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Microbial Pathogenesis
journal homepage: www.elsevier.com/locate/micpath
Review
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 12 December 2014
Received in revised form
4 February 2015
Accepted 6 February 2015
Available online xxx
Sepsis, a serious cause of morbidity in humans, has no proper single medication dedicated to it. In this
review, we look at the current treatment modalities, the different approaches attempted towards
treating it and alternative approaches that could be implemented to counter this neglected disease
condition. The use of antibiotics towards treatment of sepsis, use of combinations and strategies derived
from natural antimicrobial peptides has been dealt with in details. The social and technical difculties
associated with treating sepsis and the possible ways of combating them have also been discussed.
2015 Published by Elsevier Ltd.
Keywords:
Sepsis
Antibiotics
Antimicrobial peptides
TNF-a
1. Introduction
Globally, an estimated 18 million cases of sepsis occur each year
which means that 3 in a 1000 people get sepsis [1]. Every hour,
about 36 people die from sepsis [1]. It causes more deaths than
prostate cancer, breast cancer and HIV/AIDS combined [1]. One
million children die in the rst four weeks of life every year in India
and out of these deaths, 190,000 are caused by sepsis [1].
Sepsis: Sepsis is the systemic response to infection. It is dened
as the presence of several clinical, hematologic, biochemical and
immunologic variables associated with an infection. The clinical
parameters which are considered as symptomatic for sepsis are
furnished in Table 1. Severe sepsis is complicated by organ
dysfunction. Severe Sepsis and septicemia are the syndromes of
overwhelming response of the body to severe infections. At times,
it can be protective to body but at times it can lead to sequential
multi-organ failure leading to death. Septic shock refers to a state
of acute circulatory failure characterized by arterial hypotension
despite adequate uid resuscitation so that vasopressor therapy is
necessary to restore a minimally acceptable arterial pressure.
Hypotension is dened by a systolic arterial pressure below
90 mm Hg or a reduction of more than 40 mm Hg from baseline,
* Corresponding author.
E-mail address: jayanta@jncasr.ac.in (J. Haldar).
http://dx.doi.org/10.1016/j.micpath.2015.02.001
0882-4010/ 2015 Published by Elsevier Ltd.
Please cite this article in press as: D.S.S.M. Uppu, et al., Surviving sepsis in the era of antibiotic resistance: Are there any alternative approaches to
antibiotic therapy?, Microbial Pathogenesis (2015), http://dx.doi.org/10.1016/j.micpath.2015.02.001
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Table 1
Clinical features for diagnosis of sepsis.
Clinical parameters
Parameter values
1.
2.
3.
4.
5.
6.
7.
8.
>38.2 C
>120 beats min1
<110 mm Hg
<150 109 L1
<4 109 L1
>145 mmol L1
>30 mmol L1
>15 mmol L1
Temperature
Heart rate
Static blood pressure
Platelet count
Leukocyte count
Sodium ion
Bilirubin
Urea
Please cite this article in press as: D.S.S.M. Uppu, et al., Surviving sepsis in the era of antibiotic resistance: Are there any alternative approaches to
antibiotic therapy?, Microbial Pathogenesis (2015), http://dx.doi.org/10.1016/j.micpath.2015.02.001
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1.
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Lipopolysaccharide (LPS)
Lipoteichoic acid (LTA)
Peptidoglycan (PG)
Staphylococcal enterotoxin B (SEB)
Toxic shock syndrome toxin (TSS-1)
Unknown
Unknown
cytokine production, with tigecycline, clindamycin and trimethoprim/sulfamethoxazole being the most potent inhibitors of cytokine production at concentrations exceeding 25 mg/L [14].
The effect of trovaoxacin, ciprooxacin and ceftriaxone on
cytokine production of human peripheral blood mononuclear cells
(PBMCs) was examined [15]. PBMC responses were measured after
stimulation with lipopolysaccharide (LPS), lipoteichoic acid (LTA) or
killed or viable Streptococcus pneumoniae and Haemophilus inuenzae. Trovaoxacin inhibited the production of TNF-a, interleukin1b (IL-1b), IL-6 and IL-8 by PBMCs after stimulation with either LPS
or LTA by 83%. Similar inhibition occurred in PBMCs incubated with
killed or live bacteria and trovaoxacin, but not with ciprooxacin
or ceftriaxone. The relevance of this in vitro observation was
explored by examining TNF-a and IL-6 responses in trovaoxacintreated mice. Serum concentrations of both cytokines 1 h after
LPS challenge were 95% less than serum concentrations in mice that
were not given trovaoxacin. Reverse transcriptione polymerase
chain reaction studies of the mechanisms determining cytokine
down-regulation demonstrated that trovaoxacin reduced TNF-a,
IL-1b and IL-6 mRNA to levels similar to those of unstimulated cells.
These observations indicate that trovaoxacin can consistently and
signicantly reduce production of cytokines that play an important
role in sepsis. In vitro, this effect can occur in the presence of
bacteriolysis and is associated with inhibition of transcription of
cytokine genes [15].
Telithromycin had immunomodulatory effects as a result of
alteration of secretion of cytokines by monocytes. The antibiotic
telithromycin was examined for its effect on secretion of interleukins, IL-6, IL-10, and tumor necrosis factor alpha (TNF-a) by
lipopolysaccharide (LPS)-stimulated monocytes of eight human
donors. Secretion of each cytokine was signicantly increased by
LPS alone, whereas treatment with telithromycin signicantly
inhibited secretion of TNF-a but not secretion of IL-6, and IL-10 [16].
Q3
Table 3
The different classes of antibiotics that aggravate or reduce the sepsis disease
condition.
Antibiotics that aggravate sepsis
Macrolides
Erythromycin
Telithromycin
Tetracyclines
Tigecycline
Oxazolidinone
Linezolid
Membrane-active antibiotics
Polymyxin
Daptomycin
DNA biosynthesis inhibitors
Trovaoxacin
The mechanism of how the release of endotoxins upon antibiotic treatment causes deleterious effects on organ function of
the human body are more or less clearly understood [10,11].
Endotoxin, the lipopolysaccharide (LPS) constituent of the outer
membrane of the cell wall of gram-negative bacteria, is considered
to be the most important bacterial factor in the pathogenesis of
the gram-negative septic syndrome. It induces the release of the
cytokines TNF-a, IL-1 and IL-6. These cytokines activate a cascade
of secondary inammatory mediators, eventually leading to
endothelial damage and hemodynamic and metabolic derangements. Adequate antibiotic treatment is thought to be pivotal
in the therapy of severe gram-negative infections, but many invitro as well as animal and clinical studies have indicated that the
endotoxin concentration may increase following bacterial death
caused by exposure to antibiotics. Three mechanisms can account
for this increase: (i) accumulation of bacterial biomass following
antibiotic treatment, for instance because of lament formation;
(ii) an increase in the accessibility of endotoxin that remains
bound to the bacteria, which was demonstrated even when subMIC levels of antibiotics were used; or (iii) release of unbound
(free) endotoxin [10,11]. To avoid confusion, the overall increase in
the amount of biologically active endotoxin is best described as an
increase in endotoxin exposure.
Table 3 lists the different classes of antibiotics which either
aggravate or reduce sepsis. Overall, the use of antibiotics instead of
causing benecial effects can lead to adverse conditions of aggravating the sepsis disease condition rather than treating it. Unfortunately, the current crisis of antibiotic resistance makes even the
little benecial effects of antibiotics unavailable for the sepsis
treatment. Over 30% of neonatal sepsis deaths are attributed to
antibiotic resistance. There is an urgent need for developing alternative approaches for the treatment of sepsis in the era of antibiotic
resistance [1].
Please cite this article in press as: D.S.S.M. Uppu, et al., Surviving sepsis in the era of antibiotic resistance: Are there any alternative approaches to
antibiotic therapy?, Microbial Pathogenesis (2015), http://dx.doi.org/10.1016/j.micpath.2015.02.001
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Please cite this article in press as: D.S.S.M. Uppu, et al., Surviving sepsis in the era of antibiotic resistance: Are there any alternative approaches to
antibiotic therapy?, Microbial Pathogenesis (2015), http://dx.doi.org/10.1016/j.micpath.2015.02.001
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Please cite this article in press as: D.S.S.M. Uppu, et al., Surviving sepsis in the era of antibiotic resistance: Are there any alternative approaches to
antibiotic therapy?, Microbial Pathogenesis (2015), http://dx.doi.org/10.1016/j.micpath.2015.02.001
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the federal government is needed to tackle this ever-growing disease condition of sepsis.
Uncited reference
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Please cite this article in press as: D.S.S.M. Uppu, et al., Surviving sepsis in the era of antibiotic resistance: Are there any alternative approaches to
antibiotic therapy?, Microbial Pathogenesis (2015), http://dx.doi.org/10.1016/j.micpath.2015.02.001
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Please cite this article in press as: D.S.S.M. Uppu, et al., Surviving sepsis in the era of antibiotic resistance: Are there any alternative approaches to
antibiotic therapy?, Microbial Pathogenesis (2015), http://dx.doi.org/10.1016/j.micpath.2015.02.001
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