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Do antibiotics cause mitochondrial and immune cell dysfunction?
A literature review
Muska Miller
1
* and Mervyn Singer
1
1
Bloomsbury Institute of Intensive Care Medicine, Cruciform Building, University College London, Gower Street, London, WC1E 6BT, UK
*Corresponding author. E-mail: muska.miller@ucl.ac.uk
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.
Introduction
Antibiotics are key components of modern-day medicine. Yet,
despite their numerous benefits, they carry a significant 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
microbiome.
1
However, other adverse consequences are less
well appreciated, for instance effects on the efficacy of
anti-cancer medications,
2
organ–organ crosstalk
1
and the
Jarisch–Herxheimer reaction, in which release of pathogen con-
stituents such as endotoxin and DNA activate proinflammatory
pathways.
3
Using a rat model of caecal ligation and puncture,
Peng et al.
4
demonstrated that ampicillin/sulbactam improved
survival but at the expense of a greater inflammatory 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 host’s 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.
5
As bioenergetic/metabolic shutdown is consid-
ered a likely key component underlying multi-organ dysfunction
in sepsis,
6
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 specific
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.
7
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.
6
Immune dysregulation
is a major feature of sepsis and this is increasingly linked to
bioenergetic dysfunction.
8–11
Specific alterations are described
in immune cell mitochondrial respiratory complex activity,
oxygen consumption, mitochondrial membrane depolarization,
apoptosis and ROS production.
12–16
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 inflammatory response.
16,17
After the
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© The Author(s) 2022. Published by Oxford University Press on behalf of British Society for Antimicrobial Chemotherapy.
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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.
10
Aminoglycosides
Data on immunomodulatory effects of aminoglycosides are con-
flicting.
18–21
In some studies, therapeutic levels of gentamicin
and amikacin reduced polymorphonucleocyte (PMN) chemo-
taxis.
22,23
On the other hand, others reported no influence on
either chemotaxis or phagocytosis but an inhibitory effect on
PMN bactericidal activity.
24,25
At therapeutic doses, amikacin in-
creased superoxide production in stimulated PMNs but this was
reduced at high doses (1–5 mg/L).
26
Gentamicin, netilmicin and
tobramycin, however, had no impact.
26
Gentamicin and amikacin
at high concentrations (.40 mg/L) also inhibited macrophage
activation.
27
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-
icity
28–30
as aminoglycosides act on the mitochondrial ribosomal
A site, which has structural similarity to bacterial ribosomes. This
may activate phosphatidylinositol phospholipase C,
31
increasing
intracellular calcium
32
and ultimately leading to a proinflamma-
tory response via activation of extracellular signal-regulated
kinases (ERKs).
33
In renal and sensory hair-cell mitochondria,
gentamicin inhibited oxidative phosphorylation and mitochon-
drial membrane potential, increasing ROS and apoptosis.
34–42
Kanamycin reduced mitochondrial membrane potential, electron
transport chain activity and ATP production in epithelial cells.
43
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.
44
Gentamicin may
mobilize iron from mitochondria in a time- and dose-dependent
manner via generation of hydrogen peroxide.
45
To our knowl-
edge, no study has yet investigated aminoglycoside effects on
mitochondrial function in immune cells.
β-Lactams
β-Lactams have known immunomodulatory functions in hyper-
sensitivity
46–48
and cancer.
49,50
However, reported effects on im-
mune cells in the context of infection have been conflicting.
51
It
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
bacteria.
52–55
Variations in β-lactam-induced endotoxin release
can influence 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 significantly lower levels of
endotoxin and induced apoptotic cell death.
56
β-Lactams also
reduce granulopoiesis and may even cause neutropenia.
57,58
Paradoxically, amoxicillin increased dendritic cell maturation and
expression of activation markers such as HLA-DR, CD86 and CD80.
48
There are also conflicting data on chemotaxis and phagocyt-
osis. Some studies found penicillins, carbapenems and cephalos-
porins had no effect on PMN chemotaxis,
59–65
whereas others
reported ampicillin and cephalosporins reduced chemotaxis
across a broad concentration range.
63,66,67
Yet other papers
found cephalosporins and carbapenems increased chemotaxis
of PMNs and murine macrophages, respectively.
68–72
Similarly,
for phagocytosis, some studies found no effect of cephalosporins
on PMN phagocytosis at therapeutic doses,
63,66,73
some found
cephalosporins and carbapenems increased human PMN and
murine macrophage phagocytosis,
68,69,72,74–76
while others re-
ported that piperacillin, cephalosporins and meropenem reduced
phagocytic activity in PMNs, monocytes and rat leucocytes, re-
spectively.
61,67,77
Cefotaxime, faropenem, amoxicillin, clavulanic
acid and imipenem increased the respiratory burst and superox-
ide production in PMNs.
64,76,78–80
On the other hand, meropenem
reduced superoxide release but had no effect on PMN killing of
Candida albicans.
73
In a cell-free system, ampicillin and various
cephalosporins could scavenge hypochlorous acid (HOCl).
81
With this wide variation in findings, 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.
82
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.
73
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.
77–83
A further study using
monocytes incubated with Staphylococcus epidermidis, however,
found no effect of β-lactams on TNF-αrelease.
84
In various stud-
ies on endotoxin-stimulated monocytes, penicillin and various
cephalosporins inhibited IFN-γactivity,
85
IL-10 release
86
and
CD14 expression.
87
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.
85,87,88
In terms of adaptive immunity, benzylpenicillin, carbenicillin,
cefazolin and cefalotin did not affect lymphocyte mitogenic
responses after 3 days of incubation.
89
However, moxalactam
at different concentrations reduced chemical-induced lympho-
cyte proliferation.
90
Long-term ceftriaxone use increased the per-
ipheral blood CD4/CD8 cell ratio but reduced the number of
CD4+CD25+cells.
91
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).
92,93
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.
93
In renal mitochondria,
imipenem, cefaloridine and cefaloglycin reduced mitochondrial
respiration while imipenem and cefaloglycin reduced oxidation
of butyrate, valerate and pyruvate as early as 30–90 min.
94
Another study demonstrated that cephalosporins and penicillins
could both reduce carnitine transport in a dose-dependent man-
ner.
95
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
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activation of caspase-9 and -3 and apoptosis.
96
In neurons, pi-
peracillin lowered mitochondrial membrane potential, reducing
respiration and ATP production, but increased mitochondrial
superoxide.
97
Glycopeptides
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
degranulation,
98–103
neutropenia and decimation of gut micro-
biota.
104–108
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.
109
In the context of infection, there is a plethora of conflicting
reports. Teicoplanin at half its MIC enhanced macrophage phago-
cytosis of Staphylococcus aureus,
110
whereas teicoplanin and
vancomycin (at concentrations of 10–100 mg/L) increased intra-
cellular killing of phagocytosed organisms in both PMNs and
monocytes.
111–113
At high teicoplanin concentrations (500 mg/L),
adherence, chemotaxis, phagocytosis and killing of C. albicans
by PMNs were significantly inhibited, while vancomycin (at
0.002 mg/L) reduced PMN adherence and phagocytosis.
114
Conversely, other studies found that therapeutic concentrations
of teicoplanin and vancomycin did not affect chemotaxis, adher-
ence nor phagocytosis of human PMNs.
19,106,111,115–117
There are similar conflicting findings 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).
113
Other studies, however, reported a decrease in
TNF-αproduction in PBMCs following an 18 h incubation with
vancomycin,
118
and a reduction in IL-8, IL-1βand TNF-αwith
teicoplanin.
119
We could find 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.
120
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.
121–123
These effects
may be mediated by peroxidation of the mitochondrial mem-
brane protein cardiolipin
122
and could be partially or wholly miti-
gated by antioxidants such as vitamin E and MitoTEMPO.
121–123
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.
124
Macrolides
The immunomodulatory effects of macrolides on the lung have
been recognized since the 1970s.
125
In bronchiolitis, erythromy-
cin reduced bronchoalveolar lavage fluid accumulation of
leucocytes, particularly PMNs.
126–130
This may relate to a reduc-
tion in PMN chemotactic activity mediated by decreased produc-
tion of IL-8, LTB-4 and IL-1β.
126–130
In patients with atopic
diseases such as asthma and rhinosinusitis, various macrolides
reduced PMN and eosinophil counts in sputum, bronchoalveolar
fluid and blood, cytokine levels, PMN elastase and NADPH oxidase
activity.
131–142
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.
143
In
patients with cystic fibrosis, long-term use of clarithromycin re-
duced sputum cytokine levels but enhanced ex vivo lymphocyte
proliferation.
144
Several in vitro studies report that macrolides reduce
pro-inflammatory cytokines and chemokines (e.g. IL-1, IL-2,
IL-6, IL-8 and TNF-α),
145–147
possibly via suppression of AP-1
and nuclear factor kappa B (NF-κB) pathways
148
and by modula-
tion of TLR expression.
149
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-
ity.
150
Conflicting studies suggest that macrolides may or may
not increase chemotaxis,
151–156
cytokine release or phagocytosis
of immune cells.
157–161
Similarly, macrolides either do not affect
or reduce phagocytosis
162–164
and the respiratory burst.
165–167
Finally, there are multiple conflicting reports on the effect of
macrolides on immune cell proliferation and survival.
168–173
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.
174
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
ATP
channels.
175
Several studies report that
macrolides can increase complex I and III activity, O
2
consump-
tion and ATP synthesis.
176,177
Quinolones
The reported immunomodulatory effects of quinolones are more
consistent, particularly in hypersensitivity reactions
178–180
but
also on the gut microbiota.
181,182
Quinolones (at 5–100 mg/L)
reduced pro-inflammatory cytokine and chemokine release
(e.g. IL-1, IL-6, IL-8, TNF-α, IFN-γand GM-CSF),
183–190
partially
by down-regulation of NF-κB, ERK and c-Jun-N-terminal kinase
(JNK).
191–193
Quinolones also increased IL-8 and TNF-α
mRNA
194
and IL-2 production.
195–198
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
burst.
199–202
Ciprofloxacin may also increase phagocytosis and
intracellular killing of organisms.
203,204
Quinolones at concentrations of .50 mg/L can inhibit mam-
malian cell growth by blocking cell cycle progression.
205,206
The
increase in thymidine uptake has been attributed to increasing
IL-2 production.
207
In lymphocytes, proliferation was inhibited
by up-regulating Fas ligand, caspase-8 and -3 activity.
208,209
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In vitro ofloxacin (at 10 or 100 mg/L) did not induce apoptosis in
isolated lymphocytes.
210
Quinolones damage mitochondria by targeting mitochondrial
topoisomerases.
211
These influence 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.
211,212
Ciprofloxacin
induces mtDNA loss, decreases electron transport chain complex
I activity (as this is mtDNA encoded),
213
and decreases mito-
chondrial membrane potential.
214
This may be beneficial 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.
215,216
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.
217
In lung can-
cer, quinolones disrupted activity of complexes I and III, reduced
ATP production and increased ROS production.
218
Oxazolidinones
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.
219–222
In addition to inhib-
ition of fatty acid synthesis,
223
these bioenergetic effects have
been implicated in oxazolidinone-induced lactic acidosis.
224–226
Linezolid inhibits mitochondrial translation by binding ribosomal
peptidyl transferases and interfering with the binding of
aminoacyl-tRNAs.
219,221
This process impairs the coordinated as-
sembly of the electron transport chain from mitochondrial- and
nuclear-encoded genes.
227
Multiple in vitro studies have shown that oxazolidinones re-
duce cytokine production (e.g. TNF-α, IL-6, IFN-γand IL-1ra)
228–
236
and phagocytosis, but exert no effect on killing capacity.
237
Oxazolidinones also have no effect on chemotaxis, phagocytosis
or the respiratory burst.
238–240
There are limited studies of the effect of oxazolidinones on mi-
tochondrial functionality in muscle, liver and kidney.
222,226,224,241
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.
242
Conclusions
Different classes of antibiotics exert varying immunomodulatory
and bioenergetic effects with more consistent findings 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 fixed
doses of antibiotic.
243,244
Acknowledgements
Muska Miller thanks The London Clinic for their support.
Funding
This study was carried out as part of our routine work.
Transparency declarations
None to declare.
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