology), Hershey Medical Center, Hershey, Pennsylvania
17033,1 and
Case Western Reserve
University, Cleveland, Ohio 441062
Received 28 August 1997/Returned for modification 31 January
1998/Accepted 20 February 1998
The postantibiotic effect (PAE) (10 times the MIC of quinolones, 5 times the MIC of macrolides) and postantibiotic sub-MIC effect
(PAE-SME) at 0.125, 0.25, and 0.5 times the MIC were determined for
levofloxacin, ciprofloxacin, ofloxacin, erythromycin, azithromycin, and
clarithromycin against 20 pneumococci. Quinolone PAEs ranged between
0.5 and 6.5 h, and macrolide PAEs ranged between 1 and 6 h.
Measurable PAE-SMEs (in hours) at the three concentrations were 1 to 5, 1 to 8, and 1 to 8, respectively, for quinolones and 1 to 8, 1 to 8, and 1 to 6, respectively, for macrolides.
The past two decades, and in
particular the past 5 years, have witnessed a dramatic increase
worldwide in the incidence of pneumococci which are resistant to
penicillin G and other antimicrobials (1). In a recent study
from the United States, 23.6% of pneumococci showed lowered penicillin
susceptibility, with 14.1% intermediately resistant and 9.5%
resistant; erythromycin resistance rates of 20 and 49% were found in
penicillin intermediately resistant and penicillin-resistant strains,
respectively (7). In Europe, erythromycin resistance rates
are higher (2).
There is an urgent need for antimicrobials which can be used for oral
therapy of respiratory tract infections caused by penicillin- and
macrolide-resistant pneumococci (1, 4, 8, 11, 12). Quinolone
activity against pneumococci is independent of that of Postantibiotic effect (PAE) is the term used to describe suppression of
bacterial growth that persists after brief exposure of organisms to
antimicrobials. The PAE may have a clinical impact on antimicrobial
dosing regimens. For example, drugs with no PAEs may require more
frequent administration than those that demonstrate PAEs
(6). However, the PAE alone may not fully explain the effectiveness of intermittent dosing, since the sum of the time concentrations of most antimicrobials are above the MIC and the time
period of the PAE does not cover the entire dosing interval. Odenholt-Tornqvist et al. (17-19) have reported a long
period of growth inhibition when some bacteria in the postantibiotic
phase were exposed to 0.3 times the MIC of antibiotic and proposed the postantibiotic sub-MIC (PAE-SME) phenomenon in order to at least partially explain the latter discrepancy. Other explanations may be
concentration-dependent killing, as seen with fluoroquinolones, and the
postantibiotic leukocyte effect.
Fuursted et al. (10) tested the PAEs of macrolides against
10 pneumococcal strains and Licata et al. (13) tested the
PAEs and PAE-SMEs of ciprofloxacin and levofloxacin against 2 pneumococcal strains. To simultaneously test both drug classes against
a larger number of strains, we examined the PAEs and PAE-SMEs of
levofloxacin, ofloxacin, ciprofloxacin, erythromycin, azithromycin, and
clarithromycin against 20 pneumococci.
Twenty strains of pneumococci, for which the levofloxacin MICs were 0.5 to 2.0 µg/ml and the penicillin and macrolide MICs varied, were
selected (see Table 1). A standard broth microdilution methodology,
using Mueller-Hinton broth (Difco) with added lysed horse blood, was
employed (15). The PAE was determined by the viable plate
count method as described previously (22). For quinolones,
antibiotic exposure for 1 h was at 10 times the MIC; for
macrolides, for reasons of solubilization, 5 times the MIC was used.
Cultures were diluted 1:1,000 to remove antibiotic. The PAE was defined
(6) by the equation PAE = T The PAE-SME (17-19) was measured at 0.125, 0.25, and 0.5 times the MIC as described previously (22) and defined
according to Odenhalt-Tornqvist and coworkers (17-19) by
the equation PAE-SME = Tpa Viability counts for PAE and PAE-SME tests were determined before
exposure and immediately after dilution (0 h) and then every 2 h
until the turbidity of the tube reached a no. 1 McFarland standard, for
a total of 8 h. Recovery plates were incubated for up to 48 h. Colony counts were done only for plates with 100 to 300 CFU/ml. All
results were the means of two separate assays.
Microbroth MICs for the 20 strains tested are presented in Table
1. As can be seen, levofloxacin MICs
ranged between 0.5 and 2 µg/ml. Ten strains were macrolide
susceptible (MIC, 0.016 to 0.25 µg/ml) and nine were highly macrolide
resistant (MIC,
0066-4804/98/$04.00+0
Copyright © 1998, American Society for Microbiology. All rights reserved.
Postantibiotic Effect and Postantibiotic Sub-MIC Effect of
Levofloxacin Compared to Those of Ofloxacin, Ciprofloxacin,
Erythromycin, Azithromycin, and Clarithromycin against 20 Pneumococci
ABSTRACT
Top
Abstract
Text
References
TEXT
Top
Abstract
Text
References
-lactams and
macrolides (7, 20, 21, 23). Levofloxacin, the
l-isomer of ofloxacin, has MICs against Streptococcus
pneumoniae which are 1 to 2 dilutions lower than those of
ofloxacin and ciprofloxacin (3, 9, 16, 20), as well as good
kill kinetics (23).
C, where T is the time required for viability
counts of an antibiotic-exposed culture to increase by 1 log10 above the counts observed immediately after dilution
and C is the corresponding time for the growth control.
C,
where Tpa is the time for cultures previously
exposed to antibiotic and then reexposed to different sub-MICs to
increase by 1 log10 above the counts immediately after
dilution and C is the corresponding time for the unexposed
control.
512 µg/ml); the macrolide MIC for one strain was
0.5 µg/ml. Five strains were penicillin susceptible, six were
penicillin intermediately resistant, and nine were penicillin
resistant. Ciprofloxacin and ofloxacin MICs ranged between 0.5 and 4 µg/ml.
TABLE 1.
MICs of individual strains
In all cases, exposure to antibiotics at 0.01 times the MIC did not yield bacteriostatic activity. Growth controls did not autolyse through 8 h. PAE and PAE-SME results are presented in Table 2. Macrolide PAEs and PAE-SMEs could not be determined for highly macrolide-resistant strains. In many cases, PAE-SMEs could not be quantitated, since drugs sometimes produced complete killing, especially at higher sub-MICs. No relationship between quinolone PAE or PAE-SME and penicillin susceptibility was ascertained.
|
Levofloxacin MICs relative to those of ciprofloxacin were similar to
those reported previously (3, 9, 20, 23). Levofloxacin breakpoints of 
2 µg/ml (susceptible), 4 µg/ml (intermediately resistant), and 8 µg/ml (resistant) have been approved by the National Committee for Clinical Laboratory Standards (15).
Relative activity of macrolides against erythromycin-susceptible
strains and cross-resistance of all three compounds against strains
with erythromycin MICs of 512 µg/ml have been reported previously (7, 11, 14, 21-23).
Results of the present study show a significant PAE for all quinolones and macrolides tested. Fuursted and coworkers (10), using pneumococci with different macrolide and penicillin susceptibilities and exposure to antibiotics at 10 times the MIC, obtained macrolide PAEs similar to those reported in the present study, and Licata et al. (13) obtained similar results for ciprofloxacin and levofloxacin with one penicillin-susceptible and one penicillin-resistant pneumococcus.
PAE-SMEs were usually longer than PAEs. Complete killing of organisms in PAE-SME experiments, especially at higher subinhibitory concentrations, could have been due to drug-induced lysis; alternately, PAE-SMEs could have been longer than the 8-h period tested. In every case, drug-free controls yielded growth, and the results of separate duplicate testing were identical. More studies are required to elucidate this finding (22).
Peak concentrations of levofloxacin in serum from human volunteers have been reported as 6.55 ± 1.84 µg/ml with an oral dose of 500 mg every 24 h (5). Single oral doses of levofloxacin of 50 to 1,000 mg produce a mean maximum concentration of drug in serum and area under the concentration-time curve ranging from 0.6 to 9.4 µg/ml and 4.7 to 108 mg · h/liter, respectively, but increasing linearly in a dose-proportionate fashion (5).
Results of the present study, together with the above breakpoint and pharmacokinetic analyses, point to clinical use of levofloxacin for pneumococcal infections, irrespective of the penicillin or macrolide susceptibility status of the strains.
| |
ACKNOWLEDGMENTS |
|---|
This study was supported by a grant from the R. W. Johnson Research Institute, Raritan, N.J.
| |
FOOTNOTES |
|---|
* Corresponding author. Mailing address: Department of Pathology, Hershey Medical Center, P.O. Box 850, Hershey, PA 17033. Phone: (717) 531-5113. Fax: (717) 531-7953. E-mail: pappelbaum{at}psghs.edu.
| |
REFERENCES |
|---|
|
Top
Abstract
Text
References
|
|---|
| 1. |
Appelbaum, P. C.
1992.
Antimicrobial resistance in Streptococcus pneumoniae an overview.
Clin. Infect. Dis.
15:77-83[Medline].
|
| 2. | Baquero, F., J. Martínez-Beltrán, and E. Loza. 1991. A review of antibiotic resistance patterns of Streptococcus pneumoniae in Europe. J. Antimicrob. Chemother. 30(Suppl. A):9-14. |
| 3. |
Barry, A. L.,
P. C. Fuchs,
S. D. Allen,
S. D. Brown,
J. H. Jorgensen, and F. C. Tenover.
1996.
In-vitro susceptibility of Streptococcus pneumoniae to the d- and l-isomers of ofloxacin: interpretive criteria and quality control limits.
J. Antimicrob. Chemother.
37:365-369 |
| 4. | Block, S, C. J. Harrison, J. A. Hedrick, R. A. Tyler, E. Smith, E. Keegan, and S. A. Chartrand. 1995. Penicillin-resistant Streptococcus pneumoniae in acute otitis media: risk factors, susceptibility patterns and antimicrobial management. Pediatr. Infect. Dis. J. 14:751-759[Medline]. |
| 5. |
Child, J.,
D. Mortiboy,
J. M. Andrews,
A. T. Chow, and R. Wise.
1995.
Open-label crossover study to determine pharmacokinetics and penetration of two dose regimens of levofloxacin into inflammatory fluid.
Antimicrob. Agents. Chemother.
39:2749-2751 |
| 6. | Craig, W. A., and S. Gudmundsson. 1996. Postantibiotic effect, p. 296-329. In V. Lorian (ed.), Antibiotics in laboratory medicine. The Williams & Wilkins Co., Baltimore, Md. |
| 7. |
Doern, G. V.,
A. Brueggeman,
H. P. Holley, Jr., and A. M. Rauch.
1996.
Antimicrobial resistance of Streptococcus pneumoniae recovered from outpatients in the United States during the winter months of 1994 to 1995: results of a 30-center national surveillance study.
Antimicrob. Agents Chemother.
40:1208-1213 |
| 8. |
Friedland, I. R., and G. H. McCracken, Jr.
1994.
Management of infections caused by antibiotic-resistant Streptococcus pneumoniae.
N. Engl. J. Med.
331:377-382 |
| 9. |
Fu, K. P.,
S. C. Lafredo,
B. Foleno,
D. M. Isaacson,
J. F. Barrett,
A. J. Tobia, and M. E. Rosenthale.
1992.
In vitro and in vivo antibacterial activities of levofloxacin (l-ofloxacin), an optically active ofloxacin.
Antimicrob. Agents Chemother.
36:860-866 |
| 10. |
Fuursted, K.,
J. D. Knudsen,
M. B. Petersen,
R. K. Poulsen, and D. Rehm.
1997.
Comparative study of bactericidal activities, postantibiotic effects, and effects on bacterial virulence of penicillin G and six macrolides against Streptococcus pneumoniae.
Antimicrob. Agents Chemother.
41:781-784 |
| 11. | Jacobs, M. R. 1992. Treatment and diagnosis of infections caused by drug-resistant Streptococcus pneumoniae. Clin. Infect. Dis. 15:119-127[Medline]. |
| 12. | Jacobs, M. R., and P. C. Appelbaum. 1995. Antibiotic-resistant pneumococci. Rev. Med. Microbiol. 6:77-93. |
| 13. |
Licata, L.,
C. E. Smith,
R. M. Goldschmidt,
J. F. Barrett, and M. Frosco.
1997.
Comparison of the postantibiotic and postantibiotic sub-MIC effects of levofloxacin and ciprofloxacin on Staphylocccus aureus and Streptococcus pneumoniae.
Antimicrob. Agents Chemother.
41:950-955 |
| 14. |
Mason, E. O., Jr,
S. L. Kaplan,
L. B. Lamberth, and J. Tillman.
1992.
Increased rate of isolation of penicillin-resistant Streptococcus pneumoniae in a children's hospital and in vitro susceptibilities to antibiotics of potential therapeutic use.
Antimicrob. Agents Chemother.
36:1703-1707 |
| 15. | National Committee for Clinical Laboratory Standards. 1997. Methods for dilution antimicrobial susceptibility tests for bacteria that grow aerobically, 4th ed. Approved standard M7-A4. National Committee for Clinical Laboratory Standards, Villanova, Pa. |
| 16. |
Neu, H. C., and N.-X. Chin.
1989.
In vitro activity of S-ofloxacin.
Antimicrob. Agents Chemother.
33:1105-1107 |
| 17. |
Odenholt-Tornqvist, I.
1993.
Studies on the postantibiotic effect and the postantibiotic sub-MIC effect of meropenem.
J. Antimicrob. Chemother.
31:881-892 |
| 18. |
Odenholt-Tornqvist, I.,
E. Löwdin, and O. Cars.
1991.
Pharmacodynamic effects of subinhibitory concentrations of -lactam antibiotics in vivo.
Antimicrob. Agents Chemother.
35:1834-1839 |
| 19. |
Odenholt-Tornqvist, I.,
E. Löwdin, and O. Cars.
1992.
Postantibiotic sub-MIC effects of vancomycin, roxithromycin, sparfloxacin, and amikacin.
Antimicrob. Agents Chemother.
36:1852-1858 |
| 20. |
Pankuch, G. A.,
M. R. Jacobs, and P. C. Appelbaum.
1995.
Activity of CP 99,219 compared to DU-6859a, ciprofloxacin, ofloxacin, levofloxacin, lomefloxacin, tosufloxacin, sparfloxacin and grepafloxacin against penicillin-susceptible and -resistant pneumococci.
J. Antimicrob. Chemother.
35:230-232 |
| 21. |
Spangler, S. K.,
M. R. Jacobs, and P. C. Appelbaum.
1992.
Susceptibilities of penicillin-susceptible and -resistant strains of Streptococcus pneumoniae to RP 59500, vancomycin, erythromcyin, PD 131628, sparfloxacin, temafloxacin, Win 57273, ofloxacin, and ciprofloxacin.
Antimicrob. Agents Chemother.
36:856-859 |
| 22. |
Spangler, S. K.,
G. Lin,
M. R. Jacobs, and P. C. Appelbaum.
1997.
Postantibiotic effect of sanfetrinem compared with those of six other agents against 12 penicillin-susceptible and -resistant pneumococci.
Antimicrob. Agents Chemother.
41:2173-2176 |
| 23. |
Visalli, M. A.,
M. R. Jacobs, and P. C. Appelbaum.
1996.
MIC and time-kill study of activities of DU-6859a, ciprofloxacin, levofloxacin, sparfloxacin, cefotaxime, imipenem, and vancomycin against nine penicillin-susceptible and -resistant pneumococci.
Antimicrob. Agents Chemother.
40:362-366 |
Antimicrobial Agents and Chemotherapy, May 1998, p. 1253-1255, Vol. 42, No. 5
0066-4804/98/$04.00+0
Copyright © 1998, American Society for Microbiology. All rights reserved.
This article has been cited by other articles:
-
Athamna, A., Athamna, M., Medlej, B., Bast, D. J., Rubinstein, E.
(2004). In vitro post-antibiotic effect of fluoroquinolones, macrolides, {beta}-lactams, tetracyclines, vancomycin, clindamycin, linezolid, chloramphenicol, quinupristin/dalfopristin and rifampicin on Bacillus anthracis. J Antimicrob Chemother
53: 609-615
[Abstract] [Full Text] -
Gander, S., Finch, R.
(2000). The effects of exposure at constant (1 h) or exponentially decreasing concentrations of quinupristin/dalfopristin on biofilms of Gram-positive bacteria. J Antimicrob Chemother
46: 61-67
[Abstract] [Full Text] -
Davies, T. A., Ednie, L. M., Hoellman, D. M., Pankuch, G. A., Jacobs, M. R., Appelbaum, P. C.
(2000). Antipneumococcal Activity of ABT-773 Compared to Those of 10 Other Agents. Antimicrob. Agents Chemother.
44: 1894-1899
[Abstract] [Full Text] -
Davies, T. A., Kelly, L. M., Hoellman, D. B., Ednie, L. M., Clark, C. L., Bajaksouzian, S., Jacobs, M. R., Appelbaum, P. C.
(2000). Activities and Postantibiotic Effects of Gemifloxacin Compared to Those of 11 Other Agents against Haemophilus influenzae and Moraxella catarrhalis. Antimicrob. Agents Chemother.
44: 633-639
[Abstract] [Full Text] -
Davies, T. A., Kelly, L. M., Pankuch, G. A., Credito, K. L., Jacobs, M. R., Appelbaum, P. C.
(2000). Antipneumococcal Activities of Gemifloxacin Compared to Those of Nine Other Agents. Antimicrob. Agents Chemother.
44: 304-310
[Abstract] [Full Text] -
Spangler, S. K., Bajaksouzian, S., Jacobs, M. R., Appelbaum, P. C.
(2000). Postantibiotic Effects of Grepafloxacin Compared to Those of Five Other Agents against 12 Gram-Positive and -Negative Bacteria. Antimicrob. Agents Chemother.
44: 186-189
[Abstract] [Full Text] -
Pendland, S. L., Diaz-Linares, M., Garey, K. W., Woodward, J. G., Ryu, S., Danziger, L. H.
(1999). Bactericidal Activity and Postantibiotic Effect of Levofloxacin against Anaerobes. Antimicrob. Agents Chemother.
43: 2547-2549
[Abstract] [Full Text] -
Amsden, G. W., Graci, D. M., Cabelus, L. J., Hejmanowski, L. G.
(1999). A Randomized, Crossover Design Study of the Pharmacology of Extended-Spectrum Fluoroquinolones for Pneumococcal Infections. Chest
116: 115-119
[Abstract] [Full Text] -
Champney, W. S., Tober, C. L.
(1999). Molecular Investigation of the Postantibiotic Effects of Clarithromycin and Erythromycin on Staphylococcus aureus Cells. Antimicrob. Agents Chemother.
43: 1324-1328
[Abstract] [Full Text]
| |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Copyright © 2010 by the American Society for Microbiology. For an alternate route to Journals.ASM.org, visit: http://intl-journals.asm.org | More Info»