ArticlePDF AvailableLiterature Review

Do antibiotics cause mitochondrial and immune cell dysfunction? A literature review



While antibiotics are clearly important treatments for infection, antibiotic-induced modulation of the immune system can have detrimental effects on pathogen clearance and immune functionality, increasing the risk of secondary infection. These injurious consequences may be mediated, at least in part, through effects on the mitochondria, the functioning of which is already compromised by the underlying septic process. Here, we review the complex interactions between antibiotic administration, immune cell and mitochondrial dysfunction.
Do antibiotics cause mitochondrial and immune cell dysfunction?
A literature review
Muska Miller
* and Mervyn Singer
Bloomsbury Institute of Intensive Care Medicine, Cruciform Building, University College London, Gower Street, London, WC1E 6BT, UK
*Corresponding author. E-mail:
While antibiotics are clearly important treatments for infection, antibiotic-induced modulation of the immune
system can have detrimental effects on pathogen clearance and immune functionality, increasing the risk
of secondary infection. These injurious consequences may be mediated, at least in part, through effects on
the mitochondria, the functioning of which is already compromised by the underlying septic process. Here,
we review the complex interactions between antibiotic administration, immune cell and mitochondrial
Antibiotics are key components of modern-day medicine. Yet,
despite their numerous benets, they carry a signicant risk
of detriment and thus represent a double-edged sword.
Some harmful effects are overt and/or well recognized such as
rashes, hepatic and renal dysfunction, overgrowth by opportunis-
tic organisms, induction of resistance, and effects on the
However, other adverse consequences are less
well appreciated, for instance effects on the efcacy of
anti-cancer medications,
organorgan crosstalk
and the
JarischHerxheimer reaction, in which release of pathogen con-
stituents such as endotoxin and DNA activate proinammatory
Using a rat model of caecal ligation and puncture,
Peng et al.
demonstrated that ampicillin/sulbactam improved
survival but at the expense of a greater inammatory response
and more renal dysfunction.
The antimicrobial actions of antibiotics also impact directly, al-
beit to a lesser extent, upon mammalian cells. Antibiotics can af-
fect immune and bioenergetic function and this may potentially
compromise the hosts ability to both counter the infection and
maintain organ functionality. Sepsis represents a dysregulated
host response triggered by an infectious process that leads to or-
gan dysfunction.
As bioenergetic/metabolic shutdown is consid-
ered a likely key component underlying multi-organ dysfunction
in sepsis,
including the immune system, there may be an add-
itional and crucial iatrogenic contribution from antibiotics.
It is thus timely to review current knowledge of how specic
antibiotic classes affect immune cell processes including chemo-
taxis, phagocytosis, antigen presentation, cytotoxicity and anti-
body production, and what is known about their impact on
mitochondria. We performed a detailed search of both clinical
and preclinical literature using PubMed using the following criteria:
(antibiotics OR antimicrobials OR aminoglycosides OR beta-
lactams OR macrolides OR quinolones OR oxazolidinone) AND (im-
mune OR mitochondri*). All non-English reviews were excluded.
A brief overview of mitochondrial dysfunction
in sepsis, with particular reference to immune
cells, and the link to antibiotics
The link between antibiotics and mitochondria stems from the
endosymbiotic theory, which proposes that mitochondria share
common ancestry with Alphaproteobacteria such as Rickettsia,
Anaplasma and Ehrlichia.
Thus mitochondria may be particularly
susceptible to antibiotic mechanisms acting on nucleic acid
and protein synthesis and/or transport pathways. The ensuing
inhibition of mitochondrial functionality and biogenesis may
compromise energy substrate availability with downstream con-
sequences on host cell functionality. Importantly, mitochondria
do not simply act as intracellular powerhouses but also play other
important roles to maintain homeostasis. These include biosyn-
thesis (e.g. nucleotides, fatty acids and cholesterol), mediation
of intracellular signalling, and production and sequestration of
reactive oxygen species (ROS). Mitochondrial dysfunction is impli-
cated in multiple conditions including sepsis, neurodegeneration,
ageing and cancer cell metabolism.
In sepsis, mitochondrial dysfunction is strongly associated
with illness severity and poor outcomes.
Immune dysregulation
is a major feature of sepsis and this is increasingly linked to
bioenergetic dysfunction.
Specic alterations are described
in immune cell mitochondrial respiratory complex activity,
oxygen consumption, mitochondrial membrane depolarization,
apoptosis and ROS production.
Release of mitochondrial
DNA and cardiolipin are also sensed by immune cells as
damage-associated molecular pathogens (DAMPs) that will fur-
ther amplify the systemic inammatory response.
After the
J Antimicrob Chemother 2022; 77: 12181227 Advance Access publication 25 February 2022
© The Author(s) 2022. Published by Oxford University Press on behalf of British Society for Antimicrobial Chemotherapy.
This is an Open Access article distributed under the terms of the Creative Commons Attribution License (
by/4.0/), which permits unrestricted reuse, distribution, and reproduction in any medium, provided the original work is properly cited.
Downloaded from by guest on 22 December 2022
initial immune activation, immunoparesis follows; this can persist
for weeks, if not months, predisposing the patient to secondary
infection. An increasing evidence base links immunoparesis, at
least in part, to bioenergetic dysfunction.
Data on immunomodulatory effects of aminoglycosides are con-
In some studies, therapeutic levels of gentamicin
and amikacin reduced polymorphonucleocyte (PMN) chemo-
On the other hand, others reported no inuence on
either chemotaxis or phagocytosis but an inhibitory effect on
PMN bactericidal activity.
At therapeutic doses, amikacin in-
creased superoxide production in stimulated PMNs but this was
reduced at high doses (15 mg/L).
Gentamicin, netilmicin and
tobramycin, however, had no impact.
Gentamicin and amikacin
at high concentrations (.40 mg/L) also inhibited macrophage
Deleterious effects of aminoglycosides on mitochondrial func-
tion are also described. This mechanism has been implicated, at
least in part, in the complications of ototoxicity and nephrotox-
as aminoglycosides act on the mitochondrial ribosomal
A site, which has structural similarity to bacterial ribosomes. This
may activate phosphatidylinositol phospholipase C,
intracellular calcium
and ultimately leading to a proinamma-
tory response via activation of extracellular signal-regulated
kinases (ERKs).
In renal and sensory hair-cell mitochondria,
gentamicin inhibited oxidative phosphorylation and mitochon-
drial membrane potential, increasing ROS and apoptosis.
Kanamycin reduced mitochondrial membrane potential, electron
transport chain activity and ATP production in epithelial cells.
Aminoglycosides could also chelate mitochondrial iron, forming
a highly oxidant Fe(II)aminoglycoside complex that causes oxi-
dative damage and death in sensory hair cells.
Gentamicin may
mobilize iron from mitochondria in a time- and dose-dependent
manner via generation of hydrogen peroxide.
To our knowl-
edge, no study has yet investigated aminoglycoside effects on
mitochondrial function in immune cells.
β-Lactams have known immunomodulatory functions in hyper-
and cancer.
However, reported effects on im-
mune cells in the context of infection have been conicting.
remains unclear whether these effects are direct or secondary to
release of pathogen-associated molecular patterns (PAMPs),
which are evolutionarily conserved molecules released by killed
Variations in β-lactam-induced endotoxin release
can inuence cell death processes; when added to a co-culture
of PMNs and Escherichia coli, ampicillin and cephalosporins pro-
duced a marked release of endotoxin with resulting PMN necrosis,
whereas imipenem generated signicantly lower levels of
endotoxin and induced apoptotic cell death.
β-Lactams also
reduce granulopoiesis and may even cause neutropenia.
Paradoxically, amoxicillin increased dendritic cell maturation and
expression of activation markers such as HLA-DR, CD86 and CD80.
There are also conicting data on chemotaxis and phagocyt-
osis. Some studies found penicillins, carbapenems and cephalos-
porins had no effect on PMN chemotaxis,
whereas others
reported ampicillin and cephalosporins reduced chemotaxis
across a broad concentration range.
Yet other papers
found cephalosporins and carbapenems increased chemotaxis
of PMNs and murine macrophages, respectively.
for phagocytosis, some studies found no effect of cephalosporins
on PMN phagocytosis at therapeutic doses,
some found
cephalosporins and carbapenems increased human PMN and
murine macrophage phagocytosis,
while others re-
ported that piperacillin, cephalosporins and meropenem reduced
phagocytic activity in PMNs, monocytes and rat leucocytes, re-
Cefotaxime, faropenem, amoxicillin, clavulanic
acid and imipenem increased the respiratory burst and superox-
ide production in PMNs.
On the other hand, meropenem
reduced superoxide release but had no effect on PMN killing of
Candida albicans.
In a cell-free system, ampicillin and various
cephalosporins could scavenge hypochlorous acid (HOCl).
With this wide variation in ndings, no solid conclusions can
be drawn.
Data on the effects of β-lactams on cytokine release are also
inconsistent. In endotoxin-stimulated PBMCs, penicillin (at 5
80 mg/L) did not affect TNF-αrelease over a 3 day study period.
However, meropenem reduced TNF-αrelease from endotoxin-
stimulated monocytes after a 4 h incubation but did not affect
IL-1α, IL-6 or IL-8.
By contrast, a study using endotoxin-
stimulated PBMCs found that piperacillin (at 100 mg/L) and
co-amoxiclav (at therapeutic doses) increased release of TNF-α,
IL-1β, IL-6 and IL-8 and increased expression of TLR2 mRNA,
but reduced TLR4 mRNA expression.
A further study using
monocytes incubated with Staphylococcus epidermidis, however,
found no effect of β-lactams on TNF-αrelease.
In various stud-
ies on endotoxin-stimulated monocytes, penicillin and various
cephalosporins inhibited IFN-γactivity,
IL-10 release
CD14 expression.
Penicillins could also conjugate with human
IFN-γ, TNF-α, IL-1β, IL-4 and IL-13 but selectively disrupt
IFN-γ-dependent immune responses.
In terms of adaptive immunity, benzylpenicillin, carbenicillin,
cefazolin and cefalotin did not affect lymphocyte mitogenic
responses after 3 days of incubation.
However, moxalactam
at different concentrations reduced chemical-induced lympho-
cyte proliferation.
Long-term ceftriaxone use increased the per-
ipheral blood CD4/CD8 cell ratio but reduced the number of
There is a scarcity of literature on the effects of β-lactams on
immune cell mitochondria. Studies have mostly focused upon
effects on hepatic and renal mitochondria. Cephalosporin ne-
phrotoxicity was partially explained by effects on mitochondrial
anionic substrate transport (e.g. glutamate and malate).
Cefaloglycin competitively reduced carnitine-facilitated pyruvate
oxidation and palmitoylcarnitine-mediated mitochondrial re-
spiration, thereby reducing β-oxidation of fat and inhibiting activ-
ity of the tricarboxylic acid cycle.
In renal mitochondria,
imipenem, cefaloridine and cefaloglycin reduced mitochondrial
respiration while imipenem and cefaloglycin reduced oxidation
of butyrate, valerate and pyruvate as early as 3090 min.
Another study demonstrated that cephalosporins and penicillins
could both reduce carnitine transport in a dose-dependent man-
In rat liver mitochondria, co-amoxiclav increased ATPase
activity and induced opening of the mitochondrial transition
pore to increase release of cytochrome c, thereby triggering
Downloaded from by guest on 22 December 2022
activation of caspase-9 and -3 and apoptosis.
In neurons, pi-
peracillin lowered mitochondrial membrane potential, reducing
respiration and ATP production, but increased mitochondrial
Naturally occurring glycopeptides are involved in both innate
and adaptive immune responses, including immunoglobulins,
cytokines, chemokines, complement, adhesion molecules and
various receptors. Glycopeptides also affect the immune
system, mostly by inducing adverse reactions via mast cell
neutropenia and decimation of gut micro-
An in vivo murine study found that vancomycin
produced neutropenia and lymphocytosis in peripheral popula-
tions but increased T-helper cells and reduced T-cytotoxic cells
within the spleen.
In the context of infection, there is a plethora of conicting
reports. Teicoplanin at half its MIC enhanced macrophage phago-
cytosis of Staphylococcus aureus,
whereas teicoplanin and
vancomycin (at concentrations of 10100 mg/L) increased intra-
cellular killing of phagocytosed organisms in both PMNs and
At high teicoplanin concentrations (500 mg/L),
adherence, chemotaxis, phagocytosis and killing of C. albicans
by PMNs were signicantly inhibited, while vancomycin (at
0.002 mg/L) reduced PMN adherence and phagocytosis.
Conversely, other studies found that therapeutic concentrations
of teicoplanin and vancomycin did not affect chemotaxis, adher-
ence nor phagocytosis of human PMNs.
There are similar conicting ndings in terms of cytokine re-
lease. In LPS-stimulated monocytes, vancomycin increased
TNF-α, IL-6 and IL-10 and expression of multiple toll-like recep-
tors (TLRs).
Other studies, however, reported a decrease in
TNF-αproduction in PBMCs following an 18 h incubation with
and a reduction in IL-8, IL-1βand TNF-αwith
We could nd no studies investigating the effects of glycopep-
tides on immune cell mitochondria. Vancomycin (at 0.033 mg/L)
inhibited protein and glycoprotein synthesis in isolated rat liver
mitochondria and brain mitochondria.
Mitochondrial dysfunc-
tion has been postulated to be the cause of glycopeptide nephro-
toxicity, particularly through an increase in ROS production. In
porcine proximal tubular epithelial cell lines, vancomycin (at
2 mM concentration) increased mitochondrial ROS production,
reduced mitochondrial membrane potential, impaired activity
of complex I of the electron transport chain, and increased apop-
tosis via activation of caspase-3, -7 and -9.
These effects
may be mediated by peroxidation of the mitochondrial mem-
brane protein cardiolipin
and could be partially or wholly miti-
gated by antioxidants such as vitamin E and MitoTEMPO.
Another in vitro study, however, found that vancomycin (at 1,
2.5 and 5 mM concentrations) increased oxygen consumption
and ATP concentrations in proximal tubular epithelial cell lines.
The immunomodulatory effects of macrolides on the lung have
been recognized since the 1970s.
In bronchiolitis, erythromy-
cin reduced bronchoalveolar lavage uid accumulation of
leucocytes, particularly PMNs.
This may relate to a reduc-
tion in PMN chemotactic activity mediated by decreased produc-
tion of IL-8, LTB-4 and IL-1β.
In patients with atopic
diseases such as asthma and rhinosinusitis, various macrolides
reduced PMN and eosinophil counts in sputum, bronchoalveolar
uid and blood, cytokine levels, PMN elastase and NADPH oxidase
In patients with moderate to severe COPD, azith-
romycin (500 mg daily for 3 days) decreased blood leucocyte and
platelet counts, lowered serum acute-phase proteins and soluble
E-selectin levels, and transiently decreased serum IL-8.
patients with cystic brosis, long-term use of clarithromycin re-
duced sputum cytokine levels but enhanced ex vivo lymphocyte
Several in vitro studies report that macrolides reduce
pro-inammatory cytokines and chemokines (e.g. IL-1, IL-2,
IL-6, IL-8 and TNF-α),
possibly via suppression of AP-1
and nuclear factor kappa B (NF-κB) pathways
and by modula-
tion of TLR expression.
Macrolides reduce accumulation of
cells at affected sites such as the lung by suppressing induction
of MCP-1 and MMP-9, thereby reducing vascular hyperpermeabil-
Conicting studies suggest that macrolides may or may
not increase chemotaxis,
cytokine release or phagocytosis
of immune cells.
Similarly, macrolides either do not affect
or reduce phagocytosis
and the respiratory burst.
Finally, there are multiple conicting reports on the effect of
macrolides on immune cell proliferation and survival.
We could not identify studies on the effects of macrolides on
mitochondria in immune cells and only a few studies on mito-
chondria from other tissues. Erythromycin inhibited protein syn-
thesis in mitochondria isolated from BHK-21 renal cells, but not
in intact mitochondria due to their inability to penetrate the mito-
chondrial membrane.
In models of cerebral and myocardial is-
chaemia, rapamycin was protective; the mechanism was
suggested to be via attenuation of mitochondrial dysfunction
through inducing autophagy via the PI3K pathway and activation
of mitochondrial K
Several studies report that
macrolides can increase complex I and III activity, O
tion and ATP synthesis.
The reported immunomodulatory effects of quinolones are more
consistent, particularly in hypersensitivity reactions
also on the gut microbiota.
Quinolones (at 5100 mg/L)
reduced pro-inammatory cytokine and chemokine release
(e.g. IL-1, IL-6, IL-8, TNF-α, IFN-γand GM-CSF),
by down-regulation of NF-κB, ERK and c-Jun-N-terminal kinase
Quinolones also increased IL-8 and TNF-α
and IL-2 production.
Most reports show that quinolones do not affect chemotaxis
or phagocytosis at therapeutic doses; however, at high concen-
trations they do inhibit both phagocytosis and the respiratory
Ciprooxacin may also increase phagocytosis and
intracellular killing of organisms.
Quinolones at concentrations of .50 mg/L can inhibit mam-
malian cell growth by blocking cell cycle progression.
increase in thymidine uptake has been attributed to increasing
IL-2 production.
In lymphocytes, proliferation was inhibited
by up-regulating Fas ligand, caspase-8 and -3 activity.
Downloaded from by guest on 22 December 2022
In vitro ooxacin (at 10 or 100 mg/L) did not induce apoptosis in
isolated lymphocytes.
Quinolones damage mitochondria by targeting mitochondrial
These inuence mitochondrial DNA (mtDNA)
topology and structural availability for DNA replication. TOP2B in-
duces mtDNA supercoiling which, on inhibition by quinolones, ac-
cumulates and prevents mtDNA replication.
induces mtDNA loss, decreases electron transport chain complex
I activity (as this is mtDNA encoded),
and decreases mito-
chondrial membrane potential.
This may be benecial in colo-
rectal and bladder cancer where quinolones have inhibited
mtDNA synthesis, reduced mitochondrial membrane potential,
up-regulated Bax expression and activity of caspase-3, -8 and
-9, resulting in apoptosis.
In breast cancer, quinolones re-
duced mitochondrial membrane potential and ATP production
by suppression of the PI3K/Akt/mTOR and mitogen-activated
protein kinase (MAPK)/ERK signalling pathways.
In lung can-
cer, quinolones disrupted activity of complexes I and III, reduced
ATP production and increased ROS production.
Prolonged use of oxazolidinones is associated with myelosup-
pression, metabolic acidosis with hyperlactataemia, and periph-
eral and ophthalmic neuropathies. Myelosuppression occurs due
to reduced maturation of myeloprogenitor cells, mediated by im-
paired mitochondrial protein synthesis, complex IV activity and
mitochondrial oxidative metabolism.
In addition to inhib-
ition of fatty acid synthesis,
these bioenergetic effects have
been implicated in oxazolidinone-induced lactic acidosis.
Linezolid inhibits mitochondrial translation by binding ribosomal
peptidyl transferases and interfering with the binding of
This process impairs the coordinated as-
sembly of the electron transport chain from mitochondrial- and
nuclear-encoded genes.
Multiple in vitro studies have shown that oxazolidinones re-
duce cytokine production (e.g. TNF-α, IL-6, IFN-γand IL-1ra)
and phagocytosis, but exert no effect on killing capacity.
Oxazolidinones also have no effect on chemotaxis, phagocytosis
or the respiratory burst.
There are limited studies of the effect of oxazolidinones on mi-
tochondrial functionality in muscle, liver and kidney.
One clinical study did show impaired mitochondrial complex IV in
PBMCs taken from patients on long-term linezolid therapy devel-
oping lactic acidosis and weakness.
Different classes of antibiotics exert varying immunomodulatory
and bioenergetic effects with more consistent ndings reported
for quinolones and macrolides. This variation may be partially ex-
plained by differences in study methodology, cell types studied
and underlying disease. Most studies to date have used in vitro
or animal models and clinical data are relatively scarce. In
many of these studies, supratherapeutic antibiotic concentra-
tions have been used so the relevance to clinically relevant dos-
ing regimens remains uncertain. Nonetheless, recommendations
to increase antibiotic dose and/or frequency in critically ill pa-
tients, e.g. for quinolones and piperacillin/tazobactam, allied
with an impaired ability to metabolize/excrete antibiotics due
to concurrent organ dysfunction, altered volumes of distribution
and protein binding, and the widening use of combination ther-
apies to cover potentially resistant organisms will enhance the
risk of potential toxicity.
No hard and fast recommendations can be made at present
but we hope this review reignites interest in this forgotten area.
Newer technologies should be utilized as many of the studies
are now rather dated, and studies should be ideally performed
on patient samples taken sequentially over the duration of a
course of treatment. Better recognition of any impact on immune
or bioenergetic functionality will also require concurrent thera-
peutic drug monitoring as wide variation in blood concentrations
is recognized in critically ill patients who largely receive xed
doses of antibiotic.
Muska Miller thanks The London Clinic for their support.
This study was carried out as part of our routine work.
Transparency declarations
None to declare.
1Zheng D, Liwinski T, Elinav E. Interaction between microbiota and im-
munity in health and disease. Cell Res 2020; 30: 492506.
2Gao Y, Shang Q, Li W et al. Antibiotics for cancer treatment: a double-
edged sword. J Cancer 2020; 11: 513549.
3Nau R, Eiffert H. Modulation of release of proinammatory bacterial
compounds by antibacterials: potential impact on course of inamma-
tion and outcome in sepsis and meningitis. Clin Microbiol Rev 2002; 15:
4Peng Z-Y, Wang H-Z, Srisawat N et al. Bactericidal antibiotics temporar-
ily increase inammation and worsen acute kidney injury in experimental
sepsis. Crit Care Med 2012; 40: 53843.
5Singer M, Deutschman CS, Seymour CW et al. The Third International
Consensus Denitions for Sepsis and Septic Shock (Sepsis-3). JAMA
2016; 315: 80110.
6Brealey D, Brand M, Hargreaves I et al. Association between mitochon-
drial dysfunction and severity and outcome of septic shock. Lancet 2002;
360: 21923.
7Gray MW, Burger G, Lang BF. Mitochondrial evolution. Science 1999;
283: 147681.
8Preau S, Vodovar D, Jung B et al. Energetic dysfunction in sepsis: a nar-
rative review. Ann Intensive Care 2021; 11: 104.
9McBride MA, Owen AM, Stothers CL et al. The metabolic basis of im-
mune dysfunction following sepsis and trauma. Front Immunol 2020;
11: 1043.
10 Cheng S-C, Scicluna BP, Arts RJW et al. Broad defects in the energy
metabolism of leukocytes underlie immunoparalysis in sepsis. Nat
Immunol 2016; 17: 40613.
11 Japiassu AM, Santiago APSA, dAvila JC et al. Bioenergetic failure of
human peripheral blood monocytes in patients with septic shock is
Downloaded from by guest on 22 December 2022
mediated by reduced F1Fo adenosine-5-triphosphate synthase activity.
Crit Care Med 2011; 39: 105663.
12 Merz TM, Pereira AJ, Schurch R et al. Mitochondrial function of immune
cells in septic shock: a prospective observational cohort study. PLoS One
2017; 12: e0178946.
13 Belikova I, Lukaszewicz AC, Faivre V et al. Oxygen consumption of hu-
man peripheral blood mononuclear cells in severe human sepsis. Crit Care
Med 2007; 35: 27028.
14 Adrie C, Bachelet M, Vayssier-Taussat M et al. Mitochondrial mem-
brane potential and apoptosis of peripheral blood monocytes in severe
human sepsis. Am J Respir Crit Care Med 2001; 164: 38995.
15 Starkov AA. The role of mitochondria in reactive oxygen species me-
tabolism and signaling. Ann N Y Acad Sci 2008; 1147:3752.
16 Garrabou G, Moren C, Lopez S et al. The effects of sepsis on mitochon-
dria. J Infect Dis 2012; 205: 392400.
17 West AP, Shadel GS, Ghosh S. Mitochondria in innate immune re-
sponses. Nat Rev Immunol 2011; 11: 389402.
18 Venezio FR, Di Vincenzo CA. Effects of aminoglycoside antibiotics on
polymorphonuclear leukocyte function in vivo.Antimicrob Agents
Chemother 1985; 27: 7124.
19 Colombani T, Haudebourg T, Decossas M et al. Lipidic aminoglycoside
derivatives: a new class of immunomodulators inducing a potent innate
immune stimulation. Adv Sci 2019; 6: 1900288.
20 Grassi GG, Fietta A. Antibiotics and their interaction with the host de-
fense system in vivo.J Chemother 1991; 3Suppl 1: 1125.
21 Guchhait G, Altieri A, Gorityala B et al. Amphiphilic tobramycins with
immunomodulatory properties. Angew Chem Int Ed Engl 2015; 54:
22 Goodhart GL. Effect of aminoglycosides on the chemotactic response
of human polymorphonuclear leukocytes. Antimicrob Agents Chemother
1977; 12: 5402.
23 Khan AJ, Evans HE, Glass L et al. Abnormal neutrophil chemotaxis and
random migration induced by aminoglycoside antibiotics. J Lab Clin Med
1979; 93: 295300.
24 Dri P, Menegazzi R, Pirotta F et al. Effect of gentamicin and sisomicin
on the generation of superoxide by human monocytes. Chemioterapia
1984; 3: 15962.
25 Le Moli S, Seminara R, DAmelio R et al. In vitro and in vivo effect of si-
somicin and gentamycin on polymorphonuclear chemotaxis and phago-
cytosis. Int J Immunopharmacol 1983; 5:4954.
26 Gressier B, Brunet C, Dine T et al. In vitro activity of aminoglycosides on
the respiratory burst response in human polymorphonuclear neutrophils.
Methods Find Exp Clin Pharmacol 1998; 20: 81924.
27 Sacha PT, Zaremba ML, Jakoniuk P. The inuence of antibiotics on
phagocytic and bacteriocidal activity of rabbit peritoneal macrophages
stimulated by ltrates of cultured T-lymphocytes. Med Dosw Mikrobiol
1999; 51: 399412.
28 Mingeot-Leclercq MP, Tulkens PM. Aminoglycosides: nephrotoxicity.
Antimicrob Agents Chemother 1999; 43: 100312.
29 Henley CM 3rd, Schacht J. Pharmacokinetics of aminoglycoside anti-
biotics in blood, inner-ear uids and tissues and their relationship to oto-
toxicity. Audiology 1988; 27: 13746.
30 Hong S, Harris KA, Fanning KD et al. Evidence that antibiotics bind to
human mitochondrial ribosomal RNA has implications for aminoglyco-
side toxicity. J Biol Chem 2015; 290: 1927386.
31 Morris JC, Ping-Sheng L, Zhai HX et al. Phosphatidylinositol phospho-
lipase C is activated allosterically by the aminoglycoside G418. J Bio
Chem 1996; 271: 1546877.
32 Esterberg R, Linbo T, Pickett SB et al. Mitochondrial calcium uptake un-
derlies ROS generation during aminoglycoside-induced hair cell death.
J Clin Invest 2016; 126: 355666.
33 Ward DT, Maldonado-Perez D, Hollins L et al. Aminoglycosides induce
acute cell signaling and chronic cell death in renal cells that express the
calcium-sensing receptor. J Am Soc Nephrol 2005; 16: 123644.
34 Weinberg JM, Harding PG, Humes HD. Mechanisms of
gentamicin-induced dysfunction of renal cortical mitochondria. II.
Effects on mitochondrial monovalent cation transport. Arch Biochem
Biophys 1980; 205: 2329.
35 Weinberg JM, Simmons F Jr, Humes HD. Alterations of mitochondrial
respiration induced by aminoglycoside antibiotics. Res Commun Chem
Pathol Pharm 1980; 27: 52131.
36 Simmons CF Jr, Bogusky RT, Humes HD. Inhibitory effec ts of gentami-
cin on renal mitochondrial oxidative phosphorylation. J Pharm and Exp
Ther 1980; 214: 70915.
37 OReilly M, Young L, Kirkwood NK et al. Gentamicin affects the bioener-
getics of isolated mitochondria and collapses the mitochondrial mem-
brane potential in cochlear sensory hair cells. Front Cell Neuroscience
2019; 13: 416.
38 Yang CL, Du XH, Han YX. Renal cortical mitochondria are the source of
oxygen free radicals enhanced by gentamicin. Ren Fail 1995; 17:216.
39 Denamur S, Boland L, Beyaert M et al. Subcellular mechanisms in-
volved in apoptosis induced by aminoglycoside antibiotics: insights on
p53, proteasome and endoplasmic reticulum. Toxicol Appl Pharm 2016;
40 Morales AI, Detaille D, Prieto M et al. Metformin prevents experimental
gentamicin-induced nephropathy by a mitochondria-dependent path-
way. Kidney Int 2010; 77: 8619.
41 Desa DE, Nichols MG, Smith HJ. Aminoglycosides rapidly inhibit NAD(P)
H metabolism increasing reactive oxygen species and cochlear cell de-
mise. J Biomed Opt 2018; 24:114.
42 Servais H, Van Der Smissen P, Thirion G et al. Gentamicin-induced
apoptosis in LLC-PK1 cells: involvement of lysosomes and mitochondria.
Toxicol Appl Pharmacol 2005; 206: 32133.
43 Kalghatgi S, Spina CS, Costello JC et al. Bactericidal antibiotics induce
mitochondrial dysfunction and oxidative damage in mammalian cells. Sci
Transl Med 2013; 5: 192ra85.
44 Priuska EM, Schacht J. Mechanism and prevention of aminoglycoside
ototoxicity: outer hair cells as targets and tools. Ear Nose Throat J 1997;
76: 16471.
45 Ueda N, Guidet B, Shah SV. Gentamicin-induced mobilization of iron
from renal cortical mitochondria. Am J Physiol 1993; 265: F4359.
46 Lima CM, Schroeder JT, Galvao CES et al. Functional changes of den-
dritic cells in hypersensivity reactions to amoxicillin. Braz J Med Biol Res
2010; 43: 9648.
47 Abuaf N, Rostane H, Rajoely B et al. Comparison of two basophil acti-
vation markers CD63 and CD203c in the diagnosis of amoxicillin allergy.
Clin Exp Allerg 2008; 38: 9218.
48 Rodriguez-Pena R, Lopez S, Mayorga C et al. Potential involvement of
dendritic cells in delayed-type hypersensitivity reactions to β-lactams.
J Allergy Clin Immunol 2006; 118: 94956.
49 Smith DM, Kazi A, Smith L et al. A novel β-lactam antibiotic activates
tumor cell apoptotic program by inducing DNA damage. Mol Pharm 2002;
61: 134858.
50 Chen D, Falsetti SC, Frezza M et al. Anti-tumor activity of N-thiolated
β-lactam antibiotics. Cancer Lett 2008; 268:639.
51 Kenny MT, Balistreri FJ, Torney HL. β-Lactam antibiotic modulation of
murine neutrophil cytokinesis. Immunopharmacol Immunotoxicol 1992;
14: 797811.
Downloaded from by guest on 22 December 2022
52 Lotz S, Starke A, Ziemann C et al. β-Lactam antibiotic-induced release
of lipoteichoic acid from Staphylococcus aureus leads to activation of neu-
trophil granulocytes. Ann Clin Microbiol Antimicrob 2006; 5: 15.
53 Stuertz K, Schmidt H, Eiffert H et al. Differential release of lipoteichoic
and teichoic acids from Streptococcus pneumoniae as a result of exposure
to β-lactam antibiotics, rifamycins, trovaoxacin, and quinupristin-
dalfopristin. Antimicrob Agents Chemother 1998; 42: 27781.
54 Lotz S, Aga E, Wilde I et al. Highly puried lipoteichoic acid activates
neutrophil granulocytes and delays their spontaneous apoptosis via
CD14 and TLR2. J Leukocyte Biol 2004; 75: 46777.
55 Dofferhoff AS, Nijland JH, de Vries-Hospers HG et al. Effects of differ-
ent types and combinations of antimicrobial agents on endotoxin release
from Gram-negative bacteria: an in vitro and in vivo study. Scan J infect Dis
1991; 23: 74554.
56 Matsuda T, Saito H, Fukatsu K et al. Differences in neutrophil death
among β-lactam antibiotics after in vitro killing of bacteria. Shock 2002;
57 Neftel KA, Hauser SP, Muller MR. Inhibition of granulopoiesis in vivo
and in vitro by β-lactam antibiotics. J Infect Dis 1985; 152:908.
58 Neftel KA, Müller MR, Widmer U et al. β-Lactam antibiotics inhibit hu-
man in vitro granulopoiesis and proliferation of some other cell types. Cell
Biol Toxicol 1986; 2: 51321.
59 Sugita K, Nishimura T. Effect of antimicrobial agents on chemotaxis of
polymorphonuclear leukocytes. J Chemother 1995; 7: 11825.
60 Belsheim JA, Gnarpe GH. Antibiotics and granulocytes. Direct and in-
direct effects on granulocyte chemotaxis. Acta Pathol Microbiol Scand C
1981; 89: 21721.
61 Matera G, Berlinghieri MC, Foci A. Meropenem: effects on human
leukocyte functions and interleukin release. Int J Antimicrobial Agents
1995; 5: 12933.
62 Fietta A, Sacchi F, Bersani C et al. Effect of β-lactam antibiotics on mi-
gration and bactericidal activity of human phagocytes. J Antimicrob
Chemother 1983; 23: 9301.
63 Burgaleta C, Moreno T. Effect of β-lactams and aminoglycosides on
human polymorphonuclear leucocytes. J Antimicrob Chemother 1987;
20: 52935.
64 Labro MT, Babin-Chevaye C, Hakim J. Effects of cefotaxime and cefo-
dizime on human granulocyte functions in vitro.J Antimicrob Chemother
1986; 18: 2337.
65 Fietta A, Merlini C, Grassi GG. In vitro activity of two new oral cephalos-
porins, cexime and cefdinir on human peripheral mononuclear and poly-
morphonuclear leukocyte functions. Chemother 1994; 40: 31723.
66 Grassi GG, Fietta A, Sacchi F et al. Inuence of ceftriaxone on natural
defence systems. Am J Med 1984; 77:3741.
67 Miyata T, Shinohara M. Effect of antibiotics on rat leukocyte function.
J Osaka Dent Univ 1998; 32:915.
68 Rodriguez AB, Barriga C, De la Fuente M. In vitro effect of cefoxitin on
phagocytic function and antibody-dependent cellular cytotoxicity in hu-
man neutrophils. Comp Immunol Microb Infect Dis 1993; 16:3750.
69 Rodriguez AB, Barriga C, de la Fuente M. Stimulation of phagocytic
processes and antibody-dependent cellular cytotoxicity of human neu-
trophils by cefmetazole. Microbiol Immunol 1991; 35: 54556.
70 Morán FJ, Puente LF, Pérez-Giraldo C et al. Effects of cefpirome in com-
parison with cefuroxime against human polymorphonuclear leucocytes
in vitro.J Antimicrob Chemother 1994; 33:5762.
71 Rodriguez AB, Barriga C, De la Fuente M. Mechanisms of action in-
volved in the chemoattractant activity of three β-lactamic antibiotics
upon human neutrophils. Biochem Pharmacol 1991; 41: 9316.
72 Nunez RM, Rodriguez AB, Barriga C et al. In vitro and in vivo effects of
imipenem on phagocytic activity of murine peritoneal macrophages.
APMIS 1989; 97: 87986.
73 Pulverer G. Effects of cefodizime and cefotaxime on cellular and hu-
moral immune response. Infection 1992; 20: S414.
74 Periti P. Immunopharmacology of oral betalactams. J Chemother
1998; 10:916.
75 Scheffer J, Knoller J, Cullmann W et al. Effect of cefaclor, cefetamet
and Ro40-6890 on inammatory responses of human granulocytes.
J Antimicrob Chemother 1992; 30:5766.
76 Pasqui AL, Di Renzo M, Bruni F et al. Imipenem and immune response:
in vitro and in vivo studies. Drugs Exp Clin Res 1995; 21:1722.
77 Bode C, Diedrich B, Muenster S et al. Antibiotics regulate the immune
response in both presence and absence of lipopolysaccharide through
modulation of toll-like receptors, cytokine production and phagocytosis
in vitro.Int Immunopharmacol 2014; 18:2734.
78 Bacino C, Prezant TR, Bu X et al. Susceptibility mutations in the mito-
chondrial small ribosomal RNA gene in aminoglycoside induced deafness.
Pharmacogenetics 1995; 5: 16572.
79 Behra-Miellet J, Darchy A, Gressier B et al. Evaluation of the in vitro ac-
tivity of two betalactams on the oxidative metabolism of polymorpho-
nuclear neutrophils. Pathol Biol 2007; 55: 3907.
80 Sato K, Sato N, Shimizu H et al. Faropenem enhances superoxide an-
ion production by human neutrophils in vitro.J Antimicrob Chemother
1999; 44: 33741.
81 Carreer R, Deby-Dupont G, Deby C et al. Oxidant-scavenging activities
of β-lactam agents. Eur J Clin Microb Infect Dis 1998; 17: 436.
82 Stevens DL, Bryant AE, Hackett SP. Antibiotic effects on bacterial via-
bility, toxin production, and host response. Clin Infect Dis 1995; 20:
83 Reato G, Cufni AM, Tullio V et al. Co-amoxiclav affects cytokine pro-
duction by human polymorphonuclear cells. J Antimicrob Chemother
1999; 43: 7158.
84 Mattsson E, Van Dijk H, Verhoef J et al. Supernatants from
Staphylococcus epidermidis grown in the presence of different antibiotics
induce differential release of tumor necrosis factor alpha from human
monocytes. Infect Immun 1996; 64: 43515.
85 Brooks BM, Hart CA, Coleman JW. Differential effects of β-lactams on
human IFN-gamma activity. J Antimicrob Chemother 2005; 56: 11225.
86 Ziegeler S, Raddatz A, Hoff G et al. Antibiotics modulate the stimu-
lated cytokine response to endotoxin in a human ex-vivo,in vitro model.
Acta Anaesthesiologica Scand 2006; 50: 110310.
87 Brooks BM, Flanagan BF, Thomas AL et al. Penicillin conjugates to
interferon-gamma and reduces its activity: a novel drug-cytokine inter-
action. Biochem Biophys Res Commun 2001; 288: 117581.
88 Brooks BM, Thomas AL, Coleman JW. Benzylpenicillin differentially
conjugates to IFN-gamma, TNF-alpha, IL-1β, IL-4 and IL-13 but selective-
ly reduces IFN-gamma activity. Clin Exp Immunol 2003; 131: 26874.
89 Banck G, Forsgren A. Antibiotics and suppression of lymphocyte func-
tion in vitro.Antimicrob Agents Chemother 1979; 16: 55460.
90 Manzella JP, Clark JK. Effects of moxalactam and cefuroxime on
mitogen-stimulated human mononuclear leukocytes. Antimicrob
Agents Chemother 1983; 23: 3603.
91 Guo Y, Yang X, Qi Y et al. Long-term use of ceftriaxone sodium induced
changes in gut microbiota and immune system. Sci Rep 2017; 7: 43035.
92 Tune BM, Fravert D. Cephalosporin nephrotoxicity. Transport, cytotox-
icity and mitochondrial toxicity of cephaloglycin. JPET 1980; 215: 18690.
93 Tune BM. Mechanisms of nephrotoxicity of β-lactam antibiotics.
Contrib Nephrol 1990; 83: 2027.
Downloaded from by guest on 22 December 2022
94 Tune BM, Hsu CY. Effects of nephrotoxic β-lactam antibiotics on the
mitochondrial metabolism of monocarboxylic substrates. J Pharmacol
Exp Ther 1995; 274: 1949.
95 Pochini L, Galluccio M, Scumaci D et al. Interaction of β-lactam anti-
biotics with the mitochondrial carnitine/acylcarnitine transporter. Chem
Biol Interact 2008; 173: 18794.
96 Oyebode OT, Adebiyi OR, Olorunsogo OO. Toxicity of some broad-
spectrum antibacterials in normal rat liver: the role of mitochondrial
membrane permeability transition pore. Toxicol Mech Methods 2019;
29: 12837.
97 Jiang S, Li T, Zhou X et al. Antibiotic drug piperacillin induces neuron
cell death through mitochondrial dysfunction and oxidative damage.
Can J Physio Pharm 2018; 96: 5628.
98 Levine D. Vancomycin: a history. Clin Infect Dis 2006; 42:S512.
99 Toyoguchi T, Ebihara M, Ojima F et al. Histamine release induced by
antimicrobial agents and effects of antimicrobial agents on
vancomycin-induced histamine release from rat peritoneal mast cells.
J Pharm Pharmacol 2000; 52: 32731.
100 Hsiao S-H, Chang C-M, Tsai J-C et al. Glycopeptide-induced neutro-
penia: cross-reactivity between vancomycin and teicoplanin. Ann
Pharmacother 2007; 41: 8914.
101 Hsiao S-H, Chou C-H, Lin W-L et al. High risk of cross-reactivity be-
tween vancomycin and sequential teicoplanin therapy. J Clin Pharm
Ther 2012; 37: 296300.
102 Polk RE. Anaphylactoid reactions to glycopeptide antibiotics.
J Antimicrob Chemother 1991; 27:1729.
103 Davenport A. Allergic cross-reactivity to teicoplanin and vancomy-
cin. Nephron 1993; 63: 482.
104 Lewis BB, Bufe CG, Carter RA et al. Loss of microbiota-mediated col-
onization resistance to Clostridium difcile infection with oral vancomycin
compared with metronidazole. J Infect Dis 2015; 212: 165665.
105 van Opstal E, Kolling GL, Moore JH et al. Vancomycin treatment al-
ters humoral immunity and intestinal microbiota in an aged mouse mod-
el of Clostridium difcile infection. J Infect Dis 2016; 214: 1309.
106 Lankelma JM, Cranendonk DR, Belzer C et al. Antibiotic-induced gut
microbiota disruption during human endotoxemia: a randomised con-
trolled study. Gut 2017; 66: 162330.
107 Cheng RY, Li M, Li SS et al. Vancomycin and ceftriaxone can damage
intestinal microbiota and affect the development of the intestinal tract
and immune system to different degrees in neonatal mice. Pathog Dis
2017; 75.
108 Brandl K, Plitas G, Mihu CN et al. Vancomycin-resistant enterococci
exploit antibiotic-induced innate immune decits. Nature 2008; 455:
109 Salguero E, Plaza D, Marino A et al. Characterising vancomycins im-
munotoxic prole using Swiss and CFW mice as an experimental model.
Biomed Pharmacother 2009; 63: 43641.
110 Carlone NA, Cufni AM, Ferrero M et al. Cellular uptake, and intracel-
lular bactericidal activity of teicoplanin in human macrophages.
J Antimicrob Chemother 1989; 23: 84959.
111 Fietta A, Bersani C, De Rose V et al. The effect of teicoplanin on leuko-
cytic activity and intraleukocytic micro-organisms. J Hosp Infect 1986; 7:
112 Pedrera MI, Barriga C, Rodriguez AB. Intracellular activity of both
teicoplanin and vancomycin against Staphylococcus aureus in human
neutrophils. Microb Infect Dis 1995; 18: 1238.
113 Bode C, Muenster S, Diedrich B et al. Linezolid, vancomycin and dap-
tomycin modulate cytokine production, toll-like receptors and phagocyt-
osis in a human in vitro model of sepsis. J Antibiot 2015; 68: 48590.
114 Capodicasa E, Scaringi L, Rosati E et al. In-vitro effects of teicoplanin,
teicoplanin derivative MDL 62211 and vancomycin on human polymor-
phonuclear cell function. J Antimicrob Chemother 1991; 27: 61926.
115 Moran FJ, Puente LF, Perez-Giraldo C et al. Activity of vancomycin and
teicoplanin against human polymorphonuclear leucocytes: a compara-
tive study. Antimicrob Chemother 1991; 28: 4158.
116 Taw k AF. Effects of vancomycin, teicoplanin, daptomycin and cou-
mermycin on normal immune capabilities. J Chemother 1991; 3: 22631.
117 Barriga C, Pedrera I, Rodriguez AB. Comparative study of the effect of
teicoplanin and vancomycin upon the phagocytic process of peritoneal
macrophages. Rev Esp Fisiol 1996; 52: 21522.
118 Siedlar M, Szczepanik A, Wieckiewicz J et al. Vancomycin down-
regulates lipopolysaccharide-induced tumour necrosis factor alpha
(TNFα) production and TNFα-mRNA accumulation in human blood mono-
cytes. Immunopharmacol 1997; 35: 26571.
119 Foca A, Matera G, Berlinghieri MC. Inhibition of endotoxin-induced in-
terleukin 8 release by teicoplanin in human whole blood. Eur J Clin
Microbiol Infect Dis 1993; 12: 9404.
120 Bosmann HB, Winston RA. Antibiotics and macromolecular synth-
esis in microsomes and mitochondria. Antibiotics acting in the same
manner in mitochondria and microsomes. Chem Biol Interact 1972; 4:
121 Arimura Y, Yano T, Hirano M et al. Mitochondrial superoxide produc-
tion contributes to vancomycin-induced renal tubular cell apoptosis. Free
Rad Biol Med 2012; 52: 186573.
122 Sakamoto Y, Yano T, Hanada Y et al. Vancomycin induces reactive
oxygen species-dependent apoptosis via mitochondrial cardiolipin perox-
idation in renal tubular epithelial cells. Eur J Pharmacol 2017; 800:4856.
123 Qu S, Dai C, Guo H et al. Rutin attenuates vancomycin-induced renal
tubular cell apoptosis via suppression of apoptosis, mitochondrial dys-
function, and oxidative stress. Phytother Res 2019; 33: 205663.
124 King DW, Smith MA. Proliferative responses observed following van-
comycin treatment in renal proximal tubule epithelial cells. Toxicol In Vitro
2004; 18: 797803.
125 Zuckerman JM, Qamar F, Bono BR. Review of macrolides (azithromy-
cin, clarithromycin), ketolids (telithromycin) and glycylcyclines (tigecyc-
line). Med Clin North Am 2011; 95: 76191.
126 Alvarez-Elcoro S, Enzler MJ. The macrolides: erythromycin, clarithro-
mycin and azithromycin. Mayo Clin Proc 1999; 74: 61334.
127 Oda H, Kadota J, Kohno S et al. Leukotriene B4 in bronchoalveolar la-
vage uid of patients with diffuse panbronchiolitis. Chest 1995; 108:
128 Park S-J, Lee Y-C, Rhee Y-K et al. The effect of long-term treatment
with erythromycin on Th1 and Th2 cytokines in diffuse panbronchiolitis.
Biochem Biophys Res Commun 2004; 324: 1147.
129 Kadota J, Sakito O, Kohno S et al. A mechanism of erythromycin
treatment in patients with diffuse panbronchiolitis. Am Rev Resp Dis
1993; 147: 1539.
130 Sakito O, Kadota J, Kohno S et al. Interleukin 1β, TNF-alpha, and in-
terleukin 8 in bronchoalveolar lavage uid of patients with diffuse pan-
bronchiolitis: a potential mechanism of macrolide therapy. Respiration
1996; 63:428.
131 Suzuki H, Shimomura A, Ikeda K et al. Effects of long-term low-dose
macrolide administration on neutrophil recruitment and IL-8 in the nasal
discharge of chronic sinusitis patients. Tohoku J Exp Med 1997; 182:
132 Cervin A, Wallwork B, Mackay-Sim A et al. Effects of long-term cla-
rithromycin treatment on lavage-uid markers of inammation in chron-
ic rhinosinusitis. Clin Physiol Funct Imaging 2009; 29: 13642.
Downloaded from by guest on 22 December 2022
133 Wallwork B, Coman W, Mackay-Sim A et al. A double-blind, rando-
mized, placebo-controlled trial of macrolide in the treatment of chronic
rhinosinusitis. Laryngoscope 2006; 116: 18993.
134 Yamada T, Fujieda S, Mori S et al. Macrolide treatment decreased the
size of nasal polyps and IL-8 levels in nasal lavage. Am J Rhinol 2000; 14:
135 Kohyama TH, Takizawa S, Kawasaki N et al. Fourteen-member
macrolides inhibit interleukin-8 release by human eosinophils from atopic
donors. Antimicrob Agents Chemother 1999; 43: 90711.
136 Piacentini GL, Peroni DG, Bodini A et al. Azithromycin reduces bron-
chial hyperresponsiveness and neutrophilic airway inammation in asth-
matic children: a preliminary report. Allerg Asthma Proc 2007; 28: 1948.
137 Fonseca-Aten M, Okada PJ, Bowlware KL et al. Effect of clarithromy-
cin on cytokines and chemokines in children with an acute exacerbation
of recurrent wheezing: a double-blind, randomized, placebo-controlled
trial. Ann Allerg Asthma Immunol 2006; 97: 45763.
138 Amayasu H, Yoshida S, Ebana S et al. Clarithromycin suppresses
bronchial hyperresponsiveness associated with eosinophilic inamma-
tion in patients with asthma. Ann Allerg Asthma Immunol 2000; 84:
139 Kraft M, Cassell GH, Pak J et al. Mycoplasma pneumoniae and
Chlamydia pneumoniae in asthma: effect of clarithromycin. Chest 2002;
121: 17828.
140 Simpson JL, Powell H, Boyle MJ et al. Clarithromycin targets neutro-
philic airway inammation in refractory asthma. Am J Respir Crit Care Med
2008; 177: 14855.
141 Shoji T, Yoshida S, Sakamoto H et al. Anti-inammatory effect of rox-
ithromycin in patients with aspirin-intolerant asthma. Clin Exp Allergy
1999; 29: 9506.
142 Kamoi H, Kurihara N, Fujiwara H et al. The macrolide antibacterial
roxithromycin reduces bronchial hyperresponsiveness and superoxide
anion production by polymorphonuclear leukocytes in patients with asth-
ma. J Asthma 1995; 32: 1917.
143 Parnham MJ, Culic O, Erakovic V et al. Modulation of neutrophil and
inammation markers in chronic obstruct ive pulmonary disease by short-
term azithromycin treatment. Eur J Pharmacol 2005; 517: 13243.
144 Pukhalsky AL, Shmarina GV, Kapranov NI et al. Anti-inammatory
and immunomodulating effects of clarithromycin in patients with cystic
brosis lung disease. Mediators Inamm 2004; 13: 1117.
145 Schultz MJ, Speelman P, Zaat S et al. Erythromycin inhibits TNF-alpha
and interleukin 6 production induced by heat-killed Streptococcus pneu-
moniae in whole blood. Antimicrob Agents Chemother 1998; 42: 16059.
146 Ianaro A, Ialenti A, MafaPet al. Anti-inammatory activity of
macrolide antibiotics. J Pharmacol Exp Ther 2000; 292: 15663.
147 Ohshima A, Tokura Y, Wakita H et al. Roxithromycin down-
modulates antigen-presenting and interleukin-1 β-producing abilities of
murine Langerhans cells. J Dermatol Sci 1998; 17: 21422.
148 Kikuchi T, Hagiwara K, Honda Y et al. Clarithromycin suppresses
lipopolysaccharide-induced interleukin-8 production by human mono-
cytes through AP-1 and NF-κB transcription factors. J Antimicrob
Chemother 2002; 49: 74555.
149 Yasutomi M, Ohshima Y, Omata N et al. Erythromycin differentially
inhibits lipopolysaccharide- or poly(I:C)-induced but not
peptidoglycan-induced activation of human monocyte-derived dendritic
cells. J Immunol 2005; 175: 806976.
150 Takahashi E, Indalao IL, Sawabuchi T et al. Clarithromycin sup-
presses induction of monocyte chemoattractant protein-1 and matrix
metalloproteinase-9 and improves pathological changes in the lungs
and heart of mice infected with inuenza A virus. Comp Immunol
Microbiol Infect Dis 2018; 56:613.
151 Banerjee D, Honeybourne D, Khair OA. The effect of oral clarithromy-
cin on bronchial airway inammation in moderate-to-severe stable
COPD: a randomized controlled trial. Treat Respir Med 2004; 3:5965.
152 Cameron EJ, Chaudhuri R, Mair F et al. Randomised controlled trial of
azithromycin in smokers with asthma. Eur Respir J 2013; 42: 14125.
153 Iino Y, Sasaki Y, Kojima C et al. Effect of macrolides on the expression
of HLA-DR and costimulatory molecules on antigen-presenting cells in
nasal polyps. Ann Otol Rhinol Laryngol 2001; 110: 45763.
154 Karrow NA, McCay JA, Brown RD et al. Evaluation of the immunomo-
dulatory effects of the macrolide antibiotic, clarithromycin, in female
B6C3F1 mice: a 28-day oral gavage study. Drug Chem Toxicol 2001; 24:
155 Konno S, Adachi M, Asano K et al. Inuences of roxithromycin on
cell-mediated immune responses. Life Sci 1992; 51: l10712.
156 Anderson R. Erythromycin and roxithromycin potentiate human
neutrophil locomotion in vitro by inhibition of leuko-attractant activated
superoxide generation and autooxidation. J Infect Dis 1989; 5: 96672.
157 Yamaryo T, Oishi K, Yoshimine H et al. Fourteen-member macrolides
promote the phosphatidylserine receptor-dependent phagocytosis of
apoptotic neutrophils by alveolar macrophages. Antimicrob Agents
Chemother 2003; 47:4853.
158 Hodge S, Hodge G, Brozyna S et al. Azithromycin increases phagocyt-
osis of apoptotic bronchial epithelial cells by alveolar macrophages. Eur
Respir J 2006; 28: 48695.
159 Herrera-Insúa I, Jacques-Palaz K, Murray BE et al. The effect of anti-
biotic exposure on adherence to neutrophils of Enterococcus faecium re-
sistant to phagocytosis. J Antimicrob Chemother 1997; 39 Suppl A:
160 Noma T, Hayashi M, Yoshizawa I et al. A comparative investigation of
the restorative effects of roxithromycin on neutrophil activities. Int J
Immunopharmacol 1998; 20: 61524.
161 Scaglione F, Ferrara F, Dugnani S et al. Immunostimulation by cla-
rithromycin in healthy volunteers and chronic bronchitis patients.
J Chemother 1993; 5: 22832.
162 Wenisch C, Parschalk B, Zedtwitz-Liebenstein K et al. Effect of single
oral dose of azithromycin, clarithromycin, and roxithromycin on poly-
morphonuclear leukocyte function assessed ex vivo by ow cytometry.
Antimicrob Agents Chemother 1996; 40: 203942.
163 Ortega E, Escobar MA, Gaforio JJ et al. Modication of phagocytosis
and cytokine production in peritoneal and splenic murine cells by eryth-
romycin A, azithromycin and josamycin. J Antimicrob Chemother 2004;
53: 36770.
164 Braga PC, Maci S, Dal Sasso M et al. Effects of rokitamycin on phago-
cytosis and release of oxidant radicals of human polymorphonuclear leu-
kocytes. Chemother 1997; 43: 1907.
165 Mitsuyama T, Tanaka T, Hidaka K et al. Inhibition by erythromycin of
superoxide anion production by human polymorphonuclear leukocytes
through the action of cyclic AMP-dependent protein kinase. Respiration
1995; 62: 26973.
166 Cui CH, Honda K, Saito N et al. Effect of roxithromycin on eotaxin-
primed reactive oxygen species from eosinophils. Int Arch Allerg
Immunol 2001; 125:3841.
167 Eswarappa SM, Basu N, Joy O et al. Folimycin (concanamycin A) in-
hibits LPS-induced nitric oxide production and reduces surface localiza-
tion of TLR4 in murine macrophages. Innate Immunity 2008; 14: 1324.
168 Mizunoe S, Kadota JI, Tokimatsu I et al. Clarithromycin and azithro-
mycin induce apoptosis of activated lymphocytes via down-regulation of
Bcl-xL. Int Immunopharmacol 2004; 4: 12017.
169 Ishimatsu Y, Kadota JI, Iwashita T et al. Macrolide antibiotics induce
apoptosis of human peripheral lymphocytes in vitro.Int J Antimicrob
Agents 2004; 24: 24753.
Downloaded from by guest on 22 December 2022
170 Jun Y-T, Kim H-J, Song M-J et al. In vitro effects of ciprooxacin and
roxithromycin on apoptosis of Jurkat T lymphocytes. Antimicrob Agents
Chemother 2003; 47: 11614.
171 Ratzinger F, Haslacher H, Poeppl W et al. Azithromycin suppresses
CD4(+) T-cell activation by direct modulation of mTOR activity. Sci Rep
2014; 4: 7438.
172 Aoshiba K, Nagai A, Konno K. Erythromycin shortens neutrophil sur-
vival by accelerating apoptosis. Antimicrob Agents Chemother 1995; 39:
173 Koch CC, Esteban DJ, Chin AC et al. Apoptosis, oxidative metabolism
and interleukin-8 production in human neutrophils exposed to azithro-
mycin: effects of Streptococcus pneumoniae.J Antimicrob Chemother
2000; 46:1926.
174 de Vries H, Arendzen AJ, Kroon AM. The interference ofthe macrolide
antibiotics with mitochondrial protein synthesis. Biochim Biophys Acta
1973; 331: 26475.
175 Yang S-S, Liu Y-B, Yu J-B et al. Rapamycin protects heart from ische-
mia/reperfusion injury independent of autophagy by activating PI3
kinase-Akt pathway and mitochondria KATP channel. Pharmazie 2010;
65: 7605.
176 Goormaghtigh E, Pollakis G, Ruysschaert JM. Mitochondrial mem-
brane modication by adriamycin-mediated electron transport.
Biochemical Pharm 1983; 32: 88993.
177 Bravo-Sagua R, Lopez-Crisosto C, Parra V et al. mTORC1 inhibitor ra-
pamycin and ER stressor tunicamycin induce differential patterns of
ER-mitochondria coupling. Sci Rep 2016; 6: 36394.
178 Schmid DA, Campi P, Pichler WJ. Hypersensitivity reactions to quino-
lones. Curr Pharm Des 2006; 12: 331326.
179 Schmid DA, Depta JPH, Pichler WJ. T cell-mediated hypersensitivity
to quinolones: mechanisms and cross-reactivity. Clin Exp Allerg 2006;
180 Scherer K, Bircher AJ. Hypersensitivity reactions to uoroquinolones.
Curr Allerg Asthma Rep 2005; 5: 1521.
181 Strzępa A, Majewska-Szczepanik M, Kowalczyk P et al. Oral treat-
ment with enrooxacin early in life promotes Th2-mediated immune re-
sponse in mice. Pharmacol Rep 2016; 68:4450.
182 Juanola O, Gómez-Hurtado I, Zapater P et al. Selective intestinal de-
contamination with noroxacin enhances a regulatory T cell-mediated
inammatory control mechanism in cirrhosis. Liver Int 2016; 36:
183 Bailly S, Fay M, Roche Y et al. Effects of quinolones on TNF production
by human monocytes. Int J Immunopharmacol 1990; 12:316.
184 Ogino H, Fujii M, Ono M et al. In vivo and in vitro effects of uoroqui-
nolones on lipopolysaccharide-induced pro-inammatory cytokine pro-
duction. J Infect Chemother 2009; 15: 16873.
185 Riesbeck K, Forsgren A. Selective enhancement of synthesis of
interleukin-2 in lymphocytes in the presence of ciprooxacin. Eur J Clin
Microb Infect Dis 1990; 9: 40913.
186 Yoshimura T, Kurita C, Usami E et al. Immunomodulatory action of
levooxacin on cytokine production by human peripheral blood mono-
nuclear cells. Chemother 1996; 42: 45964.
187 Katsuno G, Takahashi HK, Iwagaki H et al. The effect of ciprooxacin
on CD14 and toll-like receptor-4 expression on human monocytes. Shock
2006; 25: 24753.
188 Mori S, Takahashi HK,Liu K et al. Ciprooxacin inhibits advanced gly-
cation end products-induced adhesion molecule expression on human
monocytes. Br J Pharmacol 2010; 161: 22940.
189 Vickers IE, Smikle MF. The immunomodulatory effect of antibiotics
on the secretion of tumour necrosis factor alpha by peripheral blood
mononuclear cells in response to Stenotrophomonas maltophilia stimula-
tion. West Indian Med J 2006; 55: 13841.
190 Yao M, Gao W, Tao H et al. The regulation effects of danooxacin on
pig immune stress induced by LPS. Res Vet Sci 2017; 110:6571.
191 Araujo FG, Slifer TL, Remington JS. Effect of moxioxacin on secre-
tion of cytokines by human monocytes stimulated with lipopolysacchar-
ide. Clin Microbiol Infect 2002; 8:2630.
192 Weiss T, Shalit I, Blau H et al. Anti-inammatory effects of moxi-
oxacin on activated human monocytic cells: inhibition of NF-κB and
mitogen-activated protein kinase activation and of synthesis of proin-
ammatory cytokines. Antimicrob Agents Chemother 2004; 48: 197482.
193 Choi J-H, Song M-J, Kim S-H et al. Effect of moxioxacin on produc-
tion of proinammatory cytokines from human peripheral blood mono-
nuclear cells. Antimicrob Agents Chemother 2003; 47: 37047.
194 Nakajima A, Sato H, Oda S et al. Fluoroquinolones and propionic acid
derivatives induce inammatory responses in vitro. Cell Biol Toxicol 2018;
195 Riesbeck K, Forsgren A. Increased IL-2 transcription in murine lym-
phocytes by ciprooxacin. Immunopharmacol 1994; 27: 15564.
196 Riesbeck K, Schatz H, Östraat O et al. Enhancement of the immuno-
suppressive effect of cyclosporin A by ciprooxacin in a rat cardiac trans-
plantation model. Transplant Int 1995; 8:96102.
197 Blau H, Klein K, Shalit I et al. Moxioxacin but not ciprooxacin or
azithromycin selectively inhibits IL-8, IL-6, ERK1/2, JNK, and NF-κB activa-
tion in a cystic brosis epithelial cell line. Am J Physiol Lung Cell Mol Phys
2007; 292: L34352.
198 Kwak S-H, Kang J-A, Kim M et al. Discovery and structure-activity re-
lationship studies of quinolinone derivatives as potent IL-2 suppressive
agents. Bioorg Med Chem 2016; 24: 535767.
199 Riesbeck K. Immunomodulating activity of quinolones: review.
J Chemother 2002; 14:312.
200 Mato R, Corrales I, Prieto J. Inuence of lomeoxacin on phagocyt-
osis and killing activity of macrophages and neutrophils. J Antimicrob
Chemother 1992; 30: 5589.
201 Forsgren A, Bergkvist PI. Effect of ciprooxacin on phagocytosis. Eur J
Clin Microbiol 1985; 4: 5758.
202 Gruger T, Morler C, Schnitzler N et al. Inuence of uoroquinolones
on phagocytosis and killing of Candida albicans by human polymorpho-
nuclear neutrophils. Med Mycol 2008; 46: 67584.
203 Nielsen SL, Obel N, Storgaard M et al. The effect of quinolones on the
intracellular killing of Staphylococcus aureus in neutrophil granulocytes.
J Antimicrob Chemother 1997; 39: 61722.
204 Lianou PE, Votta EG, Papavassiliou JT et al. In vivo potentiation of
polymorphonuclear leukocyte function by ciprooxacin. J Chemother
1993; 5: 2237.
205 Forsgren A, Schlossman SF, Tedder TF. 4-Quinolone drugs affect cell
cycle progression and function of human lymphocytes in vitro.Antimicrob
Agent Chemother 1987; 31: 76873.
206 Roche Y, Gougerot-Pocidalo MA, Fay M et al. Comparative effects of
quinolones on human mononuclear leucocyte functions. J Antimicrob
Chemother 1987; 19: 78190.
207 Riesbeck K, Forsgren A. Commentary on ciprooxacin-dependent
superinduction of IL-2 synthesis and thymidine uptake. Transplantation
1998; 65: 12823.
208 Chide OE, Orisakwe OE. Structural development, haematological im-
munological and pharmacological effects of quinolones. Recent Pat
Antiinfect Drug Discov 2007; 2: 15768.
209 Plekhova NG, Kondrashova NM, Somova LM et al. Effects of immuno-
modulators on functional activity of innate immunity cells infected with
Streptococcus pneumoniae.Bull Exp Biol Med 2015; 158: 4614.
Downloaded from by guest on 22 December 2022
210 Kadota J-I, Mizunoe S, Kishi K et al. Antibiotic-induced apoptosis in
human activated peripheral lymphocytes. Int J Antimicrob Agents 2005;
25: 21620.
211 Hangas A, Aasumets K, Kekalainen NJ et al. Ciprooxacin impairs
mitochondrial DNA replication initiation through inhibition of topoisomer-
ase 2. Nucleic Acids Res 2018; 46: 962536.
212 Lawrence JW, Claire DC, Weissig V et al. Delayed cytotoxicity and
cleavage of mitochondrial DNA in ciprooxacin-treated mammalian cells.
Mol Pharmacol 1996; 50: 117888.
213 Kaminski MM, Sauer SW, Klemke C-D et al. Mitochondrial reactive
oxygen species control T cell activation by regulating IL-2 and IL-4 ex-
pression: mechanism of ciprooxacin-mediated immunosuppression.
J Immunol 2010; 184: 482741.
214 Koziel R, Zablocki K, Duszynski J. Calcium signals are affected by ci-
prooxacin as a consequence of reduction of mitochondrial DNA content
in Jurkat cells. Antimicrob Agents Chemother 2006; 50: 166471.
215 Herold C, Ocker M, Ganslmayer M et al. Ciprooxacin induces apop-
tosis and inhibits proliferation of human colorectal carcinoma cells. Br J
Cancer 2002; 86: 4438.
216 Aranha O, Zhu L, Alhasan S et al. Role of mitochondria in ciprooxa-
cin induced apoptosis in bladder cancer cells. J Urol 2002; 167: 128894.
217 Yu M, Li R, Zhang J. Repositioning of antibiotic levooxacin as a mito-
chondrial biogenesis inhibitor to target breast cancer. Biochem Biophys
Res Comm 2016; 471: 63945.
218 Song M, Wu H, Wu S et al. Antibiotic drug levooxacin inhibits prolif-
eration and induces apoptosis of lung cancer cells through inducing mito-
chondrial dysfunction and oxidative damage. Biomed Pharmacother
2016; 84: 113743.
219 Leach KL, Swaney SM, Colca JR et al. The site of action of oxazolidi-
none antibiotics in living bacteria and in human mitochondria. Mol Cell
2007; 26: 393402.
220 Nagiec EE, Wu L, Swaney SM et al. Oxazolidinones inhibit cellular pro-
liferation via inhibition of mitochondrial protein synthesis. Antimicrob
Agents Chemother 2005; 49: 3896902.
221 McKee EE, Ferguson M, Bentley AT et al. Inhibition of mammalian
mitochondrial protein synthesis by oxazolidinones. Antimicrob Agents
Chemother 2006; 50: 20429.
222 De Vriese AS, Coster RV, Smet J et al. Linezolid-induced inhibition of
mitochondrial protein synthesis. Clin Infect Dis 2006; 42: 11117.
223 Ye X, Huang A, Wang X et al. Linezolid inhibited synthesis of ATP in
mitochondria: based on GC-MS metabolomics and HPLC method.
BioMed Res Int 2018; 2018: 3128270.
224 Santini A, Ronchi D, Garbellini M et al. Linezolid-induced lactic acid-
osis: the thin line between bacterial and mitochondrial ribosomes.
Expert Opin Drug Saf 2017; 16: 83343.
225 Garrabou G, Soriano À, Pinós T et al. Inuence of mitochondrial gen-
etics on the mitochondrial toxicity of linezolid in blood cells and skin nerve
bers. Antimicrob Agents Chemother 2017; 61: e00542-17.
226 Protti A, Ronchi D, Bassi G et al. Changes in whole-body oxygen con-
sumption and skeletal muscle mitochondria during linezolid-induced lac-
tic acidosis. Crit Care Med 2016; 44: e57982.
227 Priesnitz C, Becker T. Pathways to balance mitochondrial translation
and protein import. Genes Dev 2018; 32: 128596.
228 Garcia-Roca P, Mancilla-Ramirez J, Santos-Segura A et al. Linezolid
diminishes inammatory cytokine production from human peripheral
blood mononuclear cells. Arch Med Res 2006; 37:315.
229 Pichereau S, Moran JJM, Hayney MS et al. Concentration-dependent
effects of antimicrobials on Staphylococcus aureus toxin-mediated cyto-
kine production from peripheral blood mononuclear cells. J Antimicrob
Chemother 2012; 67: 1239.
230 Franks Z, Campbell RA, de Abreu AV et al. Methicillin-resistant
Staphylococcus aureus-induced thrombo-inammatory response is re-
duced with timely antibiotic administration. Thromb Haemost 2013;
109: 68495.
231 Yanagihara K, Kihara R, Araki N et al. Efcacy of linezolid against
Panton-Valentine leukocidin (PVL)-positive methicillin-resistant
Staphylococcus aureus (MRSA) in a mouse model of haematogenous pul-
monary infection. Int J Antimicrob Agents 2009; 34: 47781.
232 Luna CM, Bruno DA, Garcia-Morato J et al. Effect of linezolid com-
pared with glycopeptides in methicillin-resistant Staphylococcus aureus
severe pneumonia in piglets. Chest 2009; 135: 156471.
233 Breslow-Deckman JM, Mattingly CM, Birket SE et al. Linezolid de-
creases susceptibility to secondary bacterial pneumonia post-inuenza
infection in mice through its effects on IFN-gamma. J Immunol 2013;
191: 17929.
234 Jacqueline C, Broquet A, Roquilly A et al. Linezolid dampens
neutrophil-mediated inammation in methicillin-resistant
Staphylococcus aureus-induced pneumonia and protects the lung of as-
sociated damages. J Infect Dis 2014; 210: 81423.
235 Kaku N, Morinaga Y, Takeda K et al. Antimicrobial and immunomo-
dulatory effects of tedizolid against methicillin-resistant Staphylococcus
aureus in a murine model of hematogenous pulmonary infection. Int J
Med Microbiol 2016; 306: 4218.
236 Verma AK, Bauer C, Yajjala VK et al. Linezolid attenuates lethal lung
damage during post-inuenza methicillin-resistant Staphylococcus aur-
eus pneumonia. Infect Immun 2019; 87: e00538-19.
237 Grüger T, Schmidt T, Schnitzler N et al. Negative impact of linezolid
on human neutrophil functions in vitro.Chemother 2012; 58: 20611.
238 Naess A, Stenhaug Kilhus K, Nystad TW et al. Linezolid and human
polymorphonuclear leukocyte function. Chemother 2006; 52: 1224.
239 Ballesta S, Pascual A, García I et al. Effect of linezolid on the phago-
cytic functions of human polymorphonuclear leukocytes. Chemother
2003; 49: 1636.
240 Kushiya K, Nakagawa S, Taneike I et al. Inhibitory effect of antimicro-
bial agents and anisodamine on the staphylococcal superantigenic
toxin-induced overproduction of proinammatory cytokines by human
peripheral blood mononuclear cells. J Infect Chemother 2005; 11: 1925.
241 Del Pozo JL, Fernandez-Ros N, Saez E et al. Linezolid-induced lactic
acidosis in two liver transplant patients with the mitochondrial DNA
A2706G polymorphism. Antimicrob Agents Chemother 2014; 58: 42279.
242 Soriano A, Miró O, Mensa J. Mitochondrial toxicity associated with
linezolid. N Engl J Med 2005; 353: 23056.
243 Roberts JA, Paul SK, Akova M et al. DALI: dening antibiotic levels in
intensive care unit patients: are current β-lactam antibiotic doses suf-
cient for critically ill patients? Clin Infect Dis 2014; 58: 107283.
244 Lonsdale DO, Kipper K, Baker EH et al. β-Lactam antimicrobial phar-
macokinetics and target attainment in critically ill patients aged 1 day to
90 years: the ABDose study. J Antimicrob Chemother 2020; 75: 362534.
Downloaded from by guest on 22 December 2022
... The gut microbiota is a complex ecosystem composed of viruses, fungi, yeast, and bacteria, retaining a mutual balance within the host known as eubiosis [1][2][3][4][5][6]. Microbiota is dynamic and forms an ecological community in the human body that is shaped by genomic factors, diet, lifestyle, improved personal hygiene, and exposure to medication, as well as the mode of delivery at birth [7]. ...
... Antibiotics are known to disrupt the gut microbiota [16,17] and long-term use can lead to drug resistance via the disruption of the microbiota composition [18]. Recent research involving mouse models, human tissues, and patient samples across various cancer types has shown that antibiotics can reduce the effectiveness of chemotherapy and immunotherapy by metabolising or deactivating chemotherapeutic drugs, altering immune responses, or causing mucosal damage that may lead to sepsis [1][2][3][4][5][6][7]. Furthermore, a recent observational study of 291 cancer patients revealed that antibiotic exposure within the 2 weeks before or the 6 weeks after immunotherapy may increase the risk of all-cause mortality compared to patients who do not receive antibiotics [19]. ...
Full-text available
Background: There is limited evidence in humans as to whether antibiotics impact the effectiveness of cancer treatments. Rodent studies have shown that disruption in gut microbiota due to antibiotics decreases cancer therapy effectiveness. We evaluated the associations between the antibiotic treatment of different time periods before cancer diagnoses and long-term mortality. Methods: Using the Clinical Practice Research Datalink GOLD, linked to the Cancer Registry's and the Office for National Statistics' mortality records, we delineated a study cohort that involved cancer patients who were prescribed antibiotics 0-3 months; 3-24 months; or more than 24 months before cancer diagnosis. Patients' exposure to antibiotics was compared according to the recency of prescriptions and time-to-event (all-cause mortality) by applying Cox models. Results: 111,260 cancer patients from England were included in the analysis. Compared with antibiotic prescriptions that were issued in the past, patients who had been prescribed antibiotics shortly before cancer diagnosis presented an increased hazard ratio (HR) for mortality. For leukaemia, the HR in the Cancer Registry was 1.32 (95% CI 1.16-1.51), for lymphoma it was 1.22 (1.08-1.36), for melanoma it was 1.28 (1.10-1.49), and for myeloma it was 1.19 (1.04-1.36). Increased HRs were observed for cancer of the uterus, bladder, and breast and ovarian and colorectal cancer. Conclusions: Antibiotics that had been issued within the three months prior to cancer diagnosis may reduce the effectiveness of chemotherapy and immunotherapy. Judicious antibiotic prescribing is needed among cancer patients.
... Common examples include catecholamines, vasopressin or its analogues, corticosteroids and insulin. The stress response and immune function are also modified by other routine interventions, for example the use of immunomodulating sedative drugs [154] and a decrease in sympathetic activity due to the patient being asleep. ...
Full-text available
Sepsis is a dysregulated host response to infection that results in life-threatening organ dysfunction. Virtually every body system can be affected by this syndrome to greater or lesser extents. Gene transcription and downstream pathways are either up- or downregulated, albeit with considerable fluctuation over the course of the patient's illness. This multi-system complexity contributes to a pathophysiology that remains to be fully elucidated. Consequentially, little progress has been made to date in developing new outcome-improving therapeutics. Endocrine alterations are well characterised in sepsis with variations in circulating blood levels and/or receptor resistance. However, little attention has been paid to an integrated view of how these hormonal changes impact upon the development of organ dysfunction and recovery. Here, we present a narrative review describing the impact of the altered endocrine system on mitochondrial dysfunction and immune suppression, two interlinked and key aspects of sepsis pathophysiology.
... However, the effect of gentamicin-loaded apatite cement/α-TCP composites on the cell-to-cell communication in osteoblasts remains unknown. Furthermore, it is speculated that there is a complex interaction between antibiotic administration and mitochondria dysfunction [31]. However, the impact of antibiotics on mitochondria function remains unclear in osteoblasts. ...
Full-text available
Apatite cement (AC), which has excellent osteoconductive ability, and alpha-tricalcium phosphate (α-TCP), which can be used for bone replacement, are useful bone substitute materials. The objective of this study was to clarify the physical properties and antimicrobial release ability of antibiotic-loaded AC/α-TCP composites in vitro. Gentamicin-loaded, rapid setting AC/α-TCP composites were prepared in 2 mixing ratios (10:3 and 10:6). The cement paste of AC/α-TCP composites was prepared in a plastic mold and dried in a thermostatic chamber at 37 °C and 100% relative humidity for 24 h. A diametral tensile strength test, powder X-ray diffraction analysis, and gentamicin release test were performed. The diametral tensile strengths of the AC/α-TCP composites were significantly less than that of AC alone. Powder X-ray diffraction patterns exhibited the characteristic peaks of hydroxyapatite in the AC/α-TCP composites and gentamicin-loaded AC/α-TCP composites. The concentration of the released gentamicin was maintained above the minimum inhibitory concentration of Staphylococcus aureus until Day 30 in both the gentamicin-loaded AC/α-TCP composites (10:3 and 10:6). Our results suggest that a gentamicin-loaded AC/α-TCP composite has potential as a drug delivery system. Further study is essential to investigate the antimicrobial activity and safety of the gentamicin-loaded AC/α-TCP composites in animal models.
Translocation of gut bacteria into the pancreas promotes the development of severe acute pancreatitis (SAP). Recent clinical studies have also highlighted the association between fungal infections and SAP. The sensing of gut bacteria by pattern recognition receptors promotes the development of SAP via the production of proinflammatory cytokines; however, the mechanism by which gut fungi mediate SAP remains largely unknown. Leucine-rich repeat kinase 2 (LRRK2) is a multifunctional protein that regulates innate immunity against fungi via Dectin-1 activation. Here, we investigated the role of LRRK2 in SAP development and observed that administration of LRRK2 inhibitors attenuated SAP development. The degree of SAP was greater in Lrrk2 transgenic (Tg) mice than in control mice and was accompanied by an increased production of nuclear factor-kappaB-dependent proinflammatory cytokines. Ablation of the fungal mycobiome by anti-fungal drugs inhibited SAP development in Lrrk2 Tg mice, whereas the degree of SAP was comparable in Lrrk2 Tg mice with or without gut sterilization by a broad range of antibiotics. Pancreatic mononuclear cells from Lrrk2 Tg mice produced large amounts of IL-6 and TNF-α upon stimulation with Dectin-1 ligands, and inhibition of the Dectin-1 pathway by a spleen tyrosine kinase inhibitor protected Lrrk2 Tg mice from SAP. These data indicate that LRRK2 activation is involved in the development of SAP through proinflammatory cytokine responses upon fungal exposure.
Bacterial infections of the gut are one of the major causes of morbidity and mortality worldwide. The interplay between the pathogen and the host is finely balanced, with the bacteria evolving to proliferate and establish infection. In contrast, the host mounts a response to first restrict and then eliminate the infection. The intestine is a rapidly proliferating tissue, and metabolism is tuned to cater to the demands of proliferation and differentiation along the crypt‐villus axis (CVA) in the gut. As bacterial pathogens encounter the intestinal epithelium, they elicit changes in the host cell, and core metabolic pathways such as the tricarboxylic acid (TCA) cycle, lipid metabolism, and glycolysis are affected. This review highlights the mechanisms utilized by diverse gut bacterial pathogens to subvert host metabolism and describes host responses to the infection.
Full-text available
Background: Growing evidence associates organ dysfunction(s) with impaired metabolism in sepsis. Recent research has increased our understanding of the role of substrate utilization and mitochondrial dysfunction in the pathophysiology of sepsis-related organ dysfunction. The purpose of this review is to present this evidence as a coherent whole and to highlight future research directions. Main text: Sepsis is characterized by systemic and organ-specific changes in metabolism. Alterations of oxygen consumption, increased levels of circulating substrates, impaired glucose and lipid oxidation, and mitochondrial dysfunction are all associated with organ dysfunction and poor outcomes in both animal models and patients. The pathophysiological relevance of bioenergetics and metabolism in the specific examples of sepsis-related immunodeficiency, cerebral dysfunction, cardiomyopathy, acute kidney injury and diaphragmatic failure is also described. Conclusions: Recent understandings in substrate utilization and mitochondrial dysfunction may pave the way for new diagnostic and therapeutic approaches. These findings could help physicians to identify distinct subgroups of sepsis and to develop personalized treatment strategies. Implications for their use as bioenergetic targets to identify metabolism- and mitochondria-targeted treatments need to be evaluated in future studies.
Full-text available
Various antibiotics have been used in the treatment of cancers, via their anti-proliferative, pro-apoptotic and anti-epithelial-mesenchymal-transition (EMT) capabilities. However, increasingly studies have indicated that antibiotics may also induce cancer generation by disrupting intestinal microbiota, which further promotes chronic inflammation, alters normal tissue metabolism, leads to genotoxicity and weakens the immune response to bacterial malnutrition, thereby adversely impacting cancer treatment. Despite the advent of high-throughput sequencing technology in recent years, the potential adverse effects of antibiotics on cancer treatments via causing microbial imbalance has been largely ignored. In this review, we discuss the double-edged sword of antibiotics in the field of cancer treatments, explore their potential mechanisms and provide solutions to reduce the potential negative effects of antibiotics.