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Antimicrobial activity of psychotropic drugs: selective serotonin reuptake inhibitors

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Psychotropic drugs have been shown to have antimicrobial activity against several groups of microorganisms. Some of these drugs, such as the new antidepressant agents sertraline, fluoxetine and paroxetine are known to act as efflux pump inhibitors in human cells. Their activity has been studied, alone and combined with antibiotics, against bacterial species, mainly in multiply resistant strains. These agents have surprising activity, mainly against Gram positive microorganisms. They also show synergistic activity when combined with some antibiotics against several bacteria, shown by a decrease in MICs, that converts strains previously resistant to the category of sensitive, and modify physiological aspects related with pathogenicity.
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International Journal of Antimicrobial Agents 14 (2000) 177180
Antimicrobial activity of psychotropic drugs
Selective serotonin reuptake inhibitors
J.L. Munoz-Bellido, S. Munoz-Criado, J.A. Garcı`a-Rodrı`guez *
Department of Microbiology,Hospital Uni6ersitario de Salamanca,Paseo de San Vicente
108
,
37007
Salamanca,Spain
Abstract
Psychotropic drugs have been shown to have antimicrobial activity against several groups of microorganisms. Some of these
drugs, such as the new antidepressant agents sertraline, fluoxetine and paroxetine are known to act as efflux pump inhibitors in
human cells. Their activity has been studied, alone and combined with antibiotics, against bacterial species, mainly in multiply
resistant strains. These agents have surprising activity, mainly against Gram positive microorganisms. They also show synergistic
activity when combined with some antibiotics against several bacteria, shown by a decrease in MICs, that converts strains
previously resistant to the category of sensitive, and modify physiological aspects related with pathogenicity. © 2000 Elsevier
Science B.V. and International Society of Chemotherapy. All rights reserved.
Keywords
:
Psychotropic drugs; Serotonin; Antimicrobial activity
www.ischemo.org
Almost 40 years ago, in 1959, antimicrobial activity
was described for the first time in a psychotropic drug,
chlorpromazine [1]. Since then, a number of nonantibi-
otic drugs (other psychotropic drugs, non-steroidal
anti-inflammatory drugs (NSAIDs), mucolytic agents,
calcium channel blockers, and proton pump inhibitors
have been shown to have some influence on the physiol-
ogy and on the viability of microorganisms [2 10]. This
influence may act in several ways:
Antimicrobial activity.
Modification of antimicrobial activity of antibiotics.
Activity on the physiology and the pathogenicity of
microorganisms.
Among a wide group of non-antibiotic drugs which
have been studied, antimicrobial activity was shown in
a number of non-antibiotic drugs such as the non-
steroidal anti-inflammatory drugs, cytostatic drugs and
psychotropic drugs. Antimicrobial activity was de-
scribed in some psychotropic drugs, mainly phenotiazi-
nes [2 5]. They also had the ability to reverse
chloroquine resistance in Plasmodium [11]. The highest
activity found was in a group of drugs in which antimi-
crobial activity had not been shown before. These are
the third generation antidepressants, the selective sero-
tonin re-uptake inhibitors (SSRI), namely sertraline,
fluoxetine and paroxetine (Fig. 1).
SSRIs are drugs that, in humans, act by modifying
the behaviour of 5-OH tryptamine (serotonin) in the
synapse space. This target is not new for psychotropic
drugs. In fact, the mode of action for most antidepres-
sant drugs is focused on the metabolism of
monoamines. What is new in these drugs is the way
they modify the amounts of serotonin at the synapse
space trough. Usually, there is a pump at the synapse
space that directs serotonin towards the presynapse
neurone. SSRIs inhibit this pump, thus increasing the
amount of serotonin at the synapse space (Fig. 2) [12].
The studies show that these drugs have a significant
antimicrobial activity, mainly against Gram positive
bacteria (Table 1). They are inactive against enterobac-
teria, with the exception of Citrobacter, and Pseu-
domonas aeruginosa. They, however, show surprising
activity against H.influenzae,M.catarrhalis,C.jejuni
and even against some problem organisms such as
Acinetobacter.
These drugs also show excellent activity against
staphylococci and enterococci, although not against
other streptococci that are usually susceptible to antibi-
otics, such as S.pneumoniae,S.pyogenes or S.agalac-
tiae. They are active against some anaerobes, such as
* Corresponding author. Tel.: +34-92-3264825; fax: +34-92-
3262261.
E-mail address
:
jagarrod@gugu.usal.es (J.A. Garcı`a-Rodrı`guez)
0924-8579/00/$ 20 © 2000 Elsevier Science B.V. and International Society of Chemotherapy. All rights reserved.
PII: S0924-8579(99)00154-5
J.L.Munoz-Bellido et al.
/
International Journal of Antimicrobial Agents
14 (2000) 177180
178
Fig. 1.
Some of these drugs are capable of inhibiting slime
production in coagulase-negative staphylococci [18],
and inhibit swarming in swarming species in Proteus
[19] (Table 3), a circumstance already described for
other psychotropic drugs [3].
Little is known presently on the mechanisms by
which these drugs act on microorganisms. The first
mechanism suggested was that they may act as efflux
pumps inhibitors since they also act on human cells as
pump inhibitors. This is a mechanism that may explain
their synergy with some antibiotics such as tetracyclines
and fluoroquinolones against C.urealyticum. It is more
difficult to explain the intrinsic antimicrobial activity by
this mechanism. Other efflux pump inhibitors, such as
reserpine or verapamil are able of increasing the activ-
ity of antibiotics against microorganisms expressing
efflux pumps, but they lack antimicrobial activity by
themselves. The fact that SSRIs not only show antimi-
crobial activity, but also impair a number of processes
involving biosynthesis of products in the microorgan-
isms (for example, slime synthesis, swarming) may indi-
cate that they act on basic metabolic processes, which
may or may not be related to the uptake of substances.
The target remains to be identified.
The main factors impairing their usefulness in respect
to antimicrobial activity, are the maximum serum levels
attainable and the effects on the central nervous system.
Their maximum serum levels are about 1 mg/l. These
levels may be sufficient to allow synergy with antibi-
otics, since synergy is similar for a wide concentration
range of non-antibiotic drug; from concentrations near
the MIC to those much lower [17]. These maximum
serum levels may also be sufficient to modify bacterial
metabolism, as shown in studies on slime and swarming
inhibition [18,19]. These maximum serum levels, how-
ever, remain almost always lower than the concentra-
tions required to inhibit even to the most sensitive
microorganisms. The results obtained with these drugs
support further research of the following:
Bacteroides fragilis group. This activity is not influ-
enced by their susceptibility to other antibiotics. Their
activity against Acinetobacter is independent of whether
the organisms are multiply antibiotic resistant or not,
and the activity against coagulase-positive or -negative
staphylococci is not dependent on the sensitivity to
methicillin. Their activity against penicillin-sensitive or
penicillin-resistant pneumococci is equally poor.
The SSRIs have excellent activity against Brucellae,
similar only to that of some NSAIDS, as diclofenac, a
non-antibiotic drug tested by the authors [13]. Their
influence on microorganisms is not limited to antimi-
crobial activity against some species. They have been
shown to be synergistic in combination with antibiotics
against some microorganisms, including those which
are resistant, such as against Corynebacterium ure-
alyticum, the etiologic agent of urinary tract infections
and for encrusted cystitis [1416]. SSRIs, mainly sertra-
line, are able to increase the activity of some antibiotics,
such as tetracyclines and fluoroquinolones, against
these microorganisms, reducing the MICs of about 50%
of quinolone-resistant strains to susceptible ranges [17]
(Table 2).
These drugs have been shown to be capable of mod-
ifying the normal physiology of some microorganisms.
Fig. 2.
J.L.Munoz-Bellido et al.
/
International Journal of Antimicrobial Agents
14 (2000) 177180
179
Table 1
In vitro activity of sertraline, compared to a tricyclic antidepressant (clomipramine) and clorpromazine
Microorganism ClomipramineSertraline Clorpromazine
MIC (mg/l)
90 Range(No. of strains) 5050 90 Range 50 90 Range
128 64–128 256 256 128–512 \512E.coli (32) \51264 \512
128 64–256 256 \51264 256–\512K.pneumoniae (32) \512 \512 \512
64E.cloacae (32) 64 64–128 \512 \512 \512 \512 \512 256–\512
8C.freundii (32) 16 8–64 256 512 128–512 256 256 128–\512
\512 256–\512 \512 \512256 \512S.marcescens (32) \512 \512 \512
512 32–512 \512 \512 128–\512 \512P.mirabilis (32) \512512 128–\512
512 128–512 \512 \512256 \512P.6ulgaris (32) \512 \512 256–\512
256M.morganii (32) 512 256–512 \512 \512 \512 512 \512 256–\512
\512Salmonella sp. (32) \512 \512 \512 \512 \512 \512 \512 \512
64 16–64 128 12816 128A.baumanii (32) 128 128 128
32 8–64 4 16H.influenzae (32) 2–1616 128 128 128
16 4–16 8 164 8–16M.catarrhalis (32) \512 \512 \512
4C.jejuni (32) 16 2–32 128 128 128 64 64 64–128
8S.aureus (32) 16 4–32 32 128 16–128 128 128 32–128
16 4–16 128 1288 128S.epidermidis (32) 128 128 64–128
64 16–64 32 128 16–256 128S.pneumoniae (32) 25664 64–512
64 16–64 32 12832 16–256S.pyogenes (32) 64 128 64–128
64S.agalactiae (32) 64 16–64 32 128 16–256 128 256 64–512
8E.faecalis (32) 16 2–16 128 128 32–128 128 128 32–128
64 32–128 256 25664 128–\512C.perfringens (32) 256 \512 256–\512
64 32–128 256 512 256–\512 512 512 256–\512C.difficile (32) 32
32 16–32 512 \51216 512–\512B.fragilis (32) 512 \512 256–\512
16Pre6otella spp. (32) 32 16–64 128 256 128–\512 128 \512 256–\512
16 8–16Brucella spp (32) 3216 32 32–64 256 512 256–512
Table 2
In vitro activity of psychotropic drugs and combinations sertraline+
antibiotics against Corynebacterium group D2.
MIC (mg/l)Drugs
9050 Range
3216 1–128Tetracycline
8Ciprofloxacin 64 0.01–128
32Clorpromazine 64 16–64
3232 8–32Fluoxetine
32 4–32Paroxetine 8
\512512 128–\512Risperidone
8Sertraline 8 2–8
Tetracycline+8 16 0.2–128
sertraline 1/2 MIC
8Tetracycline+16 0.5–128
sertraline 1/16 MIC
1.6 32 1–128Tetracycline+
sertraline 1/64 MIC
0.2Ciprofloxacin+4B0.008–128
sertraline 1/2 MIC
14B0.008–128Ciprofloxacin+
sertraline 1/16 MIC
14B0.008–128Ciprofloxacin+
sertraline 1/128 MIC
Influence on the physiological characteristics of bac-
teria, mainly on characteristics that are related with
their pathogenicity.
Development of molecules that have antimicrobial
activity but reducing drawbacks related to maximum
serum levels and neurological effects.
Development of their capacity as efflux pump in-
hibitors. Efflux pumps are now identified as impor-
tant mechanisms of resistance, responsible for
resistance to several antibiotics in a number of bacte-
ria (norA-mediated fluoroquinolone resistance in S.
aureus, phenotype M macrolide-resistance in S.
pneumoniae,S.pyogenes and S.agalactiae, and resis-
tance of P.aeruginosa to several antibiotics). The
availability of drugs able for inhibiting these pumps
may lead to their use in combination with antibi-
otics, as has occurred with combinations of b-lac-
tam/b-lactamase inhibitors.
Several new drugs such as venlafaxine, fluvoxamine
and citalopram, with a similar mode of action have
been recently developed. The behaviour of older SSRIs
against bacteria warrants further studies on their an-
timicrobial activity.
J.L.Munoz-Bellido et al.
/
International Journal of Antimicrobial Agents
14 (2000) 177180
180
Table 3
Inhibition of growth and swarming in Proteus and Morganella by psychotropic drugs
Swarming inhibition (mg/l)MIC (mg/l)Drugs
50 90 Range Partial Total
\512 512–\512Amitriptiline 256512 512
Clomipramine 512 \512 512–\512 – 256
Imipramine 512 \512 512–\512 256 512
\512 512–\512512 –Maprotiline 256
512Promethazine \512 512–\512 – 256
\512 256–\512Chlorpromazine –512 128
\512 \512\512 –Fluphenazine \512
512Sertraline \512 64–\512 – 32
Diazepam \512 \512 \512 \512
\512 \512 \512\512Dimenhidrinate
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... It was observed that several classes of drugs have both in vitro and in vivo antibiotic activity; however, not all of them have an elucidated hypothesis of the reason for such an effect. In addition to the antimicrobial response of non-antibiotic drugs, researchers also present interesting results regarding the synergistic effect when combined with some standard treatments in infectious combat [6][7][8][9][10][11]. ...
... Fluoxetine, a selective serotonin reuptake inhibitor in neurons, has several data on its in vitro activity against different bacterial strains, such as S. aureus, E. coli, and P. aeruginosa (Table 2) [18,19]. Studies propose as a hypothesis of this result the inhibition of efflux pump in bacteria [7,20]. From cytometric analysis, it was assumed that fluoxetine would be able to alter the integrity of the plasma membrane, as well as that of DNA, inducing apoptosis [21]. ...
... Fluoxetine has been shown to have antimicrobial activity mainly against Gram-positive microorganisms. It also shows synergistic activity when combined with some antibiotics against several bacteria (Munoz-Bellido, 2000). It can also potentially exert its toxicity by inhibiting cellular efflux pumps (Munoz-Bellido, 2000). ...
... It also shows synergistic activity when combined with some antibiotics against several bacteria (Munoz-Bellido, 2000). It can also potentially exert its toxicity by inhibiting cellular efflux pumps (Munoz-Bellido, 2000). ...
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This study investigates the effects of antidepressants fluoxetine, sertraline, and amitriptyline on the development of antibiotic resistance in clinical Acinetobacter baumannii isolates. The isolates were exposed to fluoxetine, sertraline, and amitriptyline for 30 days, respectively. The bacteria that developed resistance to gentamicin, imipenem, colistin, and ciprofloxacin were isolated and expression levels of some antibiotic resistance genes were determined by quantitative Reverse-Transcriptase PCR. Before and after the exposure, minimum inhibitory concentration (MIC) values of the bacteria were determined by the microdilution method. The statistical analysis was performed using Student's t-test. A time-dependent increase was observed in the number of bacteria that developed resistance and increased the MIC value. After exposure to fluoxetine and sertraline, decreases were observed for efflux and outer membrane porin genes in isolates that developed colistin resistance, and increases were observed in isolates that developed ciprofloxacin resistance. These observations suggest that these antidepressants have similar effects on the development of resistance. While the exposure to fluoxetine didn’t result in the development of resistance to imipenem, it was observed after exposure to sertraline and amitriptyline, and a common decrease in ompA gene expression was determined in these isolates. To our knowledge, the comparative effects of selected antidepressants on the development of antibiotic resistance in A. baumannii are reported and presented in the literature here for the first time.
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Corynebacterium group D2 (CGD2) is involved in urinary tract infections in patients with underlying predisposing factors. This microorganism is highly resistant to a number of antimicrobial agents. We tested the activities of 79 antimicrobial agents against CGD2. beta-Lactams, aminoglycosides, and macrolides were ineffective. Fluorinated quinolones showed irregular activities, ofloxacin being the most active one. Doxycycline, rifampin, and mainly glycopeptides (vancomycin and teicoplanin) were the most active antibiotics against CGD2.
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The in vitro activities of nine psychopharmacologic drugs (amitriptyline, clomipramine, imipramine, maprotiline, clorpromazine, flufenazine, promethazine, sertraline and diazepam) against 704 strains of aerobic and anaerobic microorganisms were studied. The activities were, on the whole, greater against Gram-positive strains. The most active drugs were clomipramine, flufenazine, and above all, sertraline, which demonstrated a MIC50 in Gram-positive cocci of 8-64 μg/ml.
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In May 1990 the 1st International Conference on Antimicrobial Activity of Non-Antibiotics was held in Copenhagen, Denmark. More than 200 scientists were drawn from 34 countries and from all five continents. Papers were presented dealing with the antimicrobial activity of different synthetic and natural compounds, and interactions between antibiotics and non-antibiotics. The conference pointed to the unusual properties of non-antibiotic drugs. These effects might create unexpected therapeutic possibilities and lead to new basic insights.
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In May 1990 the 1st International Conference on Antimicrobial Activity of Non-antibiotics was held in Copenhagen, Denmark. More than 200 scientists were drawn from 34 countries and from all five continents. Papers were presented dealing with the antimicrobial activity of different synthetic and natural compounds, and interactions between antibiotics and non-antibiotics. The conference pointed to the unusual properties of non-antibiotic drugs. These effects might create unexpected therapeutic possibilities and lead to new basic insights.
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The pharmacokinetic properties of the newer specific serotonin (5-HT) reuptake inhibitors are reviewed. Fluoxetine, paroxetine, sertraline, and fluvoxamine show kinetic characteristics similar to those of the older tricyclic antidepressants. They are well absorbed orally but exhibit an extensive first-pass extraction in the liver. They are widely distributed in body tissues and highly bound to plasma proteins. The clearance of these drugs by the body is accomplished almost entirely by hepatic metabolism. Fluoxetine and sertraline both produce a pharmacologically active metabolite, although insufficient data are available to evaluate the clinical significance of desmethylsertraline. With the exception of fluoxetine, which has an elimination half-life of 2 to 3 days, the other drugs have half-lives of about 1 day. Available data indicate that paroxetine and fluvoxamine achieve steady state within 4 to 14 days of chronic dosing, whereas for fluoxetine, and particularly norfluoxetine, steady state is not reached for weeks. The pharmacokinetics of these drugs are characterized by marked intersubject variability. Only preliminary data are available on steady-state plasma concentrations achieved during treatment and correlations to therapeutic or adverse effects.
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The aim of the investigation was to throw light on the question whether drugs other than antibiotics and chemotherapeutic agents exert an antimicrobial effect. In order to elucidate this, the antimicrobial effect of selected psychotherapeutic drugs and their stereo-isomeric analogues was studied. The development of psychotherapeutic drugs from aniline dyes has been reviewed against the background of its history considered as a scientific idea. It is demonstrated that psychotherapeutic drugs have an antimicrobial effect. Psychotherapeutic drugs show antimicrobial activity at high concentrations. Stereo-isomeric analogues of known psychotherapeutic drugs also have an antimicrobial effect. The selectivity of the various stereo-isomeric compounds depends on which microorganism and which chemical compound is investigated. Synergism is found between psychotherapeutic drugs (CPZ) and penicillin in vitro, and between a non-neuroleptic stereo-isomeric compound trans-CPT and penicillin in vivo, using infected mice as material. The antibacterial activity of psychotherapeutic drugs is independent of the antihistaminic, antihypersecretory, neuroleptic and antidepressant effect of these drugs. The examples chosen of investigations of the antimicrobial effect of psychotherapeutic drugs in vitro and in vivo lead to the conclusion and to the perspectives in the present study. Namely, the need for a general theory of the interplay between host organism, microorganisms and drugs. This proposition is based on a concern to argue against the view that the prokaryotic effect of eukaryote-directed drugs is without major significance, either for scientific research or for clinical treatment.
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The in vitro susceptibility of recent Danish human clinical isolates of Campylobacter pyloridis to cimetidine, sucralfate, bismuth subsalicylate and sixteen antimicrobial agents was determined by an agar-dilution technique. Benzylpenicillin was the most active drug (MIC90 = 0.1 microgram/ml); ampicillin, erythromycin, gentamicin and ciprofloxacin were slightly less active. All strains were resistant to 100 micrograms sulfamethizole, and nalidixic acid also had little activity on weight basis. Of the three anti-peptic ulcer drugs, bismuth subsalicylate was most active (MIC90 25 micrograms/ml), but sucralfate and cimetidine also had antibacterial activity, although only little (MIC90 3200 micrograms/ml).