Candida glabrata (or C. glabrata) is a yeast that belongs to Candida family. It was earlier called Torulopsis glabrata or Cryptococcus glabratus and only in 1980s was it named Candida glabrata and was included as a member of the Candida family.
Like other Candida species, C. glabrata is also a part of our normal microflora – it is therefore present in healthy people. It normally lives in human intestines without causing any harm. It is considered to be an opportunistic pathogen – an organism that is normally harmless, but causes disease when it gets an opportunity! This opportunity usually comes when the immunity of the host is somehow compromised.
In the last three decades, infections due to C. glabrata have increased – this was reported by Diekema and colleagues from USA in 2012. C. glabrata is described as currently ranking second in causing Candida infections.
DNA studies done in 1998 on C. glabrata by Kurtzman and Robnett from USA showed that it was more closely related to the baker’s yeast (Saccharomyces cerevisiae) than to Candida albicans. However, unlike baker’s yeast, it is more evolved and can live in- and cause infection in humans – Vale-Silva and Sanglard describe this in their 2015 review article. They describe how the special molecules on its surface called adhesins allow it to adhere to our cells, how it can survive our immune system and can replicate within our macrophages (type of white blood cells that engulf and digest foreign substances, microbes, etc.), and how it is also able to survive by restricting environmental stresses in various ways within the body. They also provide evidence that although Candida albicans ranks first in causing candida infections, C. glabrata is more resistant to treatment with antifungal agents. It is also found that this organism develops resistance to antifungal agents much more easily. It is likely that extensive use of antifungal therapy has led to the evolution of resistance to antifungals in C. glabrata, and consequently an increase in infections caused by it.
Drug-resistance by reorganizing chromosomes!
We know that most organisms gain drug resistance through mutations – as the mutant survives better, it proliferates. However, the way that Candida glabrata accumulates drug resistance is quite different. In 2009, an interesting report from the Swedish lab of Piskur described how, instead of just changing its DNA through mutation, this yeast can reorganize its chromosomes and make extra copies of large chromosome pieces to adapt and become more resistant to antifungal medicines. So, essentially what happens is that if there is high amount of a certain drug in the environment (here the human body), C. glabrata increases the number of drug resistance genes by duplicating the chromosomes. The reverse is also true – when there is less amount of a certain drug, the extra copies of chromosome that give resistance against this drug are lost.
Infections caused by C. glabrata
In the recent times, C. glabrata has emerged as an important hospital-acquired (nosocomial) pathogen. This means that people who are admitted to the hospital are at a higher risk for getting C. glabrata infections. Apart from this, there is also a rise in the number of non-nosocomial vulvovaginal infections (complicated vulvovaginal candidiasis and recurrent vulvovaginal candidiasis) caused by this organism due to the overuse of antifungal antibiotics.
Let us look at the different kinds of infection it has been found to cause.
C. glabrata can cause infection of the mucosa (inner lining of mouth, esophagus, vagina, or urinary tract) as well as severe, life-threatening invasive candidiasis (spreading throughout the body and infecting different organs in the body). It can cause these infections either on its own or cause mixed infections along with other Candida species like C. albicans and C. tropicalis.
According to research by Farmakotis and colleagues from USA, published in 2014 by CDC, C. glabrata can often cause blood stream infections in cancer patients due to presence of in-dwelling catheters, abdominal surgery, use of chemotherapy, intravenous feeding, antibacterial drugs, and corticosteroids. Choi and colleagues from S. Korea reported with their 2009 study on a single hospital that blood stream infections with this organism were also a high risk in hospitalized patients who had poor kidney function (renal insufficiency) or who had prior treatments with fluconazaole.
Yu and Zeng from China described in their 2016 article how C. glabrata can also cause fungal infection of the lung after kidney transplantation, although C. albicans is the most common culprit in these cases.
C. glabrata can not only cause infection in adults with low immunity, but also in newborns who are born prematurely and do not have a fully formed immune system. A study from 2016 by Benjamin and coworkers from Matinique reported that preterm newborns, who weighed less than 1.5kg and were admitted to the intensive care unit for newborns, were also at a risk of getting hospital acquired fungal infections. Of these, 5% infections were caused by C. glabrata. The newborns who got intravenous feeding or antifungal agents were more likely to get infected.
In rare cases, this yeast can cause recurrent arthritis as was found in a 40-year-old man by Erami and colleagues from Iran in 2014. They were only able to diagnose this by testing the knee fluid using specialized fungal detection systems. Treatment of C. glabrata treated the recurrent arthritis as well.
Routes of entering the host tissues
That C. glabrata is so good at sticking by the virtue of the adhesion molecules, makes it especially good at making biofilms on surfaces of medical equipment and devices like catheters. This is one way that it can enter our tissues – through medical equipment and devices.
It must be noted that, unlike other Candida species, C. glabrata does not form the invasive hyphal (filamentous) structures that hold on to and invade the epithelial tissues. It is not surprising, therefore, that the damage caused to the epithelial tissues is much less than that caused by Candida albicans. Instead it makes use of adhesion molecules to bind to our cells. It also manages to enter the cells and cross the epithelial barrier without destroying the epithelial cells as has been evidenced from animal and cell studies (reviewed by Vale-Silva and Sanglard in their review article). How it performs this feat is yet unknown.
Additionally, studies in mice have found that C. glabrata can stay in the system without causing a huge immune response or causing severe disease. This was described in a 2010 report by Jacobsen and colleagues from Germany, France and Austria working in collaboration. Thus, this organism seems to be a stealthy attacker – it can lurk around in the body until the conditions are most suitable for it to strike and cause disease.
C. glabrata is commonly found along with C. albicans in oropharyngeal candidiasis. A 2016 article from the Edgerton lab in USA reported their studies on mice where they found that C. glabrata is unable to infect the oral cavity by itself. But when C. albicans is present, it can colonize well. Their experiments revealed that C. glabrata bound to the fibrous hyphae of C. albicans and piggy-backed on these hyphae to establish infection.
The causes for C. glabrata infections are the same as those for C. albicans infection. However, except for vulvovaginal infections, most other C. glabrata infections are hospital acquired. The leading causes of this infection are:
- Dysbiosis: Frequent use of antibiotics and consequent disturbance of normal flora leads to establishment of glabrata infections.
- Frequent use of antifungals: Due to its special ability to quickly become resistant to the antifungal in the environment, frequent use of antifungals makes it easier for this organism to gain hold in the body.
- Lowered immunity: There is a basic need for reduced immunity for C. glabrata to establish infection. So, any reason that leads to reduced immunity like HIV infection, diabetes, immunosuppression due to cancer therapy, treatment with immunosuppressant drugs for organ/tissue transplant, corticosteroid treatment etc. Naturally lowered immunity as in the case of old people or premature infants could also make them susceptible to these infections.
- Barrier disruption: Mechanical injury due to surgery, catheterization, intravenous feeding, injury during sex etc. can lead to this organism getting easy entry into the tissues.
- Biofilms on hospital equipment or on dentures are a common cause of C. glabrata infections. Biofilms are especially difficult to remove. Catheters are in general susceptible to colonization on the inside because of repeated manipulation of catheters and repeated infusions. Microbes, including Candida glabrata can form biofilms on the surface and the insides of the catheters. Although catheters are coated with antimicrobial coatings, as Raad and colleagues from USA showed with their work (published in 2008), the effect of these is only limited to a few weeks. Catheters are therefore a very big factor for biofilm related infections of C. glabrata.
- Contraceptive usage: By increasing estrogen (oral contraceptive pills) or through biofilms (IUCD- intrauterine contraceptive device), or other mechanisms, C. glabrata can cause vulvovaginal infections. Significantly more C. glabrata vulvovaginal infections have been found, by a study from Turkey, in women using any form of contraception in comparison to those not using any contraception at all.
- Diabetes: People with diabetes are more prone to infections with this organism. Multiple factors like presence of glucose in urine, reduced immunity, previous exposure to antifungals and antibiotics, etc. could make a diabetic more prone to glabrata infections. A study from India by Goswami and colleagues showed in 2000 that C. glabrata apart from C. tropicalis predominantly cause vulvovaginal infections in diabetics.
- Pregnancy: Due to changes in hormones and vaginal acidity during pregnancy, a woman can get vulvovaginal infections caused by Candida species. A study by Babic and Hukic from Bosnia and Herzegovina found that 4.2% of those with VVC were infected with C. glabrata species. A study by Babic and Hukic from Bosnia and Herzegovina found that 4.2% of those with VVC were infected with C. glabrata.
- Hospitalization: Admission to ICU or being subject to medical procedures can cause these infections through hospital equipment or through hand carriage by hospital personnel.
Signs & Symptoms
Signs and symptoms of the infection will depend on the area or organ that is affected.
Generally, the signs and symptoms for C. glabrata infections will be the same as those for C. albicans. The severity of the signs may be less than those of C. albicans though. Here are some of the slight differences that have been observed in the signs and symptoms between these two species of Candida:
Vulvovaginal candidiasis (VVC)
Many women with a C. glabrata infection do not have any symptoms. According to a 2004 study by the lab of Brazilian scientist Svidzinski, nearly 54% of the women with C. glabrata showed no symptoms.
Geiger and colleagues found, in 1995, that there are small differences in the VVC signs and symptoms due to C. glabrata as compared to C. albicans. They studied 80 patients and found the following differences:
- Abnormal discharge is less frequent
- Burning sensation in contrast to itching
- Caseous discharge is rare
- Many-a-times, C. glabrata vaginitis coexists with bacterial vaginitis due to its preference for higher pH of vagina (towards the upper limit of the normal pH).
- Lower numbers of those with C. glabrata infection reported painful sexual intercourse when compare to those with C. albicans infection. This is likely due to lesser inflammation caused by C. glabrata.
Oropharyngeal candidiasis (OPC)
C. glabrata very rarely causes OPC on its own – it mostly causes infection along with C. albicans. The signs and symptoms are therefore the signs and symptoms of oropharyngeal candidiasis caused by C. albicans.
Urinary tract infections
C. glabrata causes over 20% of the candida infections of the urinary tract. Quite often, it occurs as mixed infection along with C. albicans or other bacterial pathogens. The signs and symptoms are identical to those caused by other Candida species. As described by Fidel and colleagues in their 1999 review, most of the patients are asymptomatic. In patients who are catheterized, lower urinary tract symptoms may rarely appear. It is quite rare that the infection ascends to the kidneys, but may occur in patients with stents and when there is obstruction.
The symptoms may include urinary dysuria (painful urination), frequent and urgent urination, and pelvic discomfort (pain in the lower abdomen). The urine could be dark, cloudy, or strong smelling. Feeling generally unwell and tired is common. These could be symptoms of cystitis – bladder infection by either Candida glabrata and/or Candida albicans. Microscopic examination of urine and urine culture shows presence of Candida.
There are no characteristic signs and symptoms of systemic infections by C. glabrata. The only sign is persistent fever and no response to antimicrobial drugs.
As mentioned earlier, C. glabrata is a hospital acquired pathogen. So, hospitalization seems to be one of the biggest risk factors for getting infected by this organism. Apart from this, reduced immunity due to pre-existing infections like HIV, or conditions like cancer or diabetes that reduce the patient’s immunity can put them at higher risk of getting these infections.
Antinori and colleagues from Italy did an extensive review of existing literature on invasive Candida infections. They published their findings in 2016, and according to them, the risk factors for invasive infection with C. glabrata are:
- Patients located in Europe or USA
- Patients with diabetes
- Cancer patients
- Blood cancer or stem cell recipients
- Previous treatment with azole class of antifungal drugs
- Older age
As described earlier, the study by Benjamin and coworkers has also showed that being born prematurely and being admitted in the ICU for newborns could also be a risk factor for getting C. glabrata infections.
A study by several labs in USA showed in 2016 that C. glabrata was involved in almost 25% of invasive Candida infections in patients who received organ transplants second to C. albicans which was the culprit in 46% of the cases.Wearing dentures: glabrata binds more strongly to the denture
A 2015 review of literature by the Israeli scientists Herman and coworkers found that if there is chorioamnionitis (inflammation of fetal membranes – the amnion and the chorion) after in vitro fertilization, most of the times it was caused by Candida glabrata. Thus, undergoing IVF procedure is a risk factor.
For oral infections with Candida glabrata, Redding and Dongari-Bagtzoglou from USA described the following risk factors (2007):
- Wearing dentures: C. glabrata binds more strongly to the dentures compared to C. albicans
- Previous antibiotic therapy
For vaginal infections with C. glabrata, the risk factors are listed in 1999 as the following by Fidel and colleagues from USA:
- Older patients
- Underlying medical conditions like diabetes
A study by Ehrstrom and coworkers showed in 2007 that there is a significant correlation between chronic stress in women and recurrent candida infections.
Unprotected sex with uncircumcised men is considered a risk for getting Candida infections in general. However, a study by Aridogan and colleagues from Turkey showed that C. glabrata colonized the glans penis of about 8% uncircumcised men. It is possible that unprotected receptive sexual contact with even a circumcised man could put a susceptible partner at risk for contracting this infection.
The only risk factor specific for C. glabrata infection of the urinary tract is Fluconazole use, as per an article from 2007 by Lagrotteria and colleagues from Canada. Other risk factors for presence of C. glabrata in urine (candiduria) are like those for C. albicans – Diabetes, indwelling bladder catheter, use of antibiotics and female gender.
Physical examination is not very useful in differentiating C. glabrata infections from C. albicans as the signs and symptoms are not very clearly different – although those with C. glabrata infections are likely to have fewer and less severe symptoms. According to Geiger and colleagues (1995) KOH microscopy is also unable to sufficiently distinguish C. glabrata from C. albicans and may result in misdiagnosis.
Biochemical and advanced tests
Considering that C. glabrata infections need immediate attention (especially in case of invasive infections), it becomes imperative that the diagnosis is quick and reliable. Reliability is essential since it is not simple and straightforward to distinguish C. glabrata from C. albicans. It is also important that the sensitivity or resistance to different antifungals be tested reliably so that proper decision on the treatment regime.
A specialized technique called matrix-assisted laser desorption/ionization time-of-flight mass spectrometry (MALDI-TOF MS) is increasingly being used for quick diagnosis as a supplement to the microscopic and biochemical methods. Although automated, computerized instruments like VITEK-2 that detect organisms based on their growth and biochemical characteristics are good at distinguishing C. glabrata, a study by Andersen and coworkers from Norway found that MALDI-TOF MS gave more definitive identification of the organism.
So what is done for a MALDI-TOF MS? Blood samples are collected from a patient suspected of invasive candida infection. First, one of the following two things are then done:
- The sample undergoes a blood culture where blood is injected into bottles with growth medium to find if microorganisms are present in the patient’s blood
- The blood culture then undergoes a plate culture where the organisms are separated into colonies on an agar plate meant for fungi.
A sample from the blood culture or plate culture is then used to test on the MALDI_TOF MS instrument to check for presence of any of the Candida species.
Pulcrano and colleagues from Italy found in 2013 that the detection of C. glabrata was more accurate when plate cultures were used. In cases where the results are not definite, a molecular diagnosis technique called RT-PCR is used to confirm the identity of the microbe by checking out its DNA.
Finally, a new US-FDA approved qualitative diagnostic platform for Candida glabrata detection is the T2Candida panel that utilizes the technique of magnetic resonance combined with molecular diagnostic. Whole blood sample is used for the test. This test can detect five different species of Candida including C. glabrata. This technique does not need blood culture and is therefore faster than the other methods and can give the results within 3 to 5 hours.
Antimicrobial susceptibility test
Once the organism has been found to be causing infection, tests are done to find out what antibiotics is the organism susceptible to. Most modern laboratories use automated antibiotic susceptibility testing instruments. These are efficient and fast. Vitek 2, Sensititre YeastOne, Etest, and Fungitest are some of the commercial techniques that are used by different laboratories.
As described earlier, C. glabrata is resistant to common antifungal agents and is also adapt at quickly gaining resistance to new antibiotics when it comes across them. Mostly resistant to azoles, it is more susceptible to echinocandins although reports of finding it resistant to echinocandins have also started coming up. However, a study on patients in France, done by Delliere and coworkers published in December 2016, showed that the rates of echinocandin resistance was low and resistance to this drug only occurred when the patient had a prior exposure to it. Another 2016 review on this organism, by Glockner and Cornely from Germany, describes its resistance to azole and echinocandin antifungal agents. Accordingly, following is the order of activity of various antibiotics against C. glabrata (highest to lowest):
(The -fungins are echinocandins and the rest are azoles)
There are several different new antifungals with improved activity being tested for their efficacy in treating invasive candida infections (including those by C. glabrata) – which of these will finally be approved for clinical use remains to be seen.
The treatment of infection by this organism will depend upon the type and location of the infection. Let us look at the current knowledge on treatment of different infections caused by C. glabrata:
Due to resistance of C. glabrata to azoles, echinocandins like micafungin and caspofungin are the first-line drugs of choice for treatment of bloodstream infections and other systemic infections.
Health care providers should be aware that although the echinocandin micafungin seems to be more effective in laboratory tests in comparison with caspofungin, the effects may be different in the body. Yamada and colleagues from Japan found in 2016 that if micafungin does not work against the infection, it could be worthwhile trying caspofungin instead as these two drugs, despite being echinocandins, work slightly differently.
In cases, like the one reported by Grosset and colleagues from France in 2016, where the patient is resistant to both the echinocandins, a switch to amphotericin B or a combination of two antifungals may be required.
It is important that the treatment for invasive candida infections be started well ahead in time. If there are catheters involved, the physician should consider removing them. However, if not possible due to the condition of the patient, antifungals should immediately be started. In 2015, Farmakotis and colleagues have showed that early start of treatment of blood stream infection by C. glabrata in cancer patients resulted in higher survival rates.
According to the guidelines published by Mendling and colleagues from Germany in 2015, mucocutaneous infections by C. glabrata will generally be resistant to high-dose fluconazole. There is, therefore, a suggestion to use oral posaconazole and echinocandins such as micafungin – however, echinocandins are rather expensive and not approved for vulvovaginal candidiasis.
Vaginal boric acid has been found to cure up to 70% of C. glabrata infections as per research by Sobel and colleagues from USA, published in 2007. However, some countries like Germany do not allow the use of boric acid. Hence, these countries need an alternative to boric acid. A 2005 study by Phillips from USA showed that amphotericin B suppositories are also effective in 70% C. glabrata vulvovaginal infections that are resistant to azole drugs. As stated by this article, topical flucytosine cream by itself or in combination with Amphotericin B has also been found to work, although flucytosine is considerably more expensive.
There are lab studies like the one by Chew and colleagues from Malaysia that suggest that some strains of lactobacilli may be able to prevent biofilm formation by C. glabrata. However, these studies need to be clinically tested to find out if these results can be reproduced and whether they would be feasible in treatment of RVVC or for prevention of biofilms on medical instruments.
CDC states that everyone has a role in preventing Candida infections and reducing resistance to antifungal agents. Not only is CDC tracking trends in antifungal resistance on candida isolated from blood stream infections, it is also studying how antifungal resistance evolves in Candida. Apart from this, CDC suggests the following:
- Hospital executives and infection control staff should assess their antifungal use. They should ensure that the guidelines for hand hygiene, prevention of catheter and environment associated infections are strictly followed.
- Doctors and other hospital staff should be very careful about prescription of antifungals and prescribe them properly. Each prescription should be thoroughly documented as to the dose, duration, and why the antifungal was prescribed. They should continuously be aware of which antifungals are not effective in the local area. They should ascertain that hand hygiene and other infection control measures are followed for each patient.
- The patients should make sure that everyone entering their room cleans their hands before entering. CDC also gives advice on hand hygiene, how to make sure that your own hands are clean and how to speak up for clean hands. CDC also states that if the patient has indwelling catheter, they should make sure that they do not have the catheter for longer than is needed and ask the doctor about it.
More specifically, Ozer and colleagues from Turkey suggested in their 2013 article that C. glabrata chorioamnionitis after in-vitro fertilization (IVF) procedures could be due to the transfer of this organism from the vagina or the cervix when the procedure is done. They suggest that this may be prevented by taking vaginal and cervical swabs before the IVF procedures and treating any vaginal infection and making sure that there are no C. glabrata remaining in the area before IVF is carried out.
As to catheters, it is important that these are treated properly prior to usage in a patient. When a catheter is not being used, it is said to be “locked”. There are solutions that are usually filled in the catheters when they are locked – these solutions are called “lock solutions”. Modern lock solutions work as antimicrobials and better functioning lock solutions are being invented to prevent different types of biofilms formed by different microbes. Reitzel and colleagues from USA have recently optimized a previously reported lock solution containing Nitroglycerin-Citrate-Ethanol and have found that it is very active also against C. glabrata biofilms. However, this still needs to be tested clinically. Hospitals should continuously check for newer and better lock solutions and use them.
As to the vulvovaginal and oral infections caused by this organism, it may be useful to avoid chronic stress and improve your immunity especially in case you already have a C. albicans infection. Avoiding sex with an infected person may prevent you from getting vaginal or oral infection (in case of receptive oral sex).
In general, protected sex is recommended as even a person who carries the yeast without having an infection could cause infection in a susceptible person.
- Is it a fungus?
Yes, it is.
- How common is it?
It is the second most common yeast pathogen in humans.
- Where does Candida glabrata come from?
Although it was first discovered on grapes, it is a part of our natural normal flora. It generally exists inside our gastrointestinal system, genitalia and skin without causing any disease. Antibiotic resistant Candida glabrata may be present in hospital environments, on surfaces and equipment in the hospitals and on hands of hospital personale.
- Is it contagious?
Yes, it can be transmitted through direct contact with people. Although this would not affect people with good immunity, it can cause infection in those with poor immunity, underlying medical conditions, and hospitalization.
- Is it sexually transmitted?
Vulvovaginal and oral candidiasis due to this organism can be sexually transmitted.
- Is it sensitive to fluconazole?
No, it is mostly resistant.
- Is this dangerous?
It depends upon the underlying conditions and immune status of the patient. Invasive infections caused by C. glabrata can be especially dangerous for immunocompromised patients. Infections of the blood-stream or different organs can cause further complications in the treatment of the medical condition for which they have been hospitalized. Vulvovaginal infections by this microbe can lead to inflammation of fetal membranes (chorioamnionitis) after IVF (in-vitro fertilization) procedures. This is dangerous for the fetus and there is high risk of stillbirth or death of the newborn.
- Can this kill you?
People who get invasive C. glabrata infections are generally already sick with another medical condition, so it is difficult to say whether it is only this infection that kills the patient or it is a combination of this infection and the original medical condition. However, it can be said that the infection can complicate the treatment of the original condition. In case of chorioamnionitis, it is very likely that the fetus is stillborn or the newborn dies soon after birth.
- Can it cause miscarriage?
Yes, it can – especially in the case where in-vitro fertilization or cervical-stich is used.
- Can stress cause it?
Stress is generally not directly implicated in C. glabrata infections. However, stress does lower your immunity and ability to fight infections – it is possible that stress could be a factor in change of a vulvovaginal infection to a recurrent type that is caused by this organism. In this regard, some evidence has been provided in a study by Ehrstorm and colleagues from Sweden in 2007.
- Can it be cured?
Whether the infection by this microbe can be cured depends on the site of infection, the immune status of the patient and how soon the treatment was started. Seventy percent of the vaginal infections have been found to be cured using boric acid suppositories. Invasive infections are much more difficult to treat, but chances of treating it are higher if the treatment is started early enough given that the patient is not terribly immunocompromised.
- What is fungemia?
It is a blood-stream infection caused by C. glabrata.
- What is the best treatment?
The treatment would depend on the site of infection. For vulvovaginal infections, boric acid suppositories or in cases where boric acid is not permitted, amphotericin B suppositories are good treatment. For systemic infections, the treatment will depend on the antibiotic sensitivity profile of the C. glabrata infecting the patient. Quick diagnosis and antibiotic sensitivity tests are very important in these cases.