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Abstract

tericidal activity of ceftazidime could be correlated with the MICvalue for the different strains.Results when the strains were exposed to a concentration of4 × MIC were comparable to those at 8 × MIC, suggesting that nofurther bactericidal effect can be achieved by increasing the cefta-zidime concentration above 4 MIC (no concentration effect). At×2 × MIC, bactericidal activity was seen against all isolates; in general,this activity was comparable to that observed with 4 × and 8 × MIC,even on CTZ-R strains, but in one CTZ-R, one CTZ-I and two CTZ-Sstrains, re-growth at 24 h was observed.CI has been reported to be at least as effective as intermittentadministration in severe infections.
Correspondence
1049
procedure, the patient developed fever (38°C), lethargy and neck
stiffness. Analysis of ventricular CSF revealed 105 white cells/mm
3
(90% of the white cells were neutrophils), a glucose level of 23 mg/dL
(glucose level in the blood: 106 mg/dL) and protein of 119 mg/dL.
Microscopic examination of the Gram staining showed yeast and no
other microorganisms. Cultures were positive for C. albican s in three
separate samples. The blood culture was sterile. The patient had been
treated with fluconazole 400 mg intravenously (iv) daily, oxacillin 12 g
iv daily, rifampicin 600 mg iv daily, but meningitis persisted. Twenty
days after the stroke, the patient was admitted to our Infectious
Diseases unit. The external shunt was removed and replaced immedi-
ately, and therapy with AmBisome (3 mg/kg/day) and flucytosine
(150 mg/kg/day) was started. In addition, on days 79 of the new
treatment, intraventricular amphotericin B deoxycholate was
injected into the shunt at a dose of 4 mg daily (the shunt was closed for
4 h). Despite this therapy, the patient had a torpid clinical course; his
fluids and clinical condition improved but without complete resolution.
CSF culture was positive until the 7th day of therapy and after this
was negative. Following 23 days of this drug regimen, se rial CSF and
serum samples were taken to check amphotericin B levels. Some
samples were also taken during intraventricular i nfusion. All samples
were stored at 80°C until assay. After 30 days, the patient died as a
result of a second haemorrhagic stroke. Amphotericin B concentrations
in the patients CSF and serum samples were analysed by HPLC,
as described by Bekersky et al.
1
We performed standard curves for
amphotericin B by regression analysis. The peak serum level of
amphotericin B was 15.61 mg/L and the area under the concentration
time curve (AUC) was 115.5 mg·h/L. Amphotericin B concentrations
in ventricular CSF were between 0.09 and 0.24 mg/L (AUC
3.7 mg·h/L). Concentrations of ventricular amphotericin B taken
after intrathecal administration (range +7, +24 h after intra-shunt
infusion) were between 100.5 and 1.75 mg/L. The concentration of
amphotericin B in lumbar fluid was 0.59 mg/L (the fluid sample was
obtained by single lumbar puncture, 48 h after intra-shunt infusion of
amphotericin B and 22 h after AmBisome iv).
One major concern, for therapy of fungal shunt infections, is CSF
penetration of systemically administered amphotericin B. Currently,
C. albicans is considered susceptible to amphotericin B at a concen-
tration of 1 mg/L (MIC < 1 mg/L).
2
The minimal drug concentration
achieved at the infection site should be at least equal to the MIC for
the infecting organism, and in vivo, the ratio between the maximum
concentration of the drug (C
max
) and the MIC value is the best predictor
for outcome.
3
Conventional amphotericin B deoxycholate is notorious
for its inability to achieve consistently measurable concentrations in
CSF; it ranges from undetectable to no more than 4% of serum con-
centrations.
4
A potential strategy for reducing the toxicity and increasing the
therapeutic index of amphotericin B is the use of lipid formulations of
this drug, which allow the administration of a much higher dose.
5
In
our case, administration of AmBisome at 3 mg/kg/day did not result
in significantly enhanced amphotericin B concentration in CSF; in
fact a fluid C
max
of 0.24 is a sub-MIC conc entration, and limited clinical
results were obtained. These data show the po or penetration into CSF
of liposomal amphotericin B at a dose of 3 mg/kg/day (CSF AUC was
equivalent to 3.2% of serum AUC). The intrathecal amphotericin B
therapy, administered only for 3 days in this case, achieved a temporary
elevated concentration in ventricular CSF, but this did not contribute
to the clinical outcome. If CNS penetration is based on C
max
, an
increased intravenous liposomal amphotericin dosage can be advocated
to treat CNS Candida infections. In clinical situations, the adminis-
tration, at maximal tolerable dosage, of AmBisome (510 mg/kg/day)
may provide more effective therapeutic results.
5
In addition, although
a post-antifungal effect on Candida species was disregarded, it may
have been attributable to amphotericin B and flucytosine,
6
and it
should be the aim of antimicrobial therapy to increase CSF drug con-
centration above the MIC so that there is a greater possibility of com-
pletely eradicating infection.
There exists a direct relationship between peak concentrations of
amphotericin B in plasma, AUCs and cerebral tissue concentrations.
This correlates directly with greater antifungal efficacy.
5
Thus, if
azole-resistant Candida shunt infections occur, a high dose of
AmBisome (510 mg/kg/day) may be a reasonable option.
References
1. Bekersky, I., Boswell G. W., Hiles R.
et al
. (1999). Safety and
toxicokinetics of intravenous liposomal amphotericin B (AmBisome) in
beagle dogs.
Pharmaceutical Research
16, 1694701.
2. Ellis, D. (2002). Amphotericin B: spectrum and resistance.
Journal
of Antimicrobial Chemotherapy
49,
Suppl. 1
, 710.
3. Andes, D., Stamsted, T. & Conklin, R. (2000). Pharmacodynamics
of amphotericin B in a neutropenic-mouse disseminated-candidiasis
model.
Antimicrobial Agents and Chemotherapy
45, 9226.
4. Patel, R. (1998). Antifungal agents. Part I. Amphotericin B prepar-
ations and flucytosine.
Mayo Clinic Procceedings
73, 120525.
5. Walsh, T. J., Goodman, J. L., Pappas, P.
et al
. (2001). Safety, tol-
erance and pharmacokinetics of high-dose liposomal amphotericin
B (AmBisome) in patients infected with
Aspergillus
species and other
filamentous fungi: maximum tolerated dose study.
Antimicrobial Agents
and Chemotherapy
45, 348796.
6. Turnidge, J. D., Gudmundsson, S., Vogelman, B.
et al
. (1994). The
postantibiotic effect of antifungal agents against common pathogenic
yeasts.
Journal of Antimicrobial Chemotherapy
34, 8392.
Journal of Antimicrobial Chemotherapy
DOI: 10.1093/jac/dkh002
Advance Access publication 12 November 2003
Vitamin C and SARS coronavirus
Harri Hemilä*
Department of Public Health, University of Helsinki, Helsinki,
FIN-00014 Finland
Keywords: ascorbic acid, pneumonia, severe acute respiratory
syndrome
*Tel: +359-0-191-27573; Fax: +358-0-191-2757 0;
E-mail: harri.hemila@helsinki.fi
Sir,
Recently, a new coronavirus was identified as the cause of the severe
acute respiratory syndrome (SARS).
1
In the absence of a specific
treatment for SARS, the possibility that vitamin C may show non-
specific effects on severe viral respiratory tract infections should be
considered. There are numerous reports indicating that vitamin C
may affect the immune system,
2,3
for example the function of phago-
cytes, transformation of T lymphocytes and production of interferon.
Correspondence
1050
In particular, vitamin C increased the resistance of chick embryo
tracheal organ cultures to infection caused by an avian coronavirus.
4
Studies in animals found that vitamin C modifies susceptibility to
various bacterial and viral infections,
3
for example protecting broiler
chicks against an avian coronavirus.
5
Placebo-controlled trials have
shown quite consistently that the duration and severity of common
cold episodes are reduced in the vitamin C groups,
3
indicating that
viral respiratory infections in humans are affected by vitamin C levels.
There is also evidence indicating that vitamin C may affect pneumonia.
3
In particular, three controlled trials with human subjects reported a
significantly lower incidence of pneumonia in vitamin C-supplemented
groups,
6
suggesting that vitamin C may affect susceptibility to lower
respiratory tract infections under certain conditions. The possibility
that vitamin C affects severe viral respiratory tract infections would
seem to warrant further study, especially in light of the recent SARS
epidemic.
References
1. Holmes, K. V. (2003). SARS-associated coronavirus.
New England
Journal of Medicine
348, 194851.
2. Leibovitz, B. & Siegel, B. V. (1981). Ascorbic acid and the immune
response.
Advances in Experimental Medicine and Biology
135, 125.
3. Hemilä, H. & Douglas, R. M. (1999). Vitamin C and acute respiratory
infections.
International Journal of Tuberculosis and Lung Diseases
3,
75661.
4. Atherton, J. G., Kratzing, C. C. & Fisher, A. (1978). The effect of
ascorbic acid on infection of chick-embryo ciliated tracheal organ cultures
by coronavirus.
Archives of Virology
56, 1959.
5. Davelaar, F. G. & Bos, J. (1992). Ascorbic acid and infectious
bronchitis infections in broilers.
Avian Pathology
21, 5819.
6. Hemilä, H. (1997). Vitamin C intake and susceptibility to pneumonia.
Pediatric Infectious Diseases Journal
16, 8367.
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The effect of supplementing the feed of broiler chicks with different levels of ascorbic acid on the resistance against infectious bronchitis virus was investigated. Resistance was measured by the severity of tracheal lesions and the development of airsacculitis after challenge. The effect of ascorbic acid was dose dependent. Addition of 300 to 330 ppm ascorbic acid to the feed gave the best results. High concentrations (>600 ppm) had a less beneficial effect.
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Chick embryo tracheal organ cultures showed increased resistance to infection by a coronavirus after exposure to ascorbate, while chick respiratory epithelium and allantois-on-shell preparations showed no increase in resistance to infection by an influenza virus or a paramyxovirus.
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Since the introduction of ascorbic acid as an antiviral and antibacterial agent (Klenner, 1951; McCormick, 1952; Klenner, 1974) interest has focused on the possible immunologic mechanisms involved in its protective effect. The role of ascorbic acid in the immune response is reviewed here with regard to cellular and humoral functions, and experiments pertaining to the role of ascorbic acid in autoimmunity and anaphylaxis are discussed.
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In vivo pharmacodynamic parameters have been described for a variety of antibacterials. These parameters have been studied in correlation with in vivo outcomes in order to determine which dosing parameter is predictive of outcome and the magnitude of that parameter associated with efficacy. Very little is known about pharmacodynamics for antifungal agents. We utilized a neutropenic mouse model of disseminated candidiasis to correlate pharmacodynamic parameters (percent time above MIC [T > MIC], area under the concentration time curve [AUC]/MIC ratio, and peak serum level/MIC ratio) for amphotericin B in vivo with efficacy, as measured by organism number in homogenized kidney cultures after 72 h of therapy. Amphotericin B was administered by the intraperitoneal route. Drug kinetics for amphotericin B in infected mice were nonlinear. Serum half-lives ranged from 13 to 27 h. Infection was achieved by intravenous inoculation with 10(6) CFU of yeast cells per ml via the lateral tail vein of neutropenic mice. Groups of mice were treated with fourfold escalating total doses of amphotericin B ranging from 0.08 to 20 mg/kg of body weight divided into 1, 3, or 6 doses over 72 h. Increasing doses produced concentration-dependent killing, ranging from 0 to 2 log(10) CFU/kidney compared to the organism number at the start of therapy. Amphotericin B also produced prolonged dose-dependent suppression of growth after serum levels had fallen below the MIC. Nonlinear regression analysis was used to determine which pharmacodynamic parameter best correlated with efficacy. Peak serum level in relation to the MIC (peak serum level/MIC ratio) was the parameter best predictive of outcome, while the AUC/MIC ratio and T > MIC were only slightly less predictive (peak serum level/MIC ratio, coefficient of determination [R(2)] = 90 to 93%; AUC/MIC ratio, R(2) = 49 to 69%; T > MIC, R(2) = 67 to 85%). The total amount of drug necessary to achieve various microbiological outcomes over the treatment period was 4.8- to 7.6-fold smaller when the dosing schedule called for large single doses than when the same amount of total drug was administered in 2 to 6 doses. Given the narrow therapeutic window of amphotericin B and frequent treatment failures, these results suggest the need for a reevaluation of current dosing regimens.
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Ralph A. Tripp, Lia M. Haynes, Deborah Moore, Barbara Anderson, Azaibi Tamin, Brian H. Harcourt, Les P. Jones, Mamadi Yilla, Gregory J. Babcock, Thomas Greenough, Donna M. Ambrosino, Rene Alvarez, Justin Callaway, Sheana Cavitt, Kurt Kamrud, Harold Alterson, Jonathan Smith, Jennifer L. Harcourt, Congrong Miao, Raj Razdan, James A. Comer, Pierre E. Rollin, Thomas G. Ksiazek, Anthony Sanchez, Paul A. Rota, William J. Bellini, Larry J. Anderson. (2005) Monoclonal antibodies to SARS-associated coronavirus (SARS-CoV): Identification of neutralizing and antibodies reactive to S, N, M and E viral proteins. Journal of Virological Methods 128, 21-28 CrossRef