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Antimicrobial Agents and Chemotherapy, October 2000, p. 2855-2857, Vol. 44, No. 10
Department of Clinical Microbiology,
Rigshospitalet, University of Copenhagen, Denmark
Received 13 January 2000/Returned for modification 13 April
2000/Accepted 1 July 2000
The concentrations of Staphylococci, corynebacteria, and
propionibacteria are the major genera inhabiting human skin. A few
bacteria are found on the surface of desquamated scales of normal skin,
but the bulk is found in the openings of the hair follicles. The
bacteria are also present at the openings of sweat ducts but not in the
intraepidermal portion of the ducts (15, 18). Development of
resistance to antibiotics in staphylococci (e.g., Staphylococcus
epidermidis and S. aureus) (21) is
frequently seen when patients are treated while in hospital
(9), and generally also in countries with high consumptions
of antibiotics, and spread to other patients of such strains occurs
(2, 10, 13, 16).
We have previously found (9) that the prevalence of
methicillin resistance in coagulase-negative staphylococci (CNS) in different wards of a major university hospital was significantly correlated to the total consumption of antibiotics, but not to the
consumption of Antibiotics probably have to be excreted to the surface of the skin to
interfere with the normal flora. A possible route of excretion would be
the sweat glands. We have previously shown that ciprofloxacin is
excreted in sweat (perspiration) and this leads to rapid development of
multidrug-resistant MRSE (7, 8). We speculated whether
excretion of Healthy persons.
Fourteen of us did the experiments on
ourselves. There were eight men and six women (age 33 to 56 years;
weight, 54 to 93 kg). One of us was used for pilot experiments, and on
the basis of those results the other 13 were enrolled into the study.
All were healthy, and informed signed consent was given. The
investigation was carried out according to the 1975 Tokyo revision of
the Helsinki Declaration on ethics in human experimentation, and the
protocol was approved by the Ethics Committee of Copenhagen, Denmark.
Drug administration, sample collection, and measurement of drug
concentrations.
The following antibiotics were each given to six
adults: benzylpenicillin, 1.2 g intravenously (i.v.) (5-min
bolus); phenoxymethylpenicillin, 1.2 g orally (p.o.); cefuroxime,
1.5 g (i.v.); ceftriaxone, 2 g i.v.; and ceftazidime, 2 g i.v. (3 g was administered to the biggest person in the study). The
concentrations of the antibiotics in blood, apocrine sweat (axilla),
and eccrine sweat (volar surface of the forearm) were measured as
described previously (7, 8). In brief, sweat production was
stimulated by pilocarpine iontophoresis, the sweat was collected for
30-min periods by 20-mm-diameter paper disks (30 µl of sweat), and
blood was collected midway through each of these periods at 30 min to
8 h after the antibiotics were given. A biological method was used
for antibiotic measurement (test strains: Sarcinia lutea
ATCC 9341 and Proteus rettgeri 9228/71; lower detection
limits, 0.1 to 0.4 µg/ml). The sweat from antibiotic-free persons had
no activity against these two strains. The reproducibility of the
measurements of concentrations of antibiotics in sweat was 11.8%
(variation coefficient) (7).
Benzylpenicillin.
Three of six persons had measurable
benzylpenicillin concentrations in apocrine sweat (Table
1) which remained above the MIC at which
90% of the isolates tested are inhibited (MIC90) for
penicillin-susceptible staphylococci for 8 h in two persons (Fig.
1A). Two of these persons also had
measurable benzylpenicillin concentrations in eccrine sweat. Probenecid
(1 g × 2 orally, 13 and 1 h before benzylpenicillin in one
of the test persons) did not influence the excretion of
benzylpenicillin.
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Copyright © 2000, American Society for Microbiology. All rights reserved.
Excretion of
-Lactam Antibiotics in Sweat
a
Neglected Mechanism for Development of Antibiotic Resistance?
,* and
ABSTRACT
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-lactam antibiotics after standard doses
were measured in blood and apocrine (axilla) and eccrine (forearm) sweat from six adult healthy persons. All persons had ceftazidime (axilla, 28.4 µg/ml; forearm, 11 µg/ml) and ceftriaxone (axilla, 8.9 µg/ml; forearm, 2.5 µg/ml) in sweat, and one person had
cefuroxime in sweat (axilla, 7.8 µg/ml) (all data are mean peaks).
Three persons had benzylpenicillin (axilla, 2.6 to 0.1 µg/ml) and one had phenoxymethylpenicillin (axilla, 0.4 µg/ml) in sweat. Excretion of -lactam antibiotics in the sweat may explain why staphylococci so
rapidly become resistant to these drugs.
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-lactamase-stable penicillins such as dicloxacillin or early cephalosporins. On the other hand it was significantly correlated to the consumption of expanded-spectrum cephalosporins such
as ceftazidime and carbapenems, fluoroquinolones, aminoglycosides, and
trimetoprim (9). S. epidermidis is much more
prevalent on the skin than S. aureus (15, 18),
and methicillin-resistant S. epidermidis (MRSE) is far more
prevalent than methicillin-resistant S. aureus (MRSA).
Methicillin resistance is associated with the presence of the
penicillin-binding protein 2a, which is not present in susceptible
staphylococci. This protein is encoded by the mecA gene.
Evidence exists that there is a horizontal transfer of mec sequences from CNS to S. aureus (1, 4, 5).
Antibiotics which promote development of MRSE may therefore
subsequently lead to MRSA.
-lactam antibiotics in sweat could also be the
biological background for the development of MRSE and MRSA. The aim of
this study was therefore to measure the concentrations in blood,
apocrine sweat (axilla), and eccrine sweat (volar surface of the
forearm) of selected representative -lactam antibiotics in adult
healthy persons.
TABLE 1.
Concentrations of antibiotics in sweat and blood of six
healthy persons
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FIG. 1.
Mean -lactam antibiotic concentrations in serum and
sweat obtained from axilla and volar surface of the forearm after p.o.
or i.v. (bolus) administration to six healthy persons. (A)
Benzylpenicillin, 1.2 g i.v.; (B) phenoxymethylpenicillin,
1.2 g p.o. (C) cefuroxime, 1.5 g i.v.; (D) ceftriaxone,
2 g i.v.; (E) ceftazidime, 2 g i.v. No antibacterial activity
of sweat was detectable before intake of the antibiotics. For
comparison the MIC90s for susceptible staphylococci (in
micrograms per milliliter) were as follows: benzylpenicillin, 0.03;
phenoxymethylpenicillin, 0.06. The MIC90s for
methicillin-susceptible and resistant staphylococci (in micrograms per
milliliter) were as follows: cefuroxime, 1 to 2 and 
128,
respectively; ceftriaxone, 4 and 128, respectively; ceftazidime, 4 to
8 and 128, respectively.
Phenoxymethylpenicillin. Only one of six persons had measurable phenoxymethylpenicillin concentrations in apocrine sweat (Table 1) which remained above the MIC90 for penicillin-susceptible staphylococci for 4 h (Fig. 1B).
Cefuroxime. Only one of six persons had measurable cefuroxime concentrations in apocrine sweat (Table 1) which remained above the MIC90 for methicillin-susceptible staphylococci, and this person had also measurable concentrations in eccrine sweat (Fig. 1C) above the MIC90 for methicillin-susceptible staphylococci but below the MIC90 for methicillin-resistant staphylococci.
Ceftriaxone. All six persons had measurable ceftriaxone concentrations in apocrine and eccrine sweat (Table 1) which remained above the MIC90 for methicillin-susceptible staphylococci for 0.5 to 4 h (axilla) and for 0.5 to 2 h (forearm) (Fig. 1D) but below the MIC90 for methicillin-resistant staphylococci.
Ceftazidime. All six persons had measurable ceftazidime concentrations in apocrine and eccrine sweat (Table 1) which, in both types of sweat, remained above the ceftazidime MIC90 for methicillin-susceptible staphylococci for 0.5 to 8 h (Fig. 1D) but below the ceftazidime MIC90 for methicillin-resistant staphylococci.
The first MRSA was isolated in the United Kingdom in 1960 (3), and during the following 10 years an increasing prevalence was reported in Europe before a decrease was observed in the 1970s. During the second half of the 1970s, new multidrug-resistant MRSA strains emerged, which were resistant to gentamicin and were isolated progressively in an increasing number of countries, finally resulting in the present pandemic (14). The massive use of gentamicin in the 1970s was proposed as a cause responsible for the emergence of these new MRSA strains, but many broad-spectrum antibiotics were also being marketed at that time, including expanded-spectrum cephalosporins in the 1980s. Witte et al. (22) reported an increase of MRSA in central Europe from 1984 to 1995 and that many clones were involved. The introduction of fluoroquinolones at the end of the 1980s was quickly followed by the emergence of resistant mutants among MRSA (14). Likewise, Speller et al. (19) reported an increase of MRSA in England and Wales from 1989 to 1995, including resistance to ciprofloxacin. Crowcroft et al. (6) reported the incidence of nosocomial MRSA in 50 Belgian hospitals in 1994 and 1995. They found a significant correlation with the consumption of some expanded-spectrum cephalsporins (ceftazidime and cefulodin), ciprofloxacin, and amoxicillin-clavulanic acid, but no correlation with the consumption of ceftriaxone-cefotaxime or the early cephalosporins, benzylpenicillin, phenoxymethylpenicillin, or-lactamase-stable penicillins. Recently,
rapid emergence of resistant CNS on the skin after antibiotic
prophylaxis was reported by Terpstra et al. (20) who showed
that amoxicillin-clavulanate selected for resistance to cloxacillin,
whereas ofloxacillin selected for resistance for both ofloxacillin and
cloxacillin (20).
Benzylpenicillin has been in clinical use since approximately 1943, phenoxymethylpenicillin has been in use since approximately 1953, and
cefuroxime has been in use since approximately 1980. The present study
shows that the pharmacokinetic basis exists for these early -lactam
antibiotics to influence the normal skin flora in some persons, since
the MIC for staphylococci is below the concentrations measured in sweat
of at least these persons. Ceftriaxone and ceftazidime have both been
in clinical use since approximately 1985. The pharmacokinetic basis is
indeed present for a more pronounced influence on the skin flora of
these two expanded-spectrum cephalosporins since prolonged and high
concentrations of these drugs were excreted in the sweat of all the
persons tested.
According to these results, therefore, excretion of benzylpenicillin in
sweat may have contributed to the selection of -lactamase-producing staphylococci soon after the introduction of this antibiotic more than
50 years ago (2, 13, 17). Excretion of ceftriaxone and
especially ceftazidime in sweat may, on the other hand, have contributed significantly to the present worldwide selection for and
spread of MRSA and MRSE (10, 16). This is in accordance with
the correlation found between the use of these drugs and the incidence
and prevalence of MRSE and MRSA in several studies (6, 9)
and the correlation between the decreased usage of expanded-spectrum
cephalosporins and the reduced number of patients with MRSA
(21). We have previously shown that ciprofloxacin is
excreted in sweat and this leads to rapid development of
multidrug-resistant S. epidermidis strains which are also
resistant to methicillin (7, 8). The mechanism responsible
has not been investigated, but efflux resistance may be suggested.
These findings are in accordance with the results of the study
mentioned above (20) which showed that ofloxacin prophylaxis
was followed by development of resistance to that drug and to
cloxacillin. The excretion of -lactam antibiotics, notably
expanded-spectrum cephalosporins, and fluoroquinolones in sweat may,
therefore, be the biological explanation for the close temporal
relationship between the marketing of these antibiotics and the
increase of MRSA reported in, e.g., the United Kingdom and central
Europe (19, 22).
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FOOTNOTES |
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* Corresponding author. Mailing address: Department of Clinical Microbiology 9301, Rigshospitalet, Juliane Maries Vej 22, DK-2100 Copenhagen Ø, Denmark. Phone: (45)35457788. Fax: (45)35456412. E-mail: hoiby{at}inet.uni2.dk.
Member of the Copenhagen Study Group on Antibiotics in Sweat.
Other members of the study group are Leif P. Andersen, Jette
Bangsborg, Mads Bennedsen, Niels H. Riewerts Eriksen, Susanne Gjedde,
Jens Otto Jarløv, Michael Kemp, Anne Kjerulf, Claus Moser, Annette
Nørgaard, and Jørgen Prag.
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Antimicrobial Agents and Chemotherapy, October 2000, p. 2855-2857, Vol. 44, No. 10
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