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Journal of Antimicrobial Chemotherapy (1997) 40, 622–630
Antibiotic susceptibilities of mycoplasmas and treatment of
David Taylor-Robinsona and Christiane Bébéarb
aMRC Sexually Transmitted Diseases Research Group, Department of Genitourinary Medicine, the Jefferiss Wing, Imperial College School of Medicine at St Mary's, Paddington, London W2 1NY, UK;b Centre Hospitalier Régional de Bordeaux, Place Amélie Raba Léon, 33076 Bordeaux, France Mycoplasmas are the smallest free-living microorganisms, being about 300 nm in diameter.
They are bounded by a triple-layered membrane and, unlike conventional bacteria, do not
have a rigid cell wall. Hence, they are not susceptible to penicillins and other antibiotics that
act on this structure. They are, however, susceptible to a variety of other broad-
spectrum antibiotics, most of which only inhibit their multiplication and do not kill them. The
tetracyclines have always been in the forefront of antibiotic usage, particularly for genital
tract infections, but macrolides are also widely used for respiratory tract infections. Indeed,
in comparison with the tetracyclines, erythromycin, the newer macrolides, the ketolides and
the newer quinolones have equal or sometimes greater activity. The two latter antibiotic
groups also have some cidal activity. The antibiotic susceptibility profiles of several
mycoplasmas of human origin are presented, those of Mycoplasma pneumoniae
Mycoplasma genitalium
being similar. Apart from the penicillins, mycoplasmas are innately
resistant to some other antibiotics, for example the rifampicins. In addition, some may develop
resistance, either by gene mutation or by acquisition of a resistance gene, to antibiotics to
which they are usually sensitive. Resistance of mycoplasmas to tetracyclines is common and
due to acquisition of the tetM
gene. The antibiotic susceptibility pattern may be influenced
greatly by the source of the mycoplasma; for example, one recovered from a contaminated
eukaryotic cell culture that has been subjected to extensive antibiotic treatment may have an
antibiotic profile quite different from the same mycoplasmal species that has been recovered
directly from a human or animal source. Mycoplasmas may be difficult to eradicate from
human or animal hosts or from cell cultures by antibiotic treatment because of resistance to
the antibiotic, or because it lacks cidal activity, or because there is invasion of eukaryotic
cells by some mycoplasmas. Eradication may be particularly difficult in immunosuppressed
or immunodeficient individuals, particularly those who are hypogammaglobulinaemic. The
regimes that are most likely to be effective in the treatment of respiratory or genitourinary
mycoplasmal infections are presented.

Growth occurs in nutrient media in the absence of livingtissue cells. Organisms of the genera Mycoplasma, Urea- All organisms in the class Mollicutes (‘soft skin') are here plasma, Entomoplasma, Anaeroplasma and most Spiro- referred to trivially as mycoplasmas. Their characteristics plasma spp. require sterol for growth, whereas species in and a molecular explanation for their pathogenicity have the genera Acholeplasma, Asteroleplasma, Mesoplasma been reviewed quite recently.1 In brief, they possess a and a few Spiroplasma spp. do not. Apart from the strictly triple-layered limiting membrane but no rigid bacterial cell anaerobic mycoplasmas (anaeroplasmas and asterole- wall and, therefore, tend to be pleomorphic, although some plasmas), most other mycoplasmas are facultatively aero- have a well-defined appearance with a terminal structure bic, growth often being optimal anaerobically or in an by which they attach to eukaryotic cells. The smallest atmosphere containing added CO2. Multiplication of most viable forms are about 300 nm in diameter and, although species on solid media results in the formation of small they do not possess flagella or pili, many are motile.
colonies that have a characteristic ‘fried egg' appearance, 1997 The British Society for Antimicrobial Chemotherapy Mycoplasma: susceptibility and treatment
detected in joints in inflammatory arthritides and in lungs in HIV infection a cause of acute and chronic non-gonococcal a possible cause of pelvic inflammatory disease; causes infections in immunodeficiencies associated serologically with HIV infection a cause of atypical pneumonia and sequelae non-pathogenic, but has caused arthritis in a probable cause of acute NGU; causes chronic NGU, and arthritis in hypogammaglobulinaemia; detected in joints in inflammatory arthritides genitourinary tract Primary site of colonization Primary sites of colonization, metabolism and pathogenicity of mycoplasmas isolated from humans primary site occasionally.
Mycoplasma orale Mycoplasma pirum ‘Non-pathogenic' means that no evidence for pathogenicity is available.
Metabolizes urea.
D. Taylor-Robinson and C. Bébéar
the smallest colonies being produced by organisms of the Broth dilution method genus Ureaplasma. The latter are unique in hydrolysingurea, other species fermenting carbohydrates and/or Incubation of decreasing concentrations of an antibiotic hydrolysing arginine. Some species are pathogenic, causing with a suspension of organisms in broth medium, followed diseases mainly in the respiratory tracts and genital tracts by application of aliquots of the mixtures to agar medium of vertebrates, or diseases in plants and insects. A large and further incubation to determine whether there is in- cluster of the plant pathogenic mycoplasmas (now termed hibition of colony development, is a feasible approach to phytoplasmas), which are transmitted by insect vectors or antibiotic susceptibility testing. However, for mycoplasmas grafting, have not been successfully cultured on artificial a modification of this broth dilution method in the form of medium. Many species of mycoplasma occur as part of the the metabolism inhibition test is usually used. This is much normal vertebrate or plant/insect flora. The mycoplasmas simpler and is, in fact, a simple modification of the of human origin, their characteristics and pathogenicity metabolism inhibition method used for measuring anti- have been reviewed recently2,3 and some of the important body,8 with the antibody replaced by antibiotic. Decreasing features are shown in Table I. Growth of all mycoplasmas is concentrations of antibiotics are mixed with a standard inhibited by broad-spectrum antibiotics, and the effect that concentration of organisms (usually 104/mL) in broth antibiotics have on those of human origin, together with a medium and the mixtures incubated. Multiplication of the review of current approaches to treatment is the focus of organisms results in metabolism of glucose, arginine or this article.
urea with the consequent change in pH of the mediummade visible as a colour change by incorporation of a pHindicator (usually phenol red); the antibiotic (or antibody) Antibiotic susceptibility tests
inhibits the colour change.8 Several commercially availablekits are based on this principle. The MIC is the highest dilu- The antibiotic susceptibilities of mycoplasmas may be tion of antibiotic that inhibits the colour change at the time determined in vitro by two basic methods: the agar dilution when the change in the control without antibiotic has just method4 and the broth dilution method, usually in the form developed;4–6 some investigators regard the end-point of the metabolism inhibition test.4–6 as the dilution at which there is 50% reduction (notabsence) of the colour seen in the control. Continued incu-bation results in an increasing MIC value so that, in effect, Agar dilution method it is possible to record a final inhibitory concentration some If a standard agar dilution method is used to determine the time after the initial reading.6 It is clear that results and antibiotic susceptibility of mycoplasmas, then the lowest reproducibility are strongly influenced by the time of read- concentration of antibiotic completely preventing colony ing and by the number of organisms in the inoculum and development after incubation at 37°C is usually regarded as that some effort to standardize is desirable, otherwise vary- the MIC. Investigators often disregard a single colony or a ing results in a laboratory and, particularly, differences in few colonies within the inhibition zone, but it may be results from one laboratory to another will continue.
unwise to do so since these may represent an antibiotic- Nevertheless, even if attention is not paid to these aspects it resistant strain in a mixture of sensitive and resistant ones.
is usually possible within a laboratory to distinguish a strain Indeed, an advantage of the agar dilution method over the that is susceptible to an antibiotic from one that is not.
broth dilution method is that, in using an uncloned inocu- However, resistant organisms in a mixture of resistant and lum, resistance can be detected in this way. Nevertheless, sensitive ones will multiply and may obscure those that are the agar dilution method is time-consuming and labour- sensitive. The penalty of not having an inoculum of cloned intensive. Two modifications are rapid and easy to under- organisms is obvious, although cloning is not always prac- take. The first of these involves the use of filter paper discs.
tised. Despite the difficulties mentioned in using the Organism suspensions are spread on agar medium, allowed metabolism inhibition method, it is preferred by many to dry, and filter paper discs containing serial two-fold investigators, particularly when ureaplasmas are being decreasing concentrations of antibiotic are added. After tested, since colour changes caused by these organisms are incubation, discs are sought around which there are zones easier to demonstrate than colony development. Neverthe- of colony inhibition and the lowest concentration of anti- less, a particular problem may be experienced in testing the biotic causing a zone is the MIC. The second method is the susceptibility of ureaplasmas to erythromycin,9 since the Etest.7 As before, organism suspensions on agar medium MIC value is affected greatly by pH, the antibiotic being are allowed to dry and then strips containing antibiotics much more active at pH 7 than at pH 6–6.5 (the pH of thein a concentration gradient ranging from, for example, medium used in the test). A corollary of this is the failure of 0.016 mg/L to 256 mg/L are applied. After incubation, erythromycin to eradicate ureaplasmas from the vagina10 MICs are defined as the antibiotic concentration on the as a result of the vaginal secretions being so acidic (pH  strip at the point of intersection with the zone of colony 4.5). It is unproven but interesting to speculate that eradi- cation of vaginal ureaplasmas with erythromycin might be Mycoplasma: susceptibility and treatment
achieved in women who have bacterial vaginosis, when the mycoplasmacidal activity (see below), since such activity vaginal pH can rise to 7.0.
can not be determined adequately by methods that do notallow the antibiotic to be separated from the organisms atsome stage of the test.
Tests of mycoplasmacidal activity Apart, perhaps, from the quinolones, antibiotics active against mycoplasmas tend not to be cidal, at least inconcentrations that can be achieved in vivo. Lack of cidal It has long been recognized that mycoplasmas are normally activity is seen, as mentioned above, by a ‘creeping' in- susceptible to antibiotics that inhibit protein synthesis and crease in the MIC value on continued incubation of the are resistant to those that act on bacterial cell wall com- metabolism inhibition test. However, more detailed in- ponents (because of the absence of the latter). The suscepti- formation may be gained by removing the mixture of bility of Mycoplasma pneumoniae, Mycoplasma genitalium, organisms and antibiotic, at whatever concentration of the Mycoplasma hominis, Mycoplasma fermentans and Urea- latter is considered to be inhibitory, and determining plasma urealyticum to a range of antibiotics is shown in whether the organisms are still capable of multiplication Table II. The concise representation hides the fact that the once the antibiotic has been diluted in growth medium susceptibilities shown are drawn from numerous studies in beyond its inhibitory concentration.6 Alternatively, the which there is a wide range of MICs of any particular anti- mixture may be passed through a 0.2 m pore-size filter to biotic.4 As a consequence, some investigators may find trap the organisms, the filter washed by passing clean that, when they test a particular antibiotic, its MIC does not medium through it, and then placed in growth medium to fall precisely within the category presented in Table II.
culture viable organisms.6 However, overall, the representation of the antibiotic sus- In summary, there is no agreed usage of a single test and ceptibility profiles is likely to be correct, as is the order in expediency often dictates which method is used. The agar which the antibiotics have been placed. It is noteworthy dilution method has some advantages, as outlined, and has that antibiotics other than tetracyclines and erythromycin, its proponents,4,11,12 but the broth dilution method in the particularly the streptogramins, such as pristinamycin13 and form of the metabolism inhibition test is probably used RP59500,14 some of the newer macrolides, such as clari- more often. Furthermore, it is invaluable in assessing thromycin and azithromycin, and the newer quinolones, Table II. Susceptibilities of M. pneumoniae, M. genitalium, M. hominis, M. fermentans and U. urealyticum to various
M. pneumoniae M. genitalium M. hominis M. fermentans U. urealyticum a , susceptible (MIC  1 mg/L); , partially susceptible (MIC  1–10 mg/L); –, resistant (MIC 10 mg/L). Results are presented mostly in orderof diminishing activity for M. pneumoniae.
Organisms within this species that carry the Tet M determinant are not susceptible to tetracyclines.
D. Taylor-Robinson and C. Bébéar
such as sparfloxacin,15 are active gainst M. pneumoniae.16 isms and accounting for the occurrence of relapse. This, in In addition, the ketolides, which constitute a new and turn, is a plausible reason for starting antibiotic therapy for distinct class of macrolide derivatives, are highly active respiratory mycoplasmal disease on the basis of clinical sus- against M. pneumoniae and some of the other myco- picion and for recommending extended treatment rather plasmas17 (see below); compound RU 004 seems to be the than a short course. Of course, as discussed below, if there most active. The results for the small number of strains of is innate resistance to an antibiotic or resistance develops, M. genitalium that are currently available indicate that this eradication and clinical improvement are not expected.
mycoplasma has an antibiotic susceptibility profile similarto that of M. pneumoniae, being susceptible to the tetra-cyclines and highly susceptible to a range of macrolides and In contrast to M. pneumoniae and M. genitalium, Mycoplasmas as a whole are innately resistant to certain M. hominis, although partially susceptible to the ketolides,17 antibiotics, such as the penicillins, cephalosporins and the is not susceptible to erythromycin or some of the other rifamycins, in whatever dosage. In the case of the macrolides, but is susceptible to clindamycin and lincomy- rifamycins, insusceptibility seems to be related to the pres- cin, whereas the reverse is true for U. urealyticum. Indeed, ence of a single amino acid, at position 526, in the  subunit lincomycin has been incorporated in medium to inhibit the of RNA polymerase, as determined from the sequences of growth of bacteria and select out ureaplasmas from animal the rpoB gene of Spiroplasma citri27 and from those of sources.19 M. fermentans shows some resistance to erythro- different other mycoplasmal species including M. genital- mycin,20,21 but not the complete resistance exhibited by M. ium.28 It is such insusceptibility that argues against the hominis, and is at least partially sensitive to the ketolides.17 claim for the existence of mycoplasma-like organisms in Otherwise, M. hominis and M. fermentans have similar various human diseases that are reported to be responsive susceptibility patterns. The antibiotic susceptibility profiles to rifampicin.29–31 Some mycoplasmal species are selec- of other mycoplasmas of human origin are not available in tively innately resistant to an antibiotic to which other such detail.
species are sensitive. An example of this is M. hominis, allstrains of which are resistant to erythromycin. Mycoplas-mas also develop resistance to antibiotics to which they are Mycoplasmastatic and mycoplasmacidal effects
usually considered sensitive. Such resistance to strepto- mycin is common and may develop as a one-step process.32Complete resistance to this and other aminoglycosides has It is important to emphasize that most antibiotics that are been seen in strains of M. fermentans isolated from cell cul- used successfully in treating mycoplasmal infections (see tures in which such antibiotics have been used,21 although below) have a static effect on the organisms. The greatest resistance of this kind is not seen with M. fermentans strains cidal activity is exhibited perhaps by the newer quinolones, that have been isolated directly from human sources. In for example sparfloxacin,15 which inhibit the replication of this regard, it is interesting to note that the aminoglycoside DNA, and by the ketolides.17 However, the general in- resistance of the first strain of M. fermentans (strain ‘incog- ability of antibiotics to kill mycoplasmas, despite the fact nitus'), recovered from patients with the acquired immuno- that they may suppress their growth, is one of the reasons deficiency syndrome via the use of eukaryotic cell why eradication from the host tissues is often slow. The cultures,33 was used as an argument to suggest that it was intracellular location of some mycoplasmas, by affording derived from the cells and not from the patients.21 That the protection against an antibiotic, may also be a reason for source of a mycoplasma isolate is a factor that may influ- slow eradication. Less than 10 years ago, it was dogma that ence the results of antibiotic susceptibility tests means that mycoplasmas did not gain entrance to cells other than results may be obtained that are not always in keeping with phagocytes. In the intervening period, however, it has been the data shown in Table II.
demonstrated that M. fermentans,22 M. hominis,22 M. geni- Resistance of M. hominis to fluoroquinolones, as for talium,23,24 M. pneumoniae and Mycoplasma penetrans25 do other bacterial species, is associated with a gyrA mutation enter eukaryotic cells and, in the case of the two latter at Ser83.34 Resistance of M. hominis to tetracyclines35,36 species, there has been evidence for intracellular multi- probably assumes more importance because of the plication. The same may be true for U. urealyticum.26 A widespread use of these drugs for genital tract infections, delay in eradication from the host ensues, even though the and in some areas the frequency of resistant strains has results of in-vivo testing indicate that an active antibiotic increased to 30% or more.37 The reason for this, appar- has been given in sufficient dosage. Another problem is ently, is the acquisition of a streptococcal tetM gene.38 that the diagnosis of a mycoplasmal infection, in particular U. urealyticum strains may also become resistant to tetra- infection by M. pneumoniae, is often delayed so that cyclines39 for the same reason.40 The tetM gene encodes a infection is well-established by the time antibiotic therapy protein which binds to ribosomes and in the case of U. urea- is initiated, further compromising eradication of the organ- lyticum it has been demonstrated to be associated, on the Mycoplasma: susceptibility and treatment
chromosome, with Tn916, a conjugative transposon.4 In an adequate immune response.49 Support for this concept London, the proportion of tetracycline-resistant urea- also comes from the difficulties experienced in controlling plasmal strains isolated from patients attending sexually mycoplasmal infection in plants50 and of eradicating con- transmitted disease (STD) clinics during the decade taminating mycoplasmas from cell cultures, both situations 1973–83 remained at about 10%;39 whether the proportion where a functioning immune system does not exist.
has altered subsequently has not been assessed. Erythro-mycin-resistant ureaplasmal strains in the same area alsocomprised about 10%39 but strains resistant to both anti- Treatment of infection
biotics were very infrequent. It is noteworthy that strains ofM. hominis known to be resistant to various tetracyclines Mycoplasma pneumoniae infection because of the TetM determinant have been shown to be as The value of antibiotic therapy in M. pneumoniae-induced susceptible to the glycylcyclines (new tetracycline deriva- disease was shown first in a controlled trial of dimethyl- tives) as the tetracycline-susceptible strains; tetracycline- chlortetracycline undertaken in marine recruits in the resistant strains of U. urealyticum have shown variable USA, the duration of fever, pulmonary infiltration, and susceptibility to the glycylcyclines,41 but seem to be other signs and symptoms being reduced significantly.51universally susceptible to the ketolides.17 Subsequently, other trials provided evidence for the effect- Erythromycin-resistant strains of M. pneumoniae have iveness of various tetracyclines, as well as erythromycin been isolated from treated patients. In erythromycin-resist- and other macrolides.52 It should be noted, however, that ant mutants selected in vitro, the resistance affected antibiotics tend to be more effective in planned trials thanseveral macrolide–lincosamide–streptogramin B (MLS) they are in routine clinical practice, probably because antibiotics, and was demonstrated to occur as the result of disease has become more established in routine practice point mutations in the 23S rRNA gene.42 The elimination before treatment is instituted. This should not be construed of such resistant strains by erythromycin therapy is, of as meaning that antibiotic therapy is not worthwhile, course, not expected. However, the difficulty of eradicating although clinical improvement is not always accompanied even erythromycin-sensitive M. pneumoniae strains from by early eradication of the organisms from the respiratory the respiratory tract43 indicates that the promise of in-vitro tract.43 The likely reason for this, as mentioned previously, tests does not always correlate with clinical outcome.
is that almost all antibiotics have only static activity againstmycoplasmas. The quinolones are an exception, havingcidal qualities, although the earlier ones have only moder- Role of the immune system
ate activity against M. pneumoniae.16 Failure to kill is alsoan explanation for clinical relapse in some patients and a As for other infections, there are unquestionable diffi- plausible reason for recommending a 2–3 week course of culties in controlling mycoplasmal infections in patients antibiotic treatment rather than a shorter course. It is a with immune deficiencies44 and of eradicating such infec- moot point whether early treatment might prevent some of tions from nude mice as opposed to their immunocom- the complications but, nevertheless, it should commence as petent counterparts (D. Taylor-Robinson & P. M. Furr, soon as possible. If facilities for rapid laboratory diagnosis, unpublished data). In the case of the former, although namely a PCR assay, are not available, confirmation of a M. clinicians treating mycoplasma-infected immunodeficient pneumoniae infection will inevitably be slow. A raised cold patients may not always experience a problem, failure haemagglutinin and/or single serum antibody titre (1:64)to respond microbiologically and clinically has at times that can be obtained quickly might provide some diagnos-created serious problems. The persistence for years of M. tic assurance but, nevertheless, it would seem wise to start pneumoniae in the respiratory tract45 and of ureaplasmas in suitable antibiotic treatment on the basis of the clinical the urethra,46 joints and other sites47,48 of hypogamma- evidence alone. The antibiotics used most widely are the globulinaemic patients has occurred despite multiple macrolides (erythromycin, roxithromycin) and the tetra- courses of antibiotics, sometimes given intravenously. In cylines, doxycycline in particular. Erythromycin is more some patients, the administration of high titre anti-ure- active against M. pneumoniae than against some of the aplasmal antibody prepared in goats, together with anti- other mycoplasmas of human origin (see Table II). Fortu- biotic, seems to have been responsible for clinical nately, it is also active against some of the other bacteria, recovery.44 The ability to detect M. fermentans by a poly- for example Legionella spp., that cause atypical pneu- merase chain reaction (PCR) assay in the blood of HIV- monia. In the case of pregnant women and children, it is positive patients over many months, despite courses of certainly advisable to use a macrolide rather than a tetracy- various antibiotics for other intercurrent infections, is also cline, roxithromycin being tolerated better than erythro- noteworthy (J. Ainsworth & D. Taylor-Robinson, unpub- mycin, and for the reasons given macrolides have the edge lished data). This, by inference, means that successful over tetracyclines in adults. Overall, there should be no dif- chemotherapeutic intervention in a mycoplasmal infection ficulty with therapeutic options because M. pneumoniae is depends to a large extent on the ability of the host to mount also inhibited by the newer macrolides, such as clarithro- D. Taylor-Robinson and C. Bébéar
mycin and azithromycin, and to some extent by the quinolones, such as ciprofloxacin.16 1. Maniloff, J., McElhaney, R. N., Finch, L. R. & Baseman, J. B.
(Eds) (1992). Mycoplasmas: Molecular Biology and Pathogenesis.
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3. Taylor-Robinson, D. (1995). Mycoplasma and Ureaplasma. In
Thus, for example, in the case of non-gonococcal urethritis, Manual of Clinical Microbiology (Murray, P. R., Barron, E. J., patients should receive a tetracycline that inhibits Pfaller, M. A., Tenover, F. C. & Yolken, R. H., Eds), pp. 652–62.
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been increasing (20%),37 other antibiotics such as linco- 7. Waites, K. B., Crabb, D. M., Duffy, L. B. & Cassell, G. H.
mycin, clindamycin or fluoroquinolones (often ofloxacin) (1996). Etest: a novel method for screening Mycoplasma hominis may sometimes need to be used. Azithromycin, which is for tetracycline resistance. IOM Letters. Vol. 4. In Program andAbstracts of the 11th International Congress of the International being used increasingly to treat non-gonococcal urethritis Organization for Mycoplasmology, Orlando, 1996. pp. 408–9.
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11. Kenny, G. E., Cartwright, F. D. & Roberts, M. C. (1986). Agar
As a consequence of the difficulties sometimes experi- dilution method for determination of antibiotic susceptibility of enced in treating hypogammaglobulinaemic patients, parti- Ureaplasma urealyticum. Pediatric Infectious Disease 5 (6), Suppl.
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Received 22 May 1997; accepted 4 July 1997


Microsoft word - supakit_31_36

Original Article 31 EFFICACY OF VERNONIA CINEREA FOR SMOKING CESSATION Supakit Wongwiwatthananukit1,∗, Preeda Benjanakaskul2, Thanapat Songsak3, Somporn Suwanamajo4 and Viroj Verachai4 1Department of Pharmacy Practice, College of Pharmacy, University of Hawaii at Hilo, Hilo, Hawaii 96720, USA 2Department of Pharmacy, Siriraj Hospital, Bangkok, Thailand 3Department of Pharmacognosy,