Comparative in-vitro activity of moxifloxacin, penicillin, ceftriaxone and ciprofloxacin against pneumococci isolated from meningitis
Agapito Tarasi,
Alessandro Capone,
David Tarasi,
Marco Cassone,
Gianluca Bianco and
Mario Venditti*
Divisione di Clinica Medica III, Servizio Aggregato di Consulenze
Internistico-Infettivologiche, Department of Clinical Medicine, University of Rome ` La
Sapienza' , Rome, Italy
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Abstract
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Minimum inhibitory concentrations of penicillin, ceftriaxone, ciprofloxacin, and
moxifloxacin (BAY 12-8039), a new 8-methoxyquinolone, were determined for 60 cerebrospinal
fluid isolates of Streptococcus pneumoniae collected during January 1997- April 1998
at
Italian medical centres. Three reference isolates with predetermined MIC values (two penicillin-
and multidrug-resistant isolates, one uniformly susceptible to all antibiotics) were also tested
with
the same antibiotics. The MIC90 of penicillin was
0.03 mg/L (range
0.03- 2
mg/L), of ceftriaxone 0.06 mg/L (range
0.03- 0.5 mg/L), of ciprofloxacin 2 mg/L (range
0.5-
8 mg/L) and of moxifloxacin 0.06 mg/L (range 0.03- 0.12 mg/L). Moxifloxacin was effective
against all the penicillin-resistant isolates tested, with an MIC of 0.06 mg/L. Moxifloxacin was
32-fold more active than ciprofloxacin and was not affected by penicillin and cephalosporin
resistance. These results indicate that moxifloxacin could be useful for the treatment of both
penicillin-sensitive and -resistant S. pneumoniae meningitis
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Introduction
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Streptococcus pneumoniae is a notable cause of morbidity and mortality worldwide,
being the leading cause of bacterial pneumonia as well as being an important cause of otitis
media
and meningitis. Over the past decade, there has been a dramatic increase in the prevalence of S. pneumoniae isolates resistant to penicillin and other antimicrobial agents,
1,2 making
pneumococcal meningitis exceptionally difficult to treat. Furthermore, clinicians have very few
treatment options for patient with allergy to ß-lactams. For these reasons, there is an urgent
need for antimicrobial agents with a different mechanism of action from ß-lactams, which
can
be used for therapy of meningitis caused by resistant isolates or in atopic patients. Thus, a new
quinolone antimicrobial agent which has potent activity against Gram-positive organisms and
favourable pharmacokinetics in terms of long half-life and good cerebrospinal fluid (CSF)
penetration would represent a significant therapeutic advance. One such novel fluoroquinolone is
moxifloxacin (BAY 12-8039), an 8-methoxiquinolone with enhanced activity against
Gram-positive bacteria.
3,4 The aim of this
study was to examine the activity of moxifloxacin in comparison with penicillin G, ceftriaxone
and
ciprofloxacin against 60 pneumococcal isolates from patients with meningitis.
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Materials and methods
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Sixty S. pneumoniae isolates from CSF of patients with meningitis were kindly
provided
by Dr Annalisa Pantosti, Istituto Superiore di Sanità, Rome, Italy. The isolates were
from
a variety of Italian medical centres, mainly from northern regions of the country, and included
three penicillin-resistant isolates. They were collected during January 1997- April 1998.
Antimicrobial agents were supplied as powders of known potency, as follows: moxifloxacin
and
ciprofloxacin from Bayer (Leverkusen, Germany); penicillin from Sigma Chemical Co. (St
Louis,
MO, USA); ceftriaxone from Roche Laboratories (Nutley, NJ, USA).
MICs were determined in duplicate by the agar dilution method recommended by the National
Committee for Clinical Laboratory Standards, with Mueller- Hinton agar (Difco Laboratories,
Detroit, MI, USA) supplemented with 5% sheep blood.
5 Suspensions with a turbidity equivalent to that of a 0.5
McFarland standard were prepared by suspending growth from blood agar plates in 2 mL of
Todd- Hewitt broth (Oxoid- Unipath Ltd., Basingstoke, UK). Suspensions were further diluted
1:10 to obtain a final inoculum of 10
4 cfu per spot. Plates were inoculated with a multipoint
inoculator (Denley, UK) and incubated overnight in air at 37°C. Three reference isolates,
kindly provided by Professor Alexander Tomasz, The Rockefeller University, New York, USA,
with predetermined MIC values (two penicillin- and multidrug-resistant isolates, one uniformly
susceptible to all antibiotics) were included in each run.
2 The MIC was defined as the lowest drug concentration
that inhibited growth after 20 h of incubation.5
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Results
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The results of susceptibility testing are shown in the Table as the
cumulative percentage inhibited.
The MIC90s of the antibiotics tested were as follows: penicillin G
0.03 mg/L,
with a range of
0.03- 2 mg/L; ceftriaxone 0.06 mg/L, range
0.03- 0.5 mg/L;
ciprofloxacin 2 mg/L, range 0.5- 8 mg/L; moxifloxacin 0.06 mg/L, range
0.03- 0.5 mg/L.
Three isolates were penicillin-resistant (one highly resistant, two intermediate). The only isolate
highly resistant to penicillin was also intermediate to ceftriaxone. As expected, the majority of
pneumococci were resistant to ciprofloxacin (two highly resistant and 47 intermediate), and
moxifloxacin was uniformly active against all isolates tested, being 32-fold more active than
ciprofloxacin.
View this table:
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Table. Susceptibility of 60 pneumococci isolated from CSF to moxifloxacin, penicillin G,
ciprofloxacin and ceftriaxone
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Discussion
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With the significant decline in cases of meningitis caused by Haemophilus influenzae
type
b as a result of effective polysaccharide- protein conjugate vaccines, S. pneumoniae is
now the most common cause of meningitis in children.
6 The past 20 years have witnessed a dramatic worldwide
increase in the incidence of pneumococcal isolates that are resistant to penicillin and other
antimicrobial agents.
1,2 Although
non-meningitic infections caused by penicillin-resistant pneumococci may be treated with high
doses of penicillin or other ß-lactams, clinical failure of penicillin in treatment of meningitis
caused by isolates with intermediate resistance to penicillin approaches 80%, and no cases of
meningitis caused by isolates fully resistant to penicillin have responded to penicillin therapy.
7 The potency of third generation cephalosporins is also
diminished as pneumococci develop reduced penicillin susceptibility,
8 and few therapeutic options are left for patients with
allergy to ß-lactams. Therefore, attention is being focused on the activity of new
antimicrobials that can be used for atopic patients, and for therapy of meningitis caused by
penicillin-resistant pneumococci. Quinolones are bactericidal, and are less hydrophilic than
ß-lactam and carbapenem antibiotics and therefore rapidly enter the subarachnoid space.
9 Although older compounds of this class were
insufficiently
active, new generation quinolones show good activity against Gram-positive bacteria including S. pneumoniae, and appear promising for the treatment of bacterial meningitis.
9 Moxifloxacin is an 8-methoxyquinolone with a broad
antibacterial spectrum which includes high activity against Gram-positive cocci. Its entry into the
subarachnoid space compared well with the CSF penetration of other quinolones in the rabbit
model of meningitis, and the CSF concentration is less influenced by the state of the blood- CSF
barrier.
4 Moreover, the CSF to serum ratio of this compound is not
reduced by the co-administration of dexamethasone.
4 In our study moxifloxacin was 32-fold more active than
ciprofloxacin, and was not affected by penicillin and cephalosporin resistance. These results
indicate that moxifloxacin could be useful for the treatment of meningitis caused by both
penicillin-sensitive and -resistant S. pneumoniae, and would be a valid therapeutic
option for patients allergic to ß-lactams, should it prove to be as potent in vivo.
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Notes
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* Correspondence address. Servizio Aggregato di Consulenze
Infettivologiche, Divisione di Clinica Medica III, Dipartmento di Medicina Clinica, Policlinico
Umberto I, Viale dell'Universitá, 37, 00185, Rome, Italy. Tel and Fax: +39 06
494
0421. 
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References
|
---|
1
.
Baquero, F. (1996). Epidemiology and
management of
penicillin-resistant pneumococci. Current Opinion in Infectious Diseases 9, 372 9.[ISI]
2
.
Tarasi, A., Chong, Y., Lee, K. & Tomasz, A. (1997).
Spread of the serotype 23F
multidrug-resistant Streptococcus pneumoniae clone to South Korea. Microbial
Drug Resistance 3, 105 9.[ISI][Medline]
3
.
Woodcock, J. M., Andrews, J. M., Boswell, F. J., Brenwald, N. P. & Wise, R. (1997). In
vitro activity of BAY 12-8039, a new fluoroquinolone. Antimicrobial Agents
and
Chemotherapy 41, 101 6.[Abstract]
4
.
Schmidt, H., Dalhoff, A., Stuertz, K., Trostdorf, F., Kohlsdorfer, C. & Nau, R. (1998).
Activity of moxifloxacin in experimental Streptococcus pneumoniae meningitis. In Programs and Abstracts of the Second European Congress of Chemotherapy and Seventh
Biennial Conference on Anti-infective Agents and Chemotherapy, 1998. Abstract T152, p.
73.
5
.
National Committee for Clinical Laboratory Standards. (1997). Methods for Dilution
Antimicrobial Susceptibility Tests for Bacteria that Grow Aerobically Fourth Edition:
Approved Standard M7-A4. NCCLS, Wayne, PA.
6
.
Booy, R. & Kroll, J. S. (1997). Is Haemophilus influenzae finished? Journal of
Antimicrobial Chemotherapy 40, 149 53.[Free Full Text]
7
.
Tweardy, D. J., Jacobs, M. R. & Speck, W. T. (1983). Susceptibility of
penicillin-resistant
pneumococci to eighteen antimicrobials: implications for treatment of meningitis. Journal of
Antimicrobial Chemotherapy 12, 133 9.[Abstract]
8
.
Linares, J., Alonso, T., Perez, J. L., Ayats, J., Dominguez, M. A., Pallares, R. et al.
(1992). Decreased susceptibility of penicillin-resistant pneumococci to
twenty-four ß
-lactam
antibiotics. Journal of Antimicrobial Chemotherapy 30, 279 88.[Abstract]
9
.
Nau, R. T., Schmidt, T., Kaye, K., Froula, J. L. & Tauber, M. G. (1995).
Quinolone antibiotics
in therapy of experimental pneumococcal meningitis in rabbits. Antimicrobial Agents
and
Chemotherapy 39, 593 7.[Abstract]
Received 28 July 1998;
accepted 28 February 1999