Evolving Candidiasis:
Pathogens Implications
J. Horowitz,
Benson
Over utable
MD,
Diane
Giaquinta,
in Vulvovaginal for Patient PharmD
and
Susan
Care
Ito, PharmD
the past two decades, to yeasts other than
an increasing trend in the number of vaginal infections attribCandida albicans has emerged. Of these non-albicans species, C. tropicalis and C. glabrata appear to be the most important. The change in incidence pattern of yeast vaginitis can be expected to impact greatly on the treatment of this condition, because many currently used drug therapies (e.g., imidazoles) for C. albicans vaginitis do not adequately eradicate non-albicans species. A possible explanation for the recent increased selection of these species maybe the shortened antifungal therapies that have been introduced during the past decade. These 1- to 3-day regimens with the older imidazoles may suppress C. albicans, but create an imbalance of flora that facilitate an overgrowth of non-albicans species. The recognition of yeast speciation and the need for use of a broad-spectrum antifungal preparation that covers these organisms is now apparent.
T
he incidence of infections due to Candida has greatly increased over the past 30 years, and along with this has come an increased incidence of vulvovaginal candidiasis (VC).1 The widespread use of antibiotics during this time is one of the most probable explanations for the strong emergence of Candida vaginitis,1 because suppression of normal bacterial flora, which occurs during antimicrobial therapy, is required for this vaginal commensal to become
pathogenic.
Another contributory factor may be the introduction of oral contraceptives (OCs) in the 1960s. Because of their high estrogen content, early OCs were believed to predispose women to Candida overgrowth.2’3 The effect of OCs on the incidence of Candida is controversial, however, and more studies will be needed to confirm or deny the possible link between estrogen and candidiasis. Some reports indicate that the prevalence of Candida is higher among high-estrogen OC users, but the incidence of symptomatology is the same as for women using other forms of birth control.4-6 Other studies indicate that From the Department of Obstetrics and Gynecology (Dr. Horowitz), University of Connecticut, Farmington, Connecticut, Mt. Sinai and Hartford Hospitals (Dr. Horowitz), Hartford, Connecticut, Vaginitis Section (Dr. Horowitz), International Society for the Study of Vulvar Dis-
ease, Houston, Texas, Department of Pharmacy (Dr. Giaquinta), Blue Cross of California, and the Department of Clinical Pharmacy (Dr. Ito), Blue Cross of California. Address for reprints: Benson J. Horowitz, MD, SHE. 06105.
248
Medical
S
Associates,
J CIin Pharmacol
449
Farmington
1992;32:248-255
Avenue,
Hartford,
CT
the incidence is higher in OC users.7’8 More recent studies of low-estrogen OCs, however, show no increase in Candida vaginitis.9’10 Currently, in clinical terms, the increased incidence of vaginal candidiasis translates into 13 million cases yearly in the United States alone,11 and confers on this condition the dubious honor of competing with bacterial vaginosis for first place as the most common cause of vaginitis.1’12’13 Of the more than 150 species of Candida, there are only 10 that are considered important pathogens for humans (Table I). Of these, C. aIbi cans is the most frequent cause of VC, accounting for as much as 80% of cases.14 Other Candida species account cases,14 and it is these non-albicans
for the species
balance that
of will
be the focus of this review. Although not all women who harbor non-albicans yeasts intravaginally develop symptomatology,1516 there is unequivocal evidence that vaginal candidiasis is strongly associated with high concentrations of vaginal yeasts.17 PREVALENCE VULVOVAGINAL
OF
NON-ALBICANS CANDIDIASIS
SPECIES
IN
Until recently, if physicians cultured samples from their symptomatic patients, they could be satisfied that when the culture disclosed Candida species they would be able to prescribe an effective polyene (nystatin), or more recently, imidazole (clotrimazole, miconazole) antifungal. But the large number of re-
PATHOGENS
TABLE Clinically
Important
Candida
IN
VEJLVOVAGINAL
I Pathogens
in Humans
C.aibi cans C. guilliermondi C. krusei
parapsilosis C. stellatoidea
C.
(now
included
C. tropicalis C. pseudotropicalis C. Iusitaniae C. rugosa C. glabrata (also classified
within
C. albicans)
as Torulopsis
glabrata)4
* There is ongoing debate about the correct genus of this yeast. Some mycologists no longer use the genus Torulopsis and have expanded the genus Candida to include Torulopsis, which is a yeast that does not produce true hyphae and/or pseudohyphae. Other mycologists strongly object to this assimilation and urge that the separation between the two yeasts be conserved. According to Odds, merging of the two species eliminates some clinical confusion, and the morphological distinction between the two is still easy to make in the mycology lab (Odds FC. Candida and candidosis: a review and bibliography, 2 ad. London: Balliere
Tindall,
1988:8-9).
calcitrant cases of vaginal candidiasis that currently occur in clinical practice have led investigators to search for causes. Investigation into the pathogenesis of recurrent and chronic candidal vaginitis have delineated reinfection and relapse as the two leading potential causes.18 Looking at reinfection from a persistent extravaginal source, O’Connor and Sobel14 found sexual transmission to be a possible source and reported simultaneous identical Candida strains in the sex partner of almost 48% of the women with recurrent VC. In addition, further evidence by O’Connor and Sobel14 and Horowitz et al.19 indicates that oral-genital transmission of Candida also may play a role in recurrent cases, because higher oral Candida colonization rates have been found in male partners of women with recurrent infection. Despite these findings, the role of sexual transmission in recurrent VC is still unclear, because it does not explain most recurrences. Further, three controlled studies have found that the treatment of male partners does not prevent recurrence in women.20-22 The possibility of reinfection from an intestinal reservoir also has been intensively studied. Despite the fact that women with recurrent VC are more likely to be culture positive at multiple extravaginal sites than women without VC,19 many studies have failed to find an association between recurrent vaginal candidiasis and intestinal yeast carriage14’23 or conversely, persistent intestinal yeast carriage and vaginal colonization.24
ANTI-INFECTIVE
AGENTS
CANDIDIASIS
Relapse is another possible cause of recurrent infection. Relapse of the original infection has usually been thought of as the result of inadequate therapy or a pathogen that is less susceptible to the drug used.18 Although a high degree of yeast eradication does take place with currently used antifungals, clinical efficacy rates are not as high as in vitro efficacy rates. Therefore, relapse due to initial treatment failure can be expected in a sizable number of women. According to Odds,16 approximately 15 to 20% of women who are culture negative after treatment will become culture-positive within I to 3 months after treatment discontinuation. O’Connor and Sobel14 reported that when clinical recurrence occurred later than 3 months after the previous episode, the likelihood was great that a different strain of Candida from that of the prior infection would be isolated. In addition to the well-known risk factors for vaginal candidiasis that can contribute to recurrence or relapse, other mechanisms that have been investigated include the following: (1) host immunologic factors such as Candida-antigen-specific deficiency in T-lymphocyte function,25 (2) acquired hypersensitivity reaction to Candida antigen,26’27 (3) deficiencies in normal protective vaginal flora that permit unsuppressed colonization,24 and (4) virulence factors such as secretory proteinase.28 Changes
in Causative
Pathogens
In searching for explanations, other than host factors, for the number of recurrent or recalcitrant infections, investigators have most recently focused on the incidence of non-albicans species as the cause of recurrent cases.293#{176} This research has identified a gradual increase in incidence of infections due to these species, particularly C. tropicalis and C. glabrata (formerly known as Torulopsis glabrata). Candida parapsilosis has also recently emerged as a factor.31 A review of nine studies during the 1970s involving 1,269 isolates disclosed a 9.9% incidence of non-albicans among women with VC.16’29 A further review of seven studies from the 1980s involving 728 isolates, however, showed an incidence of 21.3%. Thus, there has been more than a doubling (11.4% increase) in the incidence of non-albicans infections from the 1970s to the 1980s (Table II).16,29 Further evidence for this increase in non-albicans species is offered by Takada et al.,3#{176} who reviewed the prevalence of C. glabrata infections between 1960 and 1983 and found that the C. glabrata detection rate had indeed increased in women with vaginal candidiasis. The significance of the increased emergence of
249
HOROWITZ,
TABLE Shift
In Causative During
ClInical Isolates
C. aibicans C. glabrata C. krusei C. parapsilosis C. tropicalis Other Candida
Isolates
%
1970-79
Total
1,143
90.1
from
Isolates 1980-89 573
Candidiasis %
%
Total
Change
78.7
-11.4
1.4
49 12
6.7 1.7
+2.1 +0.2
17
1.4 1.3
9 60
1.2 8.2
-0.2 +6.9
14
1.1
25
3.4
+2.3
59
4.6
18 18
1,269
728
(9 studies)
(7 studies)
Total
Adapted
II
Pathogens of Vaginal the Past Two Decades
Spp.
GIAQUINTA,
Odds.’6
these species in recurrent vaginal candidiasis is corroborated by Kuwabara and Sugiura,32 who in 1980 reported that C. glabrata isolation among 315 women with intractable vaginal mycoses was as high as 30.5%. In 1986, Takada et al.3#{176} reported a C. glabrata detection rate of 22.7% among primary cases of vaginal candidiasis and 17.7% among relapsing cases.3#{176} In 1981, Goldacre et al.’5 reported a 27.7% incidence of non-albicans infections among 311 unselected women who attended a family planning clinic, with the majority of these infections due to C. glabrata. They also noted that these fungi were significantly more common in women of at least 35 years of age, however, and particularly in those who used the diaphragm with contraceptive jelly as a form of contraception. Although the association with age is not confirmed,4 it has been reported that spermicidal jellies and creams increase the susceptibility to vaginal candidiasis by upsetting the ecological balance of vaginal microfiora and by increasing adhesion of Candida spp to epithelial tissues.33 The recalcitrance of vaginal candidiasis due to C. tropicaiis infection was confirmed by Horowitz et al.,34 who reported that the recurrence rate for C. tropicaiis (33%) was twice that for C. aibicans (16%) after treatment. THEORIES INCIDENCE
ON THE CAUSE OF NON-ALBICANS
OF
INCREASED INFECTIONS
Two possibly related explanations for the increased incidence of non-albicans, particularly in recurrent or relapsing cases, are (1) currently used drugs are not effectively eradicating these pathogens, and (2) using the shorter courses of existing imidazole thera-
250
#{149} .1 Clin Pharmacol
1992;32:248-255
AND
ITO
pies for vaginal candidiasis have allowed overgrowth of less susceptible pathogens. Support for the theory that currently used drugs do not effectively eradicate these pathogens comes from in vitro and in vivo studies of commonly used antifungals. In
Vitro
Studies
In
vitro
comparative
studies
of
antifungal
agents
have shown that the standard imidazole antifungals miconazole, clotrimazole, and butoconazole are not as active against C. glabrata and C. tropicalis as against C. albicans.35 Takada et al.36 reported that the minimum inhibitory concentration of imidazole antimycotics, including econazole, miconazole, and clotrimazole, against C. glabi-ata was two to four times higher than that against C. albicans isolates. In
Vivo
Studies
Although in vitro data are not always comparable to in vivo data16 for many agents, including antifungals, recent clinical data confirm the higher resistance of non-albicans yeasts to standard antimycotic agents. Decreased in vitro sensitivity of C. glabrata to dotrimazole and ketoconazole was reported by Pawlik et al.37 in conjunction with low clinical usefulness in his cohort. Although Takada et al.3#{176} did not find decreased in vitro sensitivity of C. glabrata with clotrimazole, they did report that vaginal infections with this yeast were more highly resistant to clotrimazole treatment than were those with C. albicans. In addition, Horowitz et al.34 found that among six recurrent cases of C. tropicalis, preparations such as miconazole, clotrimazole, ketoconazole, nystatin, and amphotericin-B were unsuccessful in eradicating infection. According to Kerridge and Nicholas,38 it is difficult to obtain strains of C. albicans that are resistant to the imidazole antifungals, but some C. glabrata strains have been found to be less susceptible to miconazole. They note that C. glabrata is haploid and therefore the frequency with which drug-resistant strains might be expected to occur will be higher than that for diploid yeasts, such as C. aibicans. Further, the work of Horowitz et al.34 and Merz and Sanford39 showed that C. tropicalis has the ability to forego the 14-alpha demethylation pathway in its cell wall, thus making this organism less susceptible to imidazole and polyene compounds. Obviously, this reduced susceptibility plications for patients
such
infections.
will undergoing
have drug
important therapy
imfor
PATHOGENS
IN VULVOVAGINAL
Support for the theory that using shorter courses of existing imidazole therapies for vaginal candidiasis have allowed overgrowth of more resistant pathogens can be drawn from the history of such infections in neutropenic patients. The emergence of increased numbers of systemic infections in these patients due to C. glabrato, C. tropicalis, and other non-albicans prolonged
species low-dose
is related prophylactic
to the
routine antifungal
use of regi-
mens with polyenes and imidazoles to prevent oral candidiasis or septicemia due to C. albicans.402 Cauwenbergh29 asserts that a similar pattern may exist in the treatment of vaginal candidiasis. That is, subtherapeutic doses of antifungal agents may be facilitating the overgrowth of non-albicans species, which are not adequately eradicated with currently prescribed therapies. Antifungal regimens for vaginal candidiasis have become dramatically shortened over the past two decades in an effort to increase patient compliance. Thus, the original 14-day regimen with the older imidazoles has been shortened to 3-day courses as the norm, and even a 1-day course is available, although the efficacy of that regimen has yet to be consistently demonstrated.16 Although the shorter 3-day regimen is preferred by patients, trade-off for compliance has reduced efficacy. After an analysis of data from large numbers of published trials, however, Odds43 confirmed that treatment duration of 2 weeks was superior to shorter courses in mycologic efficacy and in prevention of mycologic recurrence of vaginal yeasts. The likelihood of replacement of an initial pathogen with a less sensitive pathogen as a result of antimycotic
therapy
is
quite
expectable,
and
is
con-
firmed by the results of a recent study by Takada et al.3#{176} showing replacement of initial C. albicans vaginitis
with
with
clotrimazole.
C.
IMPLICATIONS
glabrata
vaginitis
in
patients
Although some physicians attempt to establish a diagnosis based on clinical features alone, such efforts are often doomed to fail because clinical symptoms of various vaginitides often can overlap, and even the most experienced clinician will misdiagnose.” Moreover, the fact that the clinical picture of C. giabrata vaginitis can be both similar45 and dissimilar46 from that of C. albicans vaginitis underscores the low reliance of clinical symptomatology as the sole foundation for making a diagnosis. Laboratory
Diagnosis
The finding of blastospores without pseudohyphae on potassium hydroxide microscopy is strongly indicative of infection with non-albicans species, such as C. glabrata” (Figures I and 2). Culture should always follow, however, for proper identification of the specific Candida species.47 Although many culturing techniques are available, Sabouraud medium may be the most reliable means for identifying Candida spp.48 Recently, a latex agglutination test for speciation of Candida4#{176} and a simple, quick electrophoretic method have been described.50 Treatment
Considerations
Because in vitro susceptibility of non-albicans species to various antifungals does not necessarily correlate with clinical response, clinicians are faced with a real treatment dilemma. This is emphasized by the known clinical resistance to treatment of these infections with the commonly used imidazoles. If, indeed, the selection of non-albicans species in vaginal candidiasis is partly the result of shortened antifungal regimens with the currently used imidaz-
treated V
FOR
PATIENT
CARE
Recurrent or recalcitrant vaginal candidiasis presents a diagnostic and therapeutic challenge to clinicians, a fact confirmed by the large numbers of women (25%) who do not respond to initial drug treatment Often, problems in diagnosis or complications in treatment are due to concurrent infection by two or more organisms or to treatment without specific identification of the infectious pathogen.” Therefore, establishing a diagnosis based on accurate identification of not only the causative pathogen, but its species as well, is becoming necessary for the appropriate diagnosis and treatment of this condition.
ANTI-INFECTIVE
CANDIDIASIS
AGENTS
o 0
0 0
1” 0
0
‘
0
Figure 1. Identification of C. albicans using phase contrast copy of vaginal scraping. Note extensive hyphal formation of this species.
microstypical
251
HOROWITZ,
GIAQUINTA,
AND
ITO
compared
with
and
with
cal
studies
safety
an
to
used
nitrate.
mg
side
evaluate
both
conazole
to 1,200
100
advantageous
for
imidazoles)55’56
effect
profile.55
terconazole’s
placebo
and
and
control,
mi-
a positive
Miconazole
nitrate
Clini-
efficacy
was
used,
be-
considered the “gold standard” of imidazole antifungal therapy. Seven-day regimens of terconazole 0.4% cream and miconazole nitrate 2.0% cream were compared in 449 patients, achieving clinical cure rates of 96% for terconazole versus 91.6% for miconazole; microcause
it was
biologic
tively Figure 2. Vaginal scraping; budding pseudohyphe using phase contrast tive of infection with non-albicans
ole antifungals, ules, effect
a return
with emphasis improvement
to longer
better
A
approach
effective using
would
be the
broad-spectrum
development
and
be particularly not have access speciation.
Recently, a new class of antifungal triazoles-was developed for both cal treatment of numerous mycoses.
topical
triazole
broad-spectrum vantage over
against the
dermatophytes
non-albicans
potency the
available
preparation, imidazoles
as well
species.51
Also,
is equal This
topia
the adeffective
against is clearly
shown in an early study by Van Cutsem and Thienpont,52 who reported that 10 times more miconazole was necessary to kill C. tropicalis and C. glabrata than to kill C. albicans. In a later study, Van Cutsem et al.53 and Troke et al.54 reported that the triazole antifungals were 10 to 100 times more potent in vitro than the imidazoles. The relevance of candidal speciation to drug potency was verified by these studies. In clinical trials, terconazole has shown excellent mycologic
and
for the results
imidazoles are obtained
252
J Clin Pharmacol
S
clinical
cure
rates
and polyenes.’6 with lower
1992;32:248-255
that
exceed
the
51
women
to the
small
sample
using
size
parallel group, placebo-controlled proximately 1,000 patients
terconazole produced
the
its in vitro
advantage
due
mine the efficacy One of the studies
including
to that
Of
tercon-
and
were
not
trials
involving
were conducted strength in a 3-day a positive control,
of this used
ap-
to deterregimen. 2.0% mi-
conazole nitrate cream in a 7-day regimen. The study design, inclusion and exclusion criteria, and evaluation methods for all studies were similar. In the combined analysis, both the 3-day regimen of
Being has
as yeasts,
of Candida.
C. albicans
non-albicans
is terconazole. terconazole of being highly
species
against
would
species.
compoundsoral and To date,
rates.
had a clinical cure, and 80.4% showed a cure. Sixty-one women used miconacure was reported as 93.4%, whereas cure was 88.4%. These differences are
significant. Recently, 0.8% terconazole was approved by the Food and Drug Administration for use as a 3-day regimen. Three multicenter, randomized, double-blind,
advantageous to laboratories
the
respec-
83.6%,
statistically
of
that
cure
probably
formula-
non-albicans
and
91.1%
=
azole, 92.2% microbiologic zole; clinical microbiologic
sched-
antifungal
administration
C. albicans
Such therapies would to clinicians who did that perform Candida
only
similar
to happen, however, bewith protracted drug regiand treatment costs would
short-term
both
without indica-
treatment
were
rates
1.02). Both parameters were measured 8 to 10 days after therapy. Studies comparing a 3-day regimen of 80-mg terconazole suppositories versus a 7-day regimen of 100 mg miconazole nitrate yielded
on patient compliance, might in cure rates. This treatment
turnaround is not likely cause patient compliance mens is notoriously low, increase.
more tions cover
or nonbudding yeasts microscopy is strongly species-C. glabrata.
cure (P
those
Moreover, these doses (20 to 80 mg
and clinical
were statistically is interesting to terconazole with
logic were days.
the 7-day regimen and microbiologic significantly note that, miconazole,
better
in the
of miconazole cure rates that than
placebo.
study
clinical
It
comparing
and
microbio-
cure rates between the two active regimens similar at 8 to 10 days, and again at 30 to 35 Onset
of action
as
measured
by
symptomatic
also similar. Of particular interest was the continued symptomatic improvement in terconazole patients on days 4 through 7, when active therapy had ceased. This is believed to be a result of terconazole remaining in the vaginal epithelium, at concentrations above the minimal inhibitory concentration relief
was
for many Candida tion of therapy.
species,
for
days
after
the
cessa-
Terconazole has been shown to be as safe as miconazole for both pregnant (2nd/3rd trimester) and nonpregnant women. A study of 1,089 nonpregnant patients
miconazole
receiving
nitrate
0.4%
terconazole
indicates
that
cream
the
or
incidence
2.0%
of
PATHOGENS
IN
VULVOVAGINAL
minor side effects is comparable between the two agents. Similar results were shown in comparisons between the two suppository regimens. Reported minor side effects included: general body pain, headaches, rhinorrhea, fever and chills, and genital irritation. Because candidiasis is very common in pregnant women, an additional study was performed in 224 pregnant (2nd and 3rd trimester) women. Terconazole’s safety in pregnancy was evidenced in an infant follow-up study in which no differences were seen in sex, birth weight, gestational age, or Apgar scores, between the terconazole-treated group and the expected norms of a non-terconazole-treated group. Terconazole provides prescription flexibility, being the only preparation available as a 3-day regimen in either suppository or cream. Because of its potency, broad-spectrum activity, and favorable side effect
profile,
better fective
alternative treatment
terconazole
to currently of vaginal
appears
to be
used agents candidiasis.
a new
and
in the
ef-
TABLE Comparative
Cost of Current
Product
Form
Vaginal
cream
2%
Clotrimazole (OTC as of 1/91)
Vaginal
cream
1%
500 mg vaginal Miconazole
nitrate
Vaginal
tablets
tablets 2%
100 mg vaginal
suppositories
mg vaginal
suppositories
200 Terconazole
cream
Vaginal
cream
0.4%
Vaginal
cream
0.8%
80 mg vaginal suppositories
*
February
1991
ANTI-INFECTIVE
IMPACT OF AVAILABILITY MICONAZOLE
OVER-THE-COUNTER OF CLOTRIMAZOLE ON NON-ALBICANS
AND PATHOGENS
The approval for over-the-counter sales of clotrimazole and miconazole rests heavily on the safety of the agents; the success of the therapy rests heavily on the ability of a woman to self-diagnose VC. Unfortunately, the diagnosis of Candida is difficult based on symptomatology alone. The OTC products should be used only by women who previously have been diagnosed with yeast infections and thus can recognize the symptoms. Still a legitimate concern exists that some patients may mistake bacterial vaginosis, trichomoniasis, or other sexually transmitted diseases, even cancer, for candidiasis. If candidiasis is difficult to diagnose, non-albicans candidiasis is impossible to differentiate without specific tests. Because there is no home test available to perform this speciation, it is possible that the more resistant C. tropicalis and C. glabrata will be allowed to prolifer-
Ill Vaginal
Antifungals57
RegImen
Butoconazole
100 mg vaginal
CANDIDIASIS
1 applicator 3 days h.s. 1 applicator 7-14 days h.s. 2 tablets 3 days h.s. or 1 tablet 7 days h.s. 1 tablet 1 day h.s. 1 applicator 7 days h.s. 1 suppository 7 days h.s. 1 suppository 3 days h.s. 1 applicator 7 days h.s. 1 applicator 3 days h.s. 1 suppository 3 days h.s.
RetaIl Cost to Pharmacy6
$15.34 $12.42 $13.14
$13.14 $10.98 $18.50 $20.15 $18.50 $17.75 Price to come $17.75
Redbook.
AGENTS
253
HOROWITZ,
GIAQUINTA,
ate in the absence of the eradicated C. albicans. It is interesting to note that in an attempt to save the expense and time required of a physician visit, patients are likely to waste the expense of medication that is inappropriate for their particular condition and may expose themselves to more recurrent and resistant disease, which can increase the ultimate cost of therapy. Cost The cost of care is an important issue in the treatment of any disease. It is important to note that the Red Book57 cost to pharmacies of all currently available azole antifungal agents, whether over the counter or prescription only, are all within a few dollars of each other (Table III). The slightly incremental cost of the broader-spectrum triazole will minimize the need for expensive speciation; the added efficacy compared with imidazoles is a further cost advantage for terconazole. DISCUSSION In this article, we have reviewed the current literature regarding the pathogenicity of VC. It is apparent from the literature that not only is the incidence of vulvovaginitis increasing faster than the corresponding increase in population, but a larger percentage of these infections is being caused by non-albicans species of Candida. Theoretically, this shift in pathogens has been the result of shortened antifungal therapies leading to a species selection. In vivo studies have shown that C. glabrata and C. tropicalis are more resistant to the imidazole therapies. Clinically, this lower susceptibility combined with the use of shorter treatment regimens may have allowed the non-albicans pathogens to flourish. This problem may be exacerbated by the as-needed use of the over-the-counter imidazoles. The development of the broad-spectrum triazole antifungal agents, however, specifically terconazole, may eliminate many of these concerns. In vivo studies have shown that terconazole 0.8% cream and 80 mg-suppository were as efficacious in 3-day regimens as was miconazole nitrate 100 mg-suppository or 2.0% cream in a 7-day regimen. This clinical evidence, combined with in vitro data that indicates that terconazole may be more efficacious in the treatment of non-albicans Candida, leads to the expectation that terconazole and future triazole agents probably will become the new standard for this common and often frustrating clinical problem.
254
5
J ClIn Pharmacol
1992;32:248-255
ITO
AND
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Odds
FC. Candida ed.
vaginal
FC,
and
1987;
25:53-66.
CE,
infection:
their
biotypes.
A Review
Candidiasis:
Balli#{232}re-Tindall,
Webster
Candida
yeasts
and
London:
Riley
VC,
Fisk
Significance
Eur
J Obstet
18. Van Heusden AM, Merjus JM: Chronic didiasis: easy to treat, difficult to cure. treatment with a new oral antifungant. 1990; 35:75-83. 19. Horowitz BJ, Edelstein Candido. Obstet Gynecol 20. nal
Calderson-Marquez candidiasis and
Rev
Infect
21. Buch with time.
Dis
1987;
JJ: Itraconazole
A, Christensen
natamycin Acta Obstet
SW, Uippman 1987; 69:883.
effect of treatment 9(Suppl 1):5143-5145.
the
and
Bibliogra-
1988.
PG: of
Epidemiology
numbers
of
Gynecol
of vaginal
Reprod
Biol
recurrent vaginal canResults of intermittent Eur J Obstet Gynecol L: Sexual in the
transmission treatment
of the sexual
ES: Treatment of vaginal and effect of treating the partner Gynecol Scand 1982;61:393-396.
of
of vagi-
partner.
candidiasis at the same
PATHOGENS
22. Bisschop MP, Merkus JM, Scheygrond of the male partner in vaginal candidiasis: ized control study. BrJ Obstet Gynaecol 23. Sobel JD. Recurrent vulvovaginal study of the efficacy of maintenance JMed
H, et al: Co-treatment a double-blind random1986; 93:79-81.
candidiasis: ketoconazole
a prospective therapy. N EngI
1986;315:1455.
24. Sobel JD: Pathophysiology of vulvovaginal prod Med 1989; 34:572-580. 25. Witkin SS: Inhibition of Candida-induced eration by antibody to Candida albicans. 1986; 68:696. 26. Rosedale N, Browne K: Hyposensitization of recurring vaginal candidiasis. Ann Allergy 27. Palacios HJ. Hypersensitivity vaginal moniliasis resistant 1976;
IN VULVOVAGINAL
to
J
candidiasis. lymphocyte Obstet
Re-
and Allergy
37:110.
28. De Bernardis F, Agatensi U, Ross 1K, Emerson GW, Uorenzini R, Sullivan PA, Cassone A: Evidence for a role for secreted asparate proteinase of Candida albicans in vulvovaginal candidiasis. J Infect Dis 1990;161:1276-1283. 29. Cauwenbergh G: Vaginal candidiasis: incidence and treatment of non-Candida Probl Obstet Gynecol Fertil 1990;8:241-245.
evolving albicans
trends infection.
30. Takada M, Kubota T, Hogaki M, et al: Attributes ganisms that contribute to recurrence and intractability mycosis. Acta Obstet Gynaecol Jpn 1986; 38:1125-1134. 31. Horowitz BJ: Candidiasis: Obstet Gynecol Fertil 1990;1 32. Kuwabara cosis. Obstet
speciation
and
therapy.
in the Curr
of microorof vaginal Curr
of intractable
Probi
vaginal
my-
33. McGroarty JA, Soboh F, Bruce AW, Reid C: The spermicidal compound nonoxynol-9 increases adhesion of Candida species human epithelial cells in vitro. Infect Immun 1990; 58:2005-2007.
to
34. Horowitz BJ, Edelstein SW, Uippman U: Candida tropicalis vulvovaginitis. Obstet Gynecol 1985; 66:229-232. 35. Rinaldi MG: The microbiology of terconazole: results of in vitro studies, in Sobel JD (ed): Clinical Perspectives: Terconazole, An Advance in Vulvovaginal Candidiasis Therapy. New York: BMI/McGraw-l-lill, 1988; 55-64. 36. Takada M, Kubota T, Hogaki M, et al: Attributes ganisms that contribute to recurrence and intractability mycosis. Nippon Sanka Fujinka Gakkai Zasshi
of microorof vaginal Jul 1986;
38(7):1125-1134.
Pawlik B, Uiber Z, Warzynska R: Diagnostic and clinical acteristics of mycostic vaginitis cause by Candida glabrata lopsis glabrata). Med Dosw Mikrobiol 1989;41:206-214. 37.
relapse
char(Toru-
with
antifungal
therapy.
a correct diagnosis 1988;158:986-988.
V, Lynch M, Schmitt C, Cook R, Sobel vaginitis: clinical aspects and suspectibility Obstet Gynecol 1990; 76:651-655.
46. Boquet-Jimenez E, San Crist#{243}balAA: Cytologic logic aspects of vaginal torulopsis. Acta Cytologica 334. 47. Weisberg Curr Probl
48. nal
M:
Obstet
The diagnostic Gynecol Fertil
Merkus JM, Bisschop candidiasis and the
vulvovaginitis.
JM, Stolte UM: The proper nature problem of recurrence. Obstet
of vagiGynecol
1985;40:493-504.
49. Evans EG, Lacey vaginal candidiasis: Eur I Obstet Gynecol
CJ, Carney evaluation
JA: Criteria for the diagnosis of a new latex agglutination Biol 1986; 22:365-371.
Reprod
50. Bruneau S, Guinet R: Rapid tant yeasts by electrophoretic Lett 1989;49:329-333. 51. Tolman E, Issacson J, Borgers M, Van den zole,
dilemma: yeast 1990; 8:238-240.
a
broad
spectrum
of test.
identification of medically imporprotein patterns. FEMS Microbial
D, Rosenthale M, McGuire JU, Van Cutsem Bossche H: Anticidal activities of terconaantimycotic.
Antimicrob
Agents
Che-
mother 1986; 29:986-991. 52. Van Cutsem JM, Thienpont D: Miconazole, a broad spectrum antimycotic agent with antibacterial activity. Chemotherapy 1972; 17:392-404. 53. Van Cutsem JM, Van Gerven F, Saman azole: a new broad-spectrum antifungal. 322-33
R, Janssen Chemotherapy
PA: Tercon1983:29:
1.
54. Troke PF: Efficacy of fluconazole in animal models of superficial and opportunistic systemic fungal infection, in Fromtling RA (ed): Recent Trends in the Discovery, Development, and Evaluation of Antifungal Agents;Proceedings of an International Telesymposium. Barcelona: Jr Prous Science Publishers, May 1987;
103-112.
1979;
57.
AGENTS
JD: to
and microbio1978; 22:331-
55. Hirsch HA: Clinical evaluation of terconazole: European rience. J Reprod Med 1989; 34(suppl):593-596. 56. Thomason JA: Clinical evaluation of terconazole: States experience. I fleprod Med 1989; 34(Suppl):597-601.
ANTI-INFECTIVE
R
of vulvovaginal
38. Kerridge D, Nicholas RO: Drug resistance in the opportunistic pathogens Candida aibicans and Candida glabroto. I Antimicrob Chemother 1986;18(suppl B):39-49. 39. Merz WG, Sanford GR: Isolation and characterization of a polyene-resistant variant of Candida tropicalis. J Clin Microbial 9:677-680.
Proc
4):24-48.
45. Redondo-Uopez Torulopsis glabrata antifungal agents.
Surv
3:233-237.
N, Sugiura K: Treatment Gynecol Ther 1980;41.
and
44. Kaufman RH: Establishing infection. Am J Obstet Gynecol
250.
as a cause of dermatologic typical therapy. Ann
91:539-543.
43. Odds FC: Cure Soc Med 1977;70(Suppl
in the management 1979;
40. Horn R, Wong B, Kiehn TE, Armstrong D: Fungemia in a cancer hospital: changing frequency, earlier onset, and results of therapy. Rev Infect Dis 1985; 7:646-655. 41. Meunier-Carpentier F, Kiehn JR, Armstrong D: Fungemia in the immunocompromised host: changing patterns, antigenemia. high mortality. Am I Med 1981;71:363-370. 42. Wingard JR, Merz WG, Saral R: Candida tropicalis: a major pathogen in immunocompromised patients. Ann Intern Med 1979;
prolifGynecol
CANDIDIASIS
Redbook
Update.
February
expeUnited
1991
255
Pathogens Implications
J. Horowitz,
Benson
Over utable
MD,
Diane
Giaquinta,
in Vulvovaginal for Patient PharmD
and
Susan
Care
Ito, PharmD
the past two decades, to yeasts other than
an increasing trend in the number of vaginal infections attribCandida albicans has emerged. Of these non-albicans species, C. tropicalis and C. glabrata appear to be the most important. The change in incidence pattern of yeast vaginitis can be expected to impact greatly on the treatment of this condition, because many currently used drug therapies (e.g., imidazoles) for C. albicans vaginitis do not adequately eradicate non-albicans species. A possible explanation for the recent increased selection of these species maybe the shortened antifungal therapies that have been introduced during the past decade. These 1- to 3-day regimens with the older imidazoles may suppress C. albicans, but create an imbalance of flora that facilitate an overgrowth of non-albicans species. The recognition of yeast speciation and the need for use of a broad-spectrum antifungal preparation that covers these organisms is now apparent.
T
he incidence of infections due to Candida has greatly increased over the past 30 years, and along with this has come an increased incidence of vulvovaginal candidiasis (VC).1 The widespread use of antibiotics during this time is one of the most probable explanations for the strong emergence of Candida vaginitis,1 because suppression of normal bacterial flora, which occurs during antimicrobial therapy, is required for this vaginal commensal to become
pathogenic.
Another contributory factor may be the introduction of oral contraceptives (OCs) in the 1960s. Because of their high estrogen content, early OCs were believed to predispose women to Candida overgrowth.2’3 The effect of OCs on the incidence of Candida is controversial, however, and more studies will be needed to confirm or deny the possible link between estrogen and candidiasis. Some reports indicate that the prevalence of Candida is higher among high-estrogen OC users, but the incidence of symptomatology is the same as for women using other forms of birth control.4-6 Other studies indicate that From the Department of Obstetrics and Gynecology (Dr. Horowitz), University of Connecticut, Farmington, Connecticut, Mt. Sinai and Hartford Hospitals (Dr. Horowitz), Hartford, Connecticut, Vaginitis Section (Dr. Horowitz), International Society for the Study of Vulvar Dis-
ease, Houston, Texas, Department of Pharmacy (Dr. Giaquinta), Blue Cross of California, and the Department of Clinical Pharmacy (Dr. Ito), Blue Cross of California. Address for reprints: Benson J. Horowitz, MD, SHE. 06105.
248
Medical
S
Associates,
J CIin Pharmacol
449
Farmington
1992;32:248-255
Avenue,
Hartford,
CT
the incidence is higher in OC users.7’8 More recent studies of low-estrogen OCs, however, show no increase in Candida vaginitis.9’10 Currently, in clinical terms, the increased incidence of vaginal candidiasis translates into 13 million cases yearly in the United States alone,11 and confers on this condition the dubious honor of competing with bacterial vaginosis for first place as the most common cause of vaginitis.1’12’13 Of the more than 150 species of Candida, there are only 10 that are considered important pathogens for humans (Table I). Of these, C. aIbi cans is the most frequent cause of VC, accounting for as much as 80% of cases.14 Other Candida species account cases,14 and it is these non-albicans
for the species
balance that
of will
be the focus of this review. Although not all women who harbor non-albicans yeasts intravaginally develop symptomatology,1516 there is unequivocal evidence that vaginal candidiasis is strongly associated with high concentrations of vaginal yeasts.17 PREVALENCE VULVOVAGINAL
OF
NON-ALBICANS CANDIDIASIS
SPECIES
IN
Until recently, if physicians cultured samples from their symptomatic patients, they could be satisfied that when the culture disclosed Candida species they would be able to prescribe an effective polyene (nystatin), or more recently, imidazole (clotrimazole, miconazole) antifungal. But the large number of re-
PATHOGENS
TABLE Clinically
Important
Candida
IN
VEJLVOVAGINAL
I Pathogens
in Humans
C.aibi cans C. guilliermondi C. krusei
parapsilosis C. stellatoidea
C.
(now
included
C. tropicalis C. pseudotropicalis C. Iusitaniae C. rugosa C. glabrata (also classified
within
C. albicans)
as Torulopsis
glabrata)4
* There is ongoing debate about the correct genus of this yeast. Some mycologists no longer use the genus Torulopsis and have expanded the genus Candida to include Torulopsis, which is a yeast that does not produce true hyphae and/or pseudohyphae. Other mycologists strongly object to this assimilation and urge that the separation between the two yeasts be conserved. According to Odds, merging of the two species eliminates some clinical confusion, and the morphological distinction between the two is still easy to make in the mycology lab (Odds FC. Candida and candidosis: a review and bibliography, 2 ad. London: Balliere
Tindall,
1988:8-9).
calcitrant cases of vaginal candidiasis that currently occur in clinical practice have led investigators to search for causes. Investigation into the pathogenesis of recurrent and chronic candidal vaginitis have delineated reinfection and relapse as the two leading potential causes.18 Looking at reinfection from a persistent extravaginal source, O’Connor and Sobel14 found sexual transmission to be a possible source and reported simultaneous identical Candida strains in the sex partner of almost 48% of the women with recurrent VC. In addition, further evidence by O’Connor and Sobel14 and Horowitz et al.19 indicates that oral-genital transmission of Candida also may play a role in recurrent cases, because higher oral Candida colonization rates have been found in male partners of women with recurrent infection. Despite these findings, the role of sexual transmission in recurrent VC is still unclear, because it does not explain most recurrences. Further, three controlled studies have found that the treatment of male partners does not prevent recurrence in women.20-22 The possibility of reinfection from an intestinal reservoir also has been intensively studied. Despite the fact that women with recurrent VC are more likely to be culture positive at multiple extravaginal sites than women without VC,19 many studies have failed to find an association between recurrent vaginal candidiasis and intestinal yeast carriage14’23 or conversely, persistent intestinal yeast carriage and vaginal colonization.24
ANTI-INFECTIVE
AGENTS
CANDIDIASIS
Relapse is another possible cause of recurrent infection. Relapse of the original infection has usually been thought of as the result of inadequate therapy or a pathogen that is less susceptible to the drug used.18 Although a high degree of yeast eradication does take place with currently used antifungals, clinical efficacy rates are not as high as in vitro efficacy rates. Therefore, relapse due to initial treatment failure can be expected in a sizable number of women. According to Odds,16 approximately 15 to 20% of women who are culture negative after treatment will become culture-positive within I to 3 months after treatment discontinuation. O’Connor and Sobel14 reported that when clinical recurrence occurred later than 3 months after the previous episode, the likelihood was great that a different strain of Candida from that of the prior infection would be isolated. In addition to the well-known risk factors for vaginal candidiasis that can contribute to recurrence or relapse, other mechanisms that have been investigated include the following: (1) host immunologic factors such as Candida-antigen-specific deficiency in T-lymphocyte function,25 (2) acquired hypersensitivity reaction to Candida antigen,26’27 (3) deficiencies in normal protective vaginal flora that permit unsuppressed colonization,24 and (4) virulence factors such as secretory proteinase.28 Changes
in Causative
Pathogens
In searching for explanations, other than host factors, for the number of recurrent or recalcitrant infections, investigators have most recently focused on the incidence of non-albicans species as the cause of recurrent cases.293#{176} This research has identified a gradual increase in incidence of infections due to these species, particularly C. tropicalis and C. glabrata (formerly known as Torulopsis glabrata). Candida parapsilosis has also recently emerged as a factor.31 A review of nine studies during the 1970s involving 1,269 isolates disclosed a 9.9% incidence of non-albicans among women with VC.16’29 A further review of seven studies from the 1980s involving 728 isolates, however, showed an incidence of 21.3%. Thus, there has been more than a doubling (11.4% increase) in the incidence of non-albicans infections from the 1970s to the 1980s (Table II).16,29 Further evidence for this increase in non-albicans species is offered by Takada et al.,3#{176} who reviewed the prevalence of C. glabrata infections between 1960 and 1983 and found that the C. glabrata detection rate had indeed increased in women with vaginal candidiasis. The significance of the increased emergence of
249
HOROWITZ,
TABLE Shift
In Causative During
ClInical Isolates
C. aibicans C. glabrata C. krusei C. parapsilosis C. tropicalis Other Candida
Isolates
%
1970-79
Total
1,143
90.1
from
Isolates 1980-89 573
Candidiasis %
%
Total
Change
78.7
-11.4
1.4
49 12
6.7 1.7
+2.1 +0.2
17
1.4 1.3
9 60
1.2 8.2
-0.2 +6.9
14
1.1
25
3.4
+2.3
59
4.6
18 18
1,269
728
(9 studies)
(7 studies)
Total
Adapted
II
Pathogens of Vaginal the Past Two Decades
Spp.
GIAQUINTA,
Odds.’6
these species in recurrent vaginal candidiasis is corroborated by Kuwabara and Sugiura,32 who in 1980 reported that C. glabrata isolation among 315 women with intractable vaginal mycoses was as high as 30.5%. In 1986, Takada et al.3#{176} reported a C. glabrata detection rate of 22.7% among primary cases of vaginal candidiasis and 17.7% among relapsing cases.3#{176} In 1981, Goldacre et al.’5 reported a 27.7% incidence of non-albicans infections among 311 unselected women who attended a family planning clinic, with the majority of these infections due to C. glabrata. They also noted that these fungi were significantly more common in women of at least 35 years of age, however, and particularly in those who used the diaphragm with contraceptive jelly as a form of contraception. Although the association with age is not confirmed,4 it has been reported that spermicidal jellies and creams increase the susceptibility to vaginal candidiasis by upsetting the ecological balance of vaginal microfiora and by increasing adhesion of Candida spp to epithelial tissues.33 The recalcitrance of vaginal candidiasis due to C. tropicaiis infection was confirmed by Horowitz et al.,34 who reported that the recurrence rate for C. tropicaiis (33%) was twice that for C. aibicans (16%) after treatment. THEORIES INCIDENCE
ON THE CAUSE OF NON-ALBICANS
OF
INCREASED INFECTIONS
Two possibly related explanations for the increased incidence of non-albicans, particularly in recurrent or relapsing cases, are (1) currently used drugs are not effectively eradicating these pathogens, and (2) using the shorter courses of existing imidazole thera-
250
#{149} .1 Clin Pharmacol
1992;32:248-255
AND
ITO
pies for vaginal candidiasis have allowed overgrowth of less susceptible pathogens. Support for the theory that currently used drugs do not effectively eradicate these pathogens comes from in vitro and in vivo studies of commonly used antifungals. In
Vitro
Studies
In
vitro
comparative
studies
of
antifungal
agents
have shown that the standard imidazole antifungals miconazole, clotrimazole, and butoconazole are not as active against C. glabrata and C. tropicalis as against C. albicans.35 Takada et al.36 reported that the minimum inhibitory concentration of imidazole antimycotics, including econazole, miconazole, and clotrimazole, against C. glabi-ata was two to four times higher than that against C. albicans isolates. In
Vivo
Studies
Although in vitro data are not always comparable to in vivo data16 for many agents, including antifungals, recent clinical data confirm the higher resistance of non-albicans yeasts to standard antimycotic agents. Decreased in vitro sensitivity of C. glabrata to dotrimazole and ketoconazole was reported by Pawlik et al.37 in conjunction with low clinical usefulness in his cohort. Although Takada et al.3#{176} did not find decreased in vitro sensitivity of C. glabrata with clotrimazole, they did report that vaginal infections with this yeast were more highly resistant to clotrimazole treatment than were those with C. albicans. In addition, Horowitz et al.34 found that among six recurrent cases of C. tropicalis, preparations such as miconazole, clotrimazole, ketoconazole, nystatin, and amphotericin-B were unsuccessful in eradicating infection. According to Kerridge and Nicholas,38 it is difficult to obtain strains of C. albicans that are resistant to the imidazole antifungals, but some C. glabrata strains have been found to be less susceptible to miconazole. They note that C. glabrata is haploid and therefore the frequency with which drug-resistant strains might be expected to occur will be higher than that for diploid yeasts, such as C. aibicans. Further, the work of Horowitz et al.34 and Merz and Sanford39 showed that C. tropicalis has the ability to forego the 14-alpha demethylation pathway in its cell wall, thus making this organism less susceptible to imidazole and polyene compounds. Obviously, this reduced susceptibility plications for patients
such
infections.
will undergoing
have drug
important therapy
imfor
PATHOGENS
IN VULVOVAGINAL
Support for the theory that using shorter courses of existing imidazole therapies for vaginal candidiasis have allowed overgrowth of more resistant pathogens can be drawn from the history of such infections in neutropenic patients. The emergence of increased numbers of systemic infections in these patients due to C. glabrato, C. tropicalis, and other non-albicans prolonged
species low-dose
is related prophylactic
to the
routine antifungal
use of regi-
mens with polyenes and imidazoles to prevent oral candidiasis or septicemia due to C. albicans.402 Cauwenbergh29 asserts that a similar pattern may exist in the treatment of vaginal candidiasis. That is, subtherapeutic doses of antifungal agents may be facilitating the overgrowth of non-albicans species, which are not adequately eradicated with currently prescribed therapies. Antifungal regimens for vaginal candidiasis have become dramatically shortened over the past two decades in an effort to increase patient compliance. Thus, the original 14-day regimen with the older imidazoles has been shortened to 3-day courses as the norm, and even a 1-day course is available, although the efficacy of that regimen has yet to be consistently demonstrated.16 Although the shorter 3-day regimen is preferred by patients, trade-off for compliance has reduced efficacy. After an analysis of data from large numbers of published trials, however, Odds43 confirmed that treatment duration of 2 weeks was superior to shorter courses in mycologic efficacy and in prevention of mycologic recurrence of vaginal yeasts. The likelihood of replacement of an initial pathogen with a less sensitive pathogen as a result of antimycotic
therapy
is
quite
expectable,
and
is
con-
firmed by the results of a recent study by Takada et al.3#{176} showing replacement of initial C. albicans vaginitis
with
with
clotrimazole.
C.
IMPLICATIONS
glabrata
vaginitis
in
patients
Although some physicians attempt to establish a diagnosis based on clinical features alone, such efforts are often doomed to fail because clinical symptoms of various vaginitides often can overlap, and even the most experienced clinician will misdiagnose.” Moreover, the fact that the clinical picture of C. giabrata vaginitis can be both similar45 and dissimilar46 from that of C. albicans vaginitis underscores the low reliance of clinical symptomatology as the sole foundation for making a diagnosis. Laboratory
Diagnosis
The finding of blastospores without pseudohyphae on potassium hydroxide microscopy is strongly indicative of infection with non-albicans species, such as C. glabrata” (Figures I and 2). Culture should always follow, however, for proper identification of the specific Candida species.47 Although many culturing techniques are available, Sabouraud medium may be the most reliable means for identifying Candida spp.48 Recently, a latex agglutination test for speciation of Candida4#{176} and a simple, quick electrophoretic method have been described.50 Treatment
Considerations
Because in vitro susceptibility of non-albicans species to various antifungals does not necessarily correlate with clinical response, clinicians are faced with a real treatment dilemma. This is emphasized by the known clinical resistance to treatment of these infections with the commonly used imidazoles. If, indeed, the selection of non-albicans species in vaginal candidiasis is partly the result of shortened antifungal regimens with the currently used imidaz-
treated V
FOR
PATIENT
CARE
Recurrent or recalcitrant vaginal candidiasis presents a diagnostic and therapeutic challenge to clinicians, a fact confirmed by the large numbers of women (25%) who do not respond to initial drug treatment Often, problems in diagnosis or complications in treatment are due to concurrent infection by two or more organisms or to treatment without specific identification of the infectious pathogen.” Therefore, establishing a diagnosis based on accurate identification of not only the causative pathogen, but its species as well, is becoming necessary for the appropriate diagnosis and treatment of this condition.
ANTI-INFECTIVE
CANDIDIASIS
AGENTS
o 0
0 0
1” 0
0
‘
0
Figure 1. Identification of C. albicans using phase contrast copy of vaginal scraping. Note extensive hyphal formation of this species.
microstypical
251
HOROWITZ,
GIAQUINTA,
AND
ITO
compared
with
and
with
cal
studies
safety
an
to
used
nitrate.
mg
side
evaluate
both
conazole
to 1,200
100
advantageous
for
imidazoles)55’56
effect
profile.55
terconazole’s
placebo
and
and
control,
mi-
a positive
Miconazole
nitrate
Clini-
efficacy
was
used,
be-
considered the “gold standard” of imidazole antifungal therapy. Seven-day regimens of terconazole 0.4% cream and miconazole nitrate 2.0% cream were compared in 449 patients, achieving clinical cure rates of 96% for terconazole versus 91.6% for miconazole; microcause
it was
biologic
tively Figure 2. Vaginal scraping; budding pseudohyphe using phase contrast tive of infection with non-albicans
ole antifungals, ules, effect
a return
with emphasis improvement
to longer
better
A
approach
effective using
would
be the
broad-spectrum
development
and
be particularly not have access speciation.
Recently, a new class of antifungal triazoles-was developed for both cal treatment of numerous mycoses.
topical
triazole
broad-spectrum vantage over
against the
dermatophytes
non-albicans
potency the
available
preparation, imidazoles
as well
species.51
Also,
is equal This
topia
the adeffective
against is clearly
shown in an early study by Van Cutsem and Thienpont,52 who reported that 10 times more miconazole was necessary to kill C. tropicalis and C. glabrata than to kill C. albicans. In a later study, Van Cutsem et al.53 and Troke et al.54 reported that the triazole antifungals were 10 to 100 times more potent in vitro than the imidazoles. The relevance of candidal speciation to drug potency was verified by these studies. In clinical trials, terconazole has shown excellent mycologic
and
for the results
imidazoles are obtained
252
J Clin Pharmacol
S
clinical
cure
rates
and polyenes.’6 with lower
1992;32:248-255
that
exceed
the
51
women
to the
small
sample
using
size
parallel group, placebo-controlled proximately 1,000 patients
terconazole produced
the
its in vitro
advantage
due
mine the efficacy One of the studies
including
to that
Of
tercon-
and
were
not
trials
involving
were conducted strength in a 3-day a positive control,
of this used
ap-
to deterregimen. 2.0% mi-
conazole nitrate cream in a 7-day regimen. The study design, inclusion and exclusion criteria, and evaluation methods for all studies were similar. In the combined analysis, both the 3-day regimen of
Being has
as yeasts,
of Candida.
C. albicans
non-albicans
is terconazole. terconazole of being highly
species
against
would
species.
compoundsoral and To date,
rates.
had a clinical cure, and 80.4% showed a cure. Sixty-one women used miconacure was reported as 93.4%, whereas cure was 88.4%. These differences are
significant. Recently, 0.8% terconazole was approved by the Food and Drug Administration for use as a 3-day regimen. Three multicenter, randomized, double-blind,
advantageous to laboratories
the
respec-
83.6%,
statistically
of
that
cure
probably
formula-
non-albicans
and
91.1%
=
azole, 92.2% microbiologic zole; clinical microbiologic
sched-
antifungal
administration
C. albicans
Such therapies would to clinicians who did that perform Candida
only
similar
to happen, however, bewith protracted drug regiand treatment costs would
short-term
both
without indica-
treatment
were
rates
1.02). Both parameters were measured 8 to 10 days after therapy. Studies comparing a 3-day regimen of 80-mg terconazole suppositories versus a 7-day regimen of 100 mg miconazole nitrate yielded
on patient compliance, might in cure rates. This treatment
turnaround is not likely cause patient compliance mens is notoriously low, increase.
more tions cover
or nonbudding yeasts microscopy is strongly species-C. glabrata.
cure (P
those
Moreover, these doses (20 to 80 mg
and clinical
were statistically is interesting to terconazole with
logic were days.
the 7-day regimen and microbiologic significantly note that, miconazole,
better
in the
of miconazole cure rates that than
placebo.
study
clinical
It
comparing
and
microbio-
cure rates between the two active regimens similar at 8 to 10 days, and again at 30 to 35 Onset
of action
as
measured
by
symptomatic
also similar. Of particular interest was the continued symptomatic improvement in terconazole patients on days 4 through 7, when active therapy had ceased. This is believed to be a result of terconazole remaining in the vaginal epithelium, at concentrations above the minimal inhibitory concentration relief
was
for many Candida tion of therapy.
species,
for
days
after
the
cessa-
Terconazole has been shown to be as safe as miconazole for both pregnant (2nd/3rd trimester) and nonpregnant women. A study of 1,089 nonpregnant patients
miconazole
receiving
nitrate
0.4%
terconazole
indicates
that
cream
the
or
incidence
2.0%
of
PATHOGENS
IN
VULVOVAGINAL
minor side effects is comparable between the two agents. Similar results were shown in comparisons between the two suppository regimens. Reported minor side effects included: general body pain, headaches, rhinorrhea, fever and chills, and genital irritation. Because candidiasis is very common in pregnant women, an additional study was performed in 224 pregnant (2nd and 3rd trimester) women. Terconazole’s safety in pregnancy was evidenced in an infant follow-up study in which no differences were seen in sex, birth weight, gestational age, or Apgar scores, between the terconazole-treated group and the expected norms of a non-terconazole-treated group. Terconazole provides prescription flexibility, being the only preparation available as a 3-day regimen in either suppository or cream. Because of its potency, broad-spectrum activity, and favorable side effect
profile,
better fective
alternative treatment
terconazole
to currently of vaginal
appears
to be
used agents candidiasis.
a new
and
in the
ef-
TABLE Comparative
Cost of Current
Product
Form
Vaginal
cream
2%
Clotrimazole (OTC as of 1/91)
Vaginal
cream
1%
500 mg vaginal Miconazole
nitrate
Vaginal
tablets
tablets 2%
100 mg vaginal
suppositories
mg vaginal
suppositories
200 Terconazole
cream
Vaginal
cream
0.4%
Vaginal
cream
0.8%
80 mg vaginal suppositories
*
February
1991
ANTI-INFECTIVE
IMPACT OF AVAILABILITY MICONAZOLE
OVER-THE-COUNTER OF CLOTRIMAZOLE ON NON-ALBICANS
AND PATHOGENS
The approval for over-the-counter sales of clotrimazole and miconazole rests heavily on the safety of the agents; the success of the therapy rests heavily on the ability of a woman to self-diagnose VC. Unfortunately, the diagnosis of Candida is difficult based on symptomatology alone. The OTC products should be used only by women who previously have been diagnosed with yeast infections and thus can recognize the symptoms. Still a legitimate concern exists that some patients may mistake bacterial vaginosis, trichomoniasis, or other sexually transmitted diseases, even cancer, for candidiasis. If candidiasis is difficult to diagnose, non-albicans candidiasis is impossible to differentiate without specific tests. Because there is no home test available to perform this speciation, it is possible that the more resistant C. tropicalis and C. glabrata will be allowed to prolifer-
Ill Vaginal
Antifungals57
RegImen
Butoconazole
100 mg vaginal
CANDIDIASIS
1 applicator 3 days h.s. 1 applicator 7-14 days h.s. 2 tablets 3 days h.s. or 1 tablet 7 days h.s. 1 tablet 1 day h.s. 1 applicator 7 days h.s. 1 suppository 7 days h.s. 1 suppository 3 days h.s. 1 applicator 7 days h.s. 1 applicator 3 days h.s. 1 suppository 3 days h.s.
RetaIl Cost to Pharmacy6
$15.34 $12.42 $13.14
$13.14 $10.98 $18.50 $20.15 $18.50 $17.75 Price to come $17.75
Redbook.
AGENTS
253
HOROWITZ,
GIAQUINTA,
ate in the absence of the eradicated C. albicans. It is interesting to note that in an attempt to save the expense and time required of a physician visit, patients are likely to waste the expense of medication that is inappropriate for their particular condition and may expose themselves to more recurrent and resistant disease, which can increase the ultimate cost of therapy. Cost The cost of care is an important issue in the treatment of any disease. It is important to note that the Red Book57 cost to pharmacies of all currently available azole antifungal agents, whether over the counter or prescription only, are all within a few dollars of each other (Table III). The slightly incremental cost of the broader-spectrum triazole will minimize the need for expensive speciation; the added efficacy compared with imidazoles is a further cost advantage for terconazole. DISCUSSION In this article, we have reviewed the current literature regarding the pathogenicity of VC. It is apparent from the literature that not only is the incidence of vulvovaginitis increasing faster than the corresponding increase in population, but a larger percentage of these infections is being caused by non-albicans species of Candida. Theoretically, this shift in pathogens has been the result of shortened antifungal therapies leading to a species selection. In vivo studies have shown that C. glabrata and C. tropicalis are more resistant to the imidazole therapies. Clinically, this lower susceptibility combined with the use of shorter treatment regimens may have allowed the non-albicans pathogens to flourish. This problem may be exacerbated by the as-needed use of the over-the-counter imidazoles. The development of the broad-spectrum triazole antifungal agents, however, specifically terconazole, may eliminate many of these concerns. In vivo studies have shown that terconazole 0.8% cream and 80 mg-suppository were as efficacious in 3-day regimens as was miconazole nitrate 100 mg-suppository or 2.0% cream in a 7-day regimen. This clinical evidence, combined with in vitro data that indicates that terconazole may be more efficacious in the treatment of non-albicans Candida, leads to the expectation that terconazole and future triazole agents probably will become the new standard for this common and often frustrating clinical problem.
254
5
J ClIn Pharmacol
1992;32:248-255
ITO
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255
