Since the window to death is so small .. "when appropriate
antimicrobial therapy was initiated within
0 to 2 hours of hypotension, in-hospital survival rates for both
groups approached 80%" ... one might
think the cognition of said subject might be of little concern ..
meaning .. ? .. personally .. try to keep
them alive and hope they DO give me some humor while I'm at it .. ? ;)

"Exogenous apotransferrin against infections by S. epidermidis and
other opportunistic pathogens"

DGDispatch

High Mortality Rate From Septic Shock Due to Candida Infection Due to
Delay in Antimicrobial Therapy: Presented at CCCF

By Pam Harrison

TORONTO, CANADA -- November 5, 2007 -- A large part of the high
mortality rate associated with septic shock in patients with Candida
infections can be attributed to a significant delay in initiation of
appropriate antimicrobial therapy, according to findings from the
Cooperative Antimicrobial therapy of Septic Shock (CATSS) study.

In their study, Faisal Siddiqui, MD, Fellow in Critical Care
Medicine,
University of Manitoba, Winnipeg, Manitoba, Canada, and colleagues
analysed survival in 433 patients with septic shock due to bacterial
infections or candidiasis based on the time it took to administer
effective antimicrobial therapy.

Dr. Siddiqui presented the study results here at the Critical Care
Canada Forum (CCCF).

For their study, the researchers divided time to initiation of
effective antimicrobial therapy from onset of hypotension into
several
different time frames: from 0 to 2 hours; 2 to 6 hours; 6 to 12
hours;
12 to 24 hours; 24 to 72 hours and over 72 hours.

Ninety-nine patients died without ever receiving effective therapy,
while 36 patients received effective antimicrobial therapy before the
onset of septic shock.

The remaining 308 patients were subject to univariate and
multivariate
analysis. On univariate analysis, time to appropriate intervention
was
strongly associated with survival through to hospital discharge in
both the bacterial infection and the candidiasis groups, as was the
APACHE score, the according to the researchers.

"Highly significant, delay-dependent increases in mortality [P <.
0001]
were seen in both groups," Dr. Siddiqui reported.

However, there were marked differences in the distribution of delay
between those with bacterial shock and those with candiasis shock.
For
example, when appropriate antimicrobial therapy was initiated within
0
to 2 hours of hypotension, in-hospital survival rates for both groups
approached 80%.

In-hospital survival rates were also similar for both groups when
antimicrobial therapy was initiated between 2 and 6 hours after
hypotension onset.

Separation in survival rates between those with bacterial shock and
those with candidiasis shock started to occur when treatment was
initiated between 6 and 12 hours after onset of hypotension, where
only about 20% of patients with candidiasis shock survived until
hospital discharge versus about double that for those with bacterial
shock.

A similar pattern was seen between the two groups when treatment was
initiated 12 to 24 hours after hypotension onset, where survival
rates, although low, were still about double those for bacterial
shock
versus those with candidiasis shock. Survival rates were 10% and less
for both groups when treatment was initiated 24 hours and more after
hypotension onset.

However, the median duration of time before appropriate antimicrobial
therapy was initiated was 35.2 hours for those with candidiasis shock
versus 5.5 hours for those with bacterial shock.

Therefore, patients with Candida infections were far less likely to
receive early initiation of appropriate antimicrobial therapy than
those with bacterial shock.

"We all know that with bacterial sepsis, the earlier we initiate
therapy, the better," Dr. Siddiqui said in an interview.

The problem with Candida-associated septic shock is that physicians
tend not to think of fungal causes "right off the bat", he added.
Therefore, antifungal therapy is delayed for 24 to 72 hours in the
majority of patients with Candida.

"We know that we should consider fungal sepsis early in patients who
are immunocompromised as well as those who have been hospitalised for
a long period of time," Dr. Siddiqui said. "But maybe we should also
be considering antifungal therapy early in any patient with septic
shock with the understanding that we would stop therapy if there was
no sign of fungal infection after initial cultures were done."

As the investigators note, mortality for Candida-associated septic
shock exceeds 80% compared with approximately 50% for bacterial
shock.

---------------------------------------

A Pharmaceutical Human Apotransferrin Product for Iron Binding Therapy
(2003)
Bonsdorff, Leni Von

Abstract
Transferrin is the major iron binding protein in human plasma. It
binds iron with high affinity in a redox inactive form and delivers it
to growing cells.
Each molecule is capable of binding two molecules of ferric iron.
Normally, transferrin is only about 30 % saturated with iron.
In certain clinical conditions, the iron concentration in serum is
increased so that the iron binding capacity is exceeded and non-
transferrin-bound iron (NTBI) is formed in serum. NTBI is potentially
toxic because it generates free radical formation and can be taken up
by tissues, leading to excess deposits that can potentiate tissue
damage.
It is also known that iron enhances the growth of bacteria and fungi,
and can predispose patients to septic infections.
This thesis describes the development of an efficient process for
producing pharmaceutical grade iron-free apotransferrin. The
biochemical efficacy of apotransferrin for iron binding therapy was
studied in early phase clinical trials in haematological stem cell
transplant (SCT) patients.
The scope of this work did not include studying the clinical efficacy
of apotransferrin.
The manufacturing method used fraction IV of the Cohn cold ethanol
human plasma fractionation process as starting material.
Apotransferrin was purified in two ion exchange chromatography steps
and ultrafiltration with over 90 % recovery.
In order to obtain a virus-safe product, the process comprised solvent
detergent treatment as the main virus inactivation step and virus
filtration and polyethylene glycol precipitation to remove physico-
chemically resistant infectious agents.
The purity of the product was at least 98 %, main impurities being
IgG, IgA and hemopexin.
Methods for studying the iron binding capacity, the transferrin
conformation and its iron forms, and the glycosylation variants were
developed and used to study the quality of the finished product
batches.
The product had intact iron binding capacity and a native
conformation.
The results of several production batches indicated that the
manufacturing could be carried out reproducibly.
Product characterisation by electrospray and MALDI-TOF mass
spectrometry indicated no other chemical modifications than N-linked
glycan chains and disulphide bonds, except minor oxidation.
A stable liquid formulation suitable for intravenous infusion was
developed. The biochemical binding of NTBI to apotransferrin in vivo
was studied by several methods.
The bleomycin method for NTBI determination was modified for microwell
measurement and evaluated.
The bleomycin assay was reproducible and NTBI was found in serum
samples only when transferrin saturation was > 80 % and haemolysed
samples were excluded.
The bleomycin assay that measures redox-active iron underestimated the
true concentration of NTBI.
The concentration of NTBI could be calculated from the shift of
transferrin iron forms found in vivo after intravenous infusion of
apotransferrin to patients.
It could also be determined with a chelation based method, which,
however, had a lower specificity than the bleomycin method.
In haematological SCT patients, the concentration of NTBI could be as
high as 20 µmol / l.
Apotransferrin given in single intravenous doses to six patients bound
NTBI effectively, although in most cases temporarily.
With repeated high dose regimens, the appearance of NTBI was prevented
in 5 of 8 patients.
The influence of NTBI on the growth of the opportunistic pathogen
Staphylococcus epidermidis was studied both with purified transferrin
and in serum milieu.
In both cases, growth was critically dependent on NTBI and on a high
transferrin saturation. Only at high initial bacterial concentrations
could growth be detected with partially saturated transferrin.
Apotransferrin administered to SCT patients bound NTBI and restored
the growth inhibitory effect of serum.
Exogenous apotransferrin might protect the patients against infections
by S. epidermidis and other opportunistic pathogens whose growth is
dependent on NTBI.
In conclusion, the apotransferrin was pure and safe and showed in vivo
the biochemical effects that could be expected of a functional human
apotransferrin product.
In SCT patients it was possible to prevent the appearance of NTBI and
maintain the bacterial growth inhibitory effect in serum..
Academic dissertations from the Finnish Red Cross Blood Service, ISSN
1236-0341; Number 48

Publication details
Download http://lib.tkk.fi/Diss/2003/isbn9525457060/
Publisher Helsinki University of Technology
Contributors Helsinki University of Technology, Department of Chemical
Technology, Laboratory of Biochemistry and Microbiology, Finnish Red
Cross Blood Service
Repository Helsinki University of Technology, Finland, Document Server
(Finland)
Keywords apotransferrin, non-transferrin-bound iron, Staphylococcus
epidermidis, plasma protein
Type text
Language eng
Relation This thesis consists of a comprehensive summary and 5
separate articles., von Bonsdorff L., Tölö H., Lindeberg E., Nyman T.,
Harju A. and Parkkinen J., 2001. Development of a pharmaceutical
apotransferrin product for iron binding therapy. Biologicals 29, No.
1, pages 27-37. [PDF] (c) 2001 Elsevier Science. By permission., von
Bonsdorff L., Lindeberg E., Sahlstedt L., Lehto J. and Parkkinen J.,
2002. Bleomycin-detectable iron assay for non-transferrin-bound iron
in hematologic malignancies. Clinical Chemistry 48, No. 2, pages
307-314. [PDF] (c) 2002 American Association for Clinical Chemistry
(AACC). By permission., Sahlstedt L., von Bonsdorff L., Ebeling F.,
Ruutu T. and Parkkinen J., 2002. Effective binding of free iron by a
single intravenous dose of human apotransferrin in haematological stem
cell transplant patients. British Journal of Haematology 119, No. 2,
pages 547-553. [PDF] (c) 2002 Blackwell Publishing. By permission.,
Matinaho S., von Bonsdorff L., Rouhiainen A., Lönnroth M. and
Parkkinen J., 2001. Dependence of Staphylococcus epidermidis on non-
transferrin-bound iron for growth. FEMS Microbiology Letters 196, No.
2, pages 177-182. [PDF] (c) 2001 Elsevier Science. By permission., von
Bonsdorff L., Sahlstedt L., Ebeling F., Ruutu T. and Parkkinen J.,
2003. Apotransferrin administration prevents growth of Staphylococcus
epidermidis in serum of stem cell transplant patients by binding of
free iron. FEMS Immunology and Medical Microbiology 37, No. 1, pages
45-51. [PDF] (c) 2003 Elsevier Science. By permission.

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Tom

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