What are the causes of invasive candidiasis. How does Candida spread throughout the body. What are the symptoms of a systemic yeast infection. How is invasive candidiasis diagnosed and treated. Who is at risk for developing invasive candidiasis.

Understanding Invasive Candidiasis: A Systemic Yeast Infection

Invasive candidiasis is a serious fungal infection caused by Candida yeast that spreads throughout the body. Unlike localized Candida infections like oral thrush or vaginal yeast infections, invasive candidiasis can affect multiple organs and systems, including the blood, heart, brain, eyes, and bones. The most common form is candidemia, a bloodstream infection that often occurs in hospitalized patients.

Candida normally lives harmlessly in the body, but can cause infection in certain at-risk individuals when it enters the bloodstream or internal organs. In the United States, candidemia is a leading cause of healthcare-associated bloodstream infections, resulting in extended hospital stays, high medical costs, and significant mortality rates.

Common Candida Species and Their Role in Invasive Infections

While there are hundreds of Candida species, only a few are known to cause infections in humans:

• Candida albicans
• Candida glabrata
• Candida parapsilosis
• Candida tropicalis
• Candida krusei

Recently, Candida auris has emerged as a concerning cause of invasive candidiasis worldwide. This species is often resistant to multiple antifungal drugs, making infections challenging to treat.

Why is C. auris a growing concern in healthcare settings?

C. auris poses several unique challenges:

1. High drug resistance
2. Difficulty in identification with standard laboratory methods
3. Ability to persist on surfaces and spread in healthcare facilities
4. Potential to cause outbreaks

These factors make C. auris a significant threat, especially in hospital environments where vulnerable patients are at risk.

Risk Factors for Developing Invasive Candidiasis

Certain individuals are at higher risk for invasive candidiasis:

• Patients with weakened immune systems (e.g., those undergoing chemotherapy or with HIV/AIDS)
• Individuals with central venous catheters
• Patients who have undergone recent surgery, especially abdominal surgery
• Critically ill patients in intensive care units
• Very low birth weight infants
• Patients receiving broad-spectrum antibiotics
• Individuals with diabetes
• Organ transplant recipients

Understanding these risk factors is crucial for healthcare providers to implement preventive measures and monitor high-risk patients closely.

Transmission and Spread of Invasive Candidiasis

Invasive candidiasis typically occurs when Candida yeast, which normally resides on the skin or in the gut, enters the bloodstream or internal organs. This can happen through various routes:

• Central venous catheters: These medical devices can provide a direct pathway for Candida to enter the bloodstream.
• Surgical procedures: Particularly abdominal surgeries, which may allow Candida from the gut to spread to other parts of the body.
• Mucosal barrier breakdown: Conditions that damage the protective lining of the gut can allow Candida to enter the bloodstream.
• Healthcare worker transmission: In rare cases, Candida can spread through contaminated hands of healthcare workers.

Can invasive candidiasis spread from person to person?

Invasive candidiasis is not typically contagious between individuals. However, in healthcare settings, certain Candida species (particularly C. auris) can spread from patient to patient through contaminated equipment or surfaces. This underscores the importance of proper infection control measures in hospitals and long-term care facilities.

Recognizing the Symptoms of Invasive Candidiasis

The symptoms of invasive candidiasis can vary depending on which organs are affected. Common signs include:

• Fever and chills that do not improve with antibiotic treatment
• Low blood pressure (hypotension)
• Rapid heart rate
• Difficulty breathing
• Abdominal pain
• Kidney problems
• Vision changes (if the eyes are involved)
• Skin lesions

It’s important to note that these symptoms can be non-specific and may mimic other conditions, making diagnosis challenging. Healthcare providers must maintain a high index of suspicion in at-risk patients.

How quickly do symptoms of invasive candidiasis develop?

The onset of symptoms can vary widely, from rapid progression within hours to a more gradual development over days or weeks. This variability depends on factors such as the patient’s immune status, the site of infection, and the Candida species involved. Prompt recognition and treatment are crucial for improving outcomes.

Diagnostic Approaches for Invasive Candidiasis

Diagnosing invasive candidiasis can be challenging due to non-specific symptoms and the time required for traditional culture methods. Common diagnostic approaches include:

1. Blood cultures: The gold standard for diagnosing candidemia, but may take several days to yield results.
2. Tissue biopsy: For diagnosing Candida infections in specific organs.
3. Molecular tests: PCR-based methods can provide faster results and detect Candida DNA.
4. Antigen detection: Tests like the Beta-D-glucan assay can detect fungal cell wall components in blood.
5. Imaging studies: CT scans or MRIs may help identify organ involvement.

What are the advantages of newer diagnostic methods for invasive candidiasis?

Newer diagnostic techniques offer several benefits:

• Faster results, allowing for earlier treatment initiation
• Improved sensitivity, potentially detecting infections missed by blood cultures
• Ability to identify antifungal-resistant strains more quickly
• Potential for guiding targeted therapy, reducing unnecessary antifungal use

These advancements are crucial in improving patient outcomes and antimicrobial stewardship efforts.

Treatment Strategies for Invasive Candidiasis

Effective treatment of invasive candidiasis typically involves a combination of antifungal medications and supportive care. The choice of antifungal agent depends on several factors, including:

• The Candida species identified
• The patient’s clinical condition
• Potential drug interactions
• Local antifungal resistance patterns

Common antifungal medications used to treat invasive candidiasis include:

1. Echinocandins (e.g., caspofungin, micafungin, anidulafungin): Often used as first-line therapy due to their broad spectrum of activity and favorable safety profile.
2. Azoles (e.g., fluconazole, voriconazole): May be used for step-down therapy or in certain clinical scenarios.
3. Amphotericin B: Reserved for severe cases or when resistance to other antifungals is suspected.

How long does treatment for invasive candidiasis typically last?

The duration of treatment for invasive candidiasis varies depending on the extent of infection and the patient’s response to therapy. In general:

• Uncomplicated candidemia: Treatment typically continues for 2 weeks after the last positive blood culture and resolution of symptoms.
• Deep-seated infections: May require 4-6 weeks or longer of antifungal therapy.
• Suppressive therapy: Some patients may need long-term suppressive treatment to prevent recurrence.

Regular monitoring of clinical response and follow-up cultures are essential to guide treatment duration and ensure successful eradication of the infection.

Prevention Strategies and Infection Control Measures

Preventing invasive candidiasis is crucial, especially in healthcare settings. Key prevention strategies include:

• Proper hand hygiene for healthcare workers and visitors
• Appropriate use and timely removal of central venous catheters
• Judicious use of broad-spectrum antibiotics
• Implementation of antifungal stewardship programs
• Environmental cleaning and disinfection in healthcare facilities
• Screening and isolation precautions for patients with C. auris

In some high-risk patients, such as those undergoing certain cancer treatments or organ transplants, antifungal prophylaxis may be recommended to prevent invasive candidiasis.

How effective are preventive measures in reducing invasive candidiasis rates?

Studies have shown that implementing comprehensive infection control measures can significantly reduce the incidence of invasive candidiasis:

• Hand hygiene programs have been associated with up to 40% reduction in healthcare-associated Candida infections.
• Proper central line management can decrease catheter-related candidemia by 50-70%.
• Antifungal stewardship efforts have led to more appropriate use of antifungals and reduced resistance rates.

These findings highlight the importance of a multifaceted approach to prevention in healthcare settings.

The Impact of Invasive Candidiasis on Healthcare Systems

Invasive candidiasis poses a significant burden on healthcare systems worldwide:

• Extended hospital stays: Patients with invasive candidiasis often require prolonged hospitalization, increasing healthcare costs.
• High mortality rates: Despite advances in treatment, mortality rates for invasive candidiasis remain substantial, ranging from 15-40% depending on the patient population.
• Economic burden: The direct and indirect costs associated with invasive candidiasis are estimated to be in the billions of dollars annually in the United States alone.
• Antimicrobial resistance: The emergence of antifungal-resistant Candida strains complicates treatment and may lead to poorer outcomes.

How does the economic impact of invasive candidiasis compare to other healthcare-associated infections?

While direct comparisons can be challenging due to variations in study methodologies, invasive candidiasis is generally considered one of the most costly healthcare-associated infections:

• The average additional cost per case of candidemia is estimated at $40,000-$100,000.
• This places invasive candidiasis on par with or exceeding the costs associated with many bacterial bloodstream infections.
• The long-term economic impact, including lost productivity and ongoing medical care, further amplifies these costs.

These figures underscore the importance of effective prevention and management strategies for invasive candidiasis.

Emerging Research and Future Directions in Invasive Candidiasis Management

The field of invasive candidiasis research is rapidly evolving, with several promising areas of investigation:

1. Novel antifungal agents: Researchers are developing new classes of antifungals to address resistance concerns and improve treatment options.
2. Immunotherapies: Strategies to enhance the host immune response against Candida are being explored as adjunctive treatments.
3. Rapid diagnostics: Advanced molecular techniques and biomarker-based tests are being developed for faster, more accurate diagnosis.
4. Personalized medicine approaches: Tailoring antifungal therapy based on host genetics and fungal characteristics may improve outcomes.
5. Microbiome modulation: Understanding and potentially manipulating the human microbiome to prevent Candida overgrowth is an area of active research.

What potential breakthroughs in invasive candidiasis management are on the horizon?

Several exciting developments show promise for improving invasive candidiasis management:

• Novel antifungal classes like olorofim and ibrexafungerp may provide options for resistant infections.
• Engineered probiotics designed to outcompete pathogenic Candida in the gut are in early stages of development.
• AI-powered diagnostic algorithms may enhance early detection and risk stratification.
• Antifungal vaccines are being explored as a potential preventive strategy for high-risk individuals.

These advancements could significantly impact the prevention, diagnosis, and treatment of invasive candidiasis in the coming years.

In conclusion, invasive candidiasis remains a significant challenge in healthcare settings, requiring a multifaceted approach to prevention, diagnosis, and treatment. Ongoing research and advances in medical technology offer hope for improved outcomes and reduced burden of this serious fungal infection. Healthcare providers, researchers, and policymakers must continue to prioritize efforts to combat invasive candidiasis and its impact on patient health and healthcare systems worldwide.

About Invasive Candidiasis | Invasive Candidiasis | Candidiasis | Types of Diseases | Fungal Diseases

What is invasive candidiasis?

Medical illustration of Candida albicans.

Invasive candidiasis is an infection caused by a yeast (a type of fungus) called Candida.  Unlike Candida infections in the mouth and throat (also called “thrush”) or vaginal “yeast infections,” which are localized to one part of the body,  invasive candidiasis is a serious infection that can affect the blood, heart, brain, eyes, bones, or other parts of the body.¹

Candida normally lives inside the body (in places such as the mouth, throat, gut, and vagina) and on the skin without causing any problems.² However, in certain patients who are at risk, Candida can enter the bloodstream or internal organs and cause an infection. A Candida bloodstream infection, also called candidemia, is the most common form of invasive candidiasis. ¹ In the United States, candidemia is one of the most common causes of bloodstream infections in hospitalized patients,^3–4 and it often results in long hospital stays and death. It is also responsible for high medical costs.⁵

Antifungal medication can treat invasive candidiasis. Certain patients such as those with cancer or bone marrow or organ transplants might receive antifungal medication to prevent invasive candidiasis.⁶

1. Kullberg BJ, Arendrup MC. Invasive candidiasisexternal icon. N Engl J Med 2015; 373:1445-1456.
2. Nucci M, Anaissie E. Revisiting the source of candidemia: skin or gut?external icon Clin Infect Dis. 2001 Dec 15;33(12):1959-67.
3. Wisplinghoff H, Bischoff T, Tallent SM, Seifert H, Wenzel RP, Edmond MB. Nosocomial bloodstream infections in US hospitals: analysis of 24,179 cases from a prospective nationwide surveillance studyexternal icon. Clin Infect Dis. 2004 Aug 1;39(3):309-17.
4. Magill SS, O’Leary E, Janelle S, Thompson DL, Dumyati G, Nadle J, et al. Changes in prevalence of health care–associated infections in U.S. hospitalsexternal icon. N Engl J Med 2018; 379:1732-44.
5. Morgan J, Meltzer MI, Plikaytis BD, Sofair AN, Huie-White S, Wilcox S, et al. Excess mortality, hospital stay, and cost due to candidemia: a case-control study using data from population-based candidemia surveillanceexternal icon. Infect Control Hosp Epidemiol 2005 Jun;26(6):540-7.
6. Pappas PG, Kauffman CA, Andes DR, Clark CJ, Marr KA, Ostrosky-Zeichner L, et al. Clinical practice guideline for the management of candidiasis: 2016 update by the Infectious Diseases Society of Americaexternal icon. Clin Infect Dis 2016;62:e1-50.

Page last reviewed: February 2, 2021

Content source: Centers for Disease Control and Prevention, National Center for Emerging and Zoonotic Infectious Diseases (NCEZID), Division of Foodborne, Waterborne, and Environmental Diseases (DFWED)

Enter your email to get updates on C. auris

• Fungal Meningitis
• National Center for Emerging and Zoonotic Infectious Disease
• Division of Foodborne, Waterborne, and Environmental Diseases
• Mycotic Diseases Branch

Where Invasive Candidiasis Comes From | Invasive Candidiasis | Candidiasis | Types of Diseases | Fungal Diseases

Candida lives in and on the body

Candida, the fungus that causes invasive candidiasis, normally lives inside the body (in places such as the mouth, throat, gut, and vagina) and on the skin without causing any problems.¹ In some people who are at higher risk for the infection, Candida can enter the bloodstream or internal organs and cause invasive candidiasis. For example, this can happen when a central venous catheter is inserted and left in place for a long time, during surgery, or when the immune system is weakened during chemotherapy. Healthcare workers can also carry Candida on their hands. ^2,3 A few outbreaks of candidemia have been linked to healthcare workers’ hands,^4,5 so hand hygiene in healthcare settings is important for preventing the spread of infections.

Types of

Candida

There are over hundreds of species of Candida, but only a few are known to cause infections.⁶ The most common species that cause infections are C. albicans, C. glabrata, C. parapsilosis, C. tropicalis, and C. krusei.

Another species called C. auris is emerging as a cause of invasive candidiasis around the world and in certain areas of the United States – read more about this concerning and often drug-resistant species.

1. Nucci M, Anaissie E. Revisiting the source of candidemia: skin or gut?external icon Clin Infect Dis. 2001 Dec 15;33(12):1959-67.
2. Strausbaugh LJ, Sewell DL, Ward TT, Pfaller MA, Heitzman T, Tjoelker R. High frequency of yeast carriage on hands of hospital personnelexternal icon. J Clin Microbiol. 1994 Sep;32(9):2299-300.
3. Yildirim M, Sahin I, Kucukbayrak A, Ozdemir D, Tevfik Yavuz M, Oksuz S, et al. Hand carriage of Candida species and risk factors in hospital personnelexternal icon. Mycoses. 2007 May;50(3):189-92.
4. Lupetti A, Tavanti A, Davini P, Ghelardi E, Corsini V, Merusi I, et al. Horizontal transmission of Candida parapsilosis candidemia in a neonatal intensive care unitexternal icon. J Clin Microbiol. 2002 Jul;40(7):2363-9.
5. Clark TA, Slavinski SA, Morgan J, Lott T, Arthington-Skaggs BA, Brandt ME, et al. Epidemiologic and molecular characterization of an outbreak of Candida parapsilosis bloodstream infections in a community hospitalexternal icon. J Clin Microbiol. 2004 Oct;42(10):4468-72.
6. Pappas PG. Invasive candidiasisexternal icon. Infect Dis Clin North Am. 2006 Sep;20(3):485-506.

Page last reviewed: December 29, 2020

Content source: Centers for Disease Control and Prevention, National Center for Emerging and Zoonotic Infectious Diseases (NCEZID), Division of Foodborne, Waterborne, and Environmental Diseases (DFWED)

Enter your email to get updates on C. auris

• Fungal Meningitis
• National Center for Emerging and Zoonotic Infectious Disease
• Division of Foodborne, Waterborne, and Environmental Diseases
• Mycotic Diseases Branch

Thrush in women – symptoms and treatment in St. Petersburg

How the disease develops: causes and pathogenesis

Normally, the mucous membrane of the external genitalia is not sterile. The microflora of the vagina includes friendly microorganisms, including the Candida fungus, which serve as the body’s defense against infection. Under adverse conditions, when the microbiome is disturbed, the fungus spreads rapidly, causing the characteristic symptoms of thrush. In some cases, the underlying tissues and blood vessels are also involved in the pathological process, which carry the fungus throughout the body.

The causes of thrush in women are varied:

• Taking medications – antibacterial drugs, cytostatics, glucocorticosteroids, immunosuppressants.

• Decrease in general immunity against the background of chronic diseases – diabetes mellitus, pyelonephritis, blood diseases, tonsillitis, metabolic disorders.

• Changes in the hormonal background due to pathologies of the female genital area, pregnancy, hypothyroidism, the use of oral contraceptives.

• Stress factors – climate change, nervous tension, physical and emotional overload.

• Errors in matters of personal hygiene – untimely change of pads and tampons, the use of aggressive cleansers (violate the natural pH level of the vagina).

• The presence of injuries of the mucous membrane, provoked by wearing tight underwear, sexual intercourse with a deficiency of natural lubrication.

Often, a decrease in local immunity is caused by malnutrition, hypothermia, vitamin deficiency, and untreated sexually transmitted diseases.

Signs of candidiasis

Vaginal candidiasis is called “thrush” because of the characteristic cheesy discharge that accompanies the spread of fungal colonies. In some cases, the discharge may be absent or change its character depending on the phase of the menstrual cycle.

Another striking sign of candidiasis is itching and burning in the intimate area. Itchy sensations are so unbearable that they significantly worsen the quality of life of a woman. Itching increases in the morning, before menstruation, after hygiene procedures and sexual intercourse.

Other symptoms of thrush:

• burning and pain during urination;

• soreness during intimate contacts;

• pungent sour smell of discharge.

If the disease becomes chronic, relapses of fungal infections of the external genital organs occur more often than four times a year. Recurrent candidiasis has an erased clinical picture, when signs of pathology are present, but weakly expressed.

With complicated thrush, the pathological process is more difficult. Deeper tissues are affected, ulcerations and cracks are observed on the vaginal mucosa.

How candidiasis is diagnosed

The treatment of vaginal candidiasis is preceded by a comprehensive diagnosis. The disease in women can be diagnosed already during the initial gynecological examination. The mucous membrane of the vagina looks edematous and inflamed. The natural pink color of the fabrics changes to bright scarlet. Specific discharges of white or yellowish color with grains resembling cottage cheese are found.

With a complicated fungal infection, vesicles appear on the skin of the external genital organs. These are small blisters filled with a cloudy or clear liquid. They are able to open, exposing the epidermis and provoking the development of erosion.

To confirm the diagnosis, medical laboratory tests are carried out:

• smear microscopy – examination of the microflora of the vagina under a microscope;

• bakposev secretions – allows you to accurately detect the fungus-causative agent;

• PCR and ELISA of genital secretions for the detection of Candida albicans antigens;

• complete blood count – helps to see the inflammatory process.

Diagnosis is complicated if thrush occurs against the background of sexually transmitted diseases – chlamydia, gonorrhea, trichomoniasis. Therefore, an accurate diagnosis and development of a treatment plan for candidiasis in women is the prerogative of a doctor.

Methods of treatment

It is recommended to contact the clinic at the first signs of thrush – itching and specific discharge. Self-medication can lead to the fact that the symptoms will be masked, and the fungal disease will become recurrent. Dealing with it will be much more difficult, and the likelihood of complications will only increase.

Treatment methods for thrush will include both medications and medications aimed at normalizing the microflora. Doctors mainly focus on antifungal medications containing nystatitis, fluconazole, clotrimazole, nitrofungin, ketoconazole. They disrupt the synthesis of substances contained in the membrane of the fungus, which inhibits the growth of colonies or leads to the complete destruction of the pathogen. Preparations for candidal lesions of the mucous membranes are available in the form of tablets, capsules, suppositories, ointments and creams. The drug is selected individually, taking into account the clinical picture.

The program of complex treatment of candidiasis also includes:

It is important to eliminate the cause of the pathology in order to prevent the occurrence of relapses. Funds may be required to improve hormonal levels, fight dysbacteriosis and sexually transmitted diseases.

It is recommended to adjust the diet – reduce the consumption of sweets and carbohydrates. They serve as a breeding ground for the active development of the fungus and slow down recovery.

Of the physiotherapeutic methods for the treatment of thrush, darsonvalization, laser therapy, electrophoresis, and magnetotherapy contribute. During therapy and after it, it is necessary to adhere to the basic principles for the prevention of microflora disorders:

• abandon tight synthetic underwear in favor of comfortable cotton;

• timely treat common diseases – hormonal, inflammatory, infectious;

• change tampons and pads more often during menstruation;

• refuse “daily”;

• do not take antibiotics without a doctor’s prescription;

• use special means for intimate hygiene;

• when carrying out antibacterial therapy, in parallel, use means to restore normal microflora.

Do not treat candidiasis as a harmless disease. The inflammatory process caused by the fungus can spread to surrounding organs and tissues. Against the background of weakened immunity, a bacterial infection easily joins a fungal infection, which is fraught with the development of salpingitis, adnexitis, urethritis, cystitis. Only competent treatment of thrush in the clinic “MEDIONA PARNAS” is the key to a successful recovery and preservation of women’s health.

Itching of the skin all over the body, ointment for itching

THERE ARE CONTRAINDICATIONS. POSSIBLE SIDE EFFECTS. A SPECIALIST’S CONSULTATION IS REQUIRED. 49 When to prescribe antipruritic ointments for the skin

Itching is an unpleasant symptom that has a variety of causes. Antipruritic ointments for the skin help to fight it. But you can use drugs only after examination and establishing the exact cause of the itching. Otherwise, the use of these funds will not only not be beneficial, but will also cause a deterioration in the condition.

When antipruritic ointments are prescribed for the skin

Itching of the skin is caused by:

• skin pathologies (most common cause) – eczema, dermatitis, psoriasis;
• allergies;
• infectious and fungal diseases – chickenpox, ringworm, candidiasis;
• general pathologies – diabetes, liver disease, varicose veins;
• prolonged sun exposure, dry skin;
• psychological state – depression, anxiety;
• hormonal changes during pregnancy and menopause;
• insect bites, contact with parasites (scabies, pediculosis).

Antipruritic ointment is selected based on the symptoms and the cause of its occurrence. There are several categories of drugs:

• Antihistamines – reduce itching, swelling and redness. Relief occurs within a few minutes after application.
• Corticosteroids – for the treatment of skin diseases. Applies for a limited period of time.
• Local anesthetics – contain novocaine and lidocaine, which desensitize the skin. Relieve minor itching.
• Calcineurin inhibitors – relieve the inflammatory process.

Menthol and camphor oil are used in folk medicine. They cool the skin and soothe itching.

You might be interested in: Today’s Best Allergy Remedy

Itchy Foot Ointments

Itchy feet are caused by fungus, food allergies, dust, clothes, skin conditions, and infections. One of the reasons for its appearance is inadequate hygiene.

The list of the best ointments includes:

1. Advantan – suppresses allergies and inflammation. It is used to treat neurodermatitis, eczema, atopic dermatitis.
2. Sinaflan – has anti-allergic and anti-inflammatory properties. Indicated for dry skin, allergic manifestations, insect bites.
3. Elokom – relieves inflammation and itching, has a vasoconstrictive effect. It is prescribed for dermatitis, allergic skin lesions, for the treatment of lichen.

Be sure to consult your doctor if, despite all the measures taken, the symptom continues to bother you for more than 2 weeks, prevents you from sleeping at night, itching begins to spread throughout the body.

Facial products

Eruptions and itching on the face can appear as a result of allergies caused by cosmetics, changes in the state of the body, past illnesses, under the influence of stress. The skin of the face is especially sensitive and delicate, therefore, for its treatment, the means are selected with extreme care.

It is preferable to choose non-hormonal ointments for therapy. They have a mild effect. But, unfortunately, non-hormonal remedies do not cope with severe forms of allergic dermatoses. In these cases, hormonal preparations (ointment, cream, balm) are prescribed, which can quickly alleviate the condition. However, these drugs have many contraindications, so you can not choose the drug yourself and use it uncontrollably.

Genital preparations

An unpleasant symptom in the genital area occurs in both men and women. It can be caused by external influences, infections, violations of hygiene rules. Often occurs with diseases of the internal genital organs.

For the intimate area are used:

1. Oxycort – eliminates itching caused by allergies, dermatitis, insect bites, infected diaper rash.
2. Hydrocortisone ointment – used to treat psoriasis, dermatitis, eczema.
3. Prednisalone ointment – reduces symptoms caused by eczema, dermatitis.
4. Mirtoplex, Biopin, Acyclovir are used to treat genital herpes. The drugs effectively relieve itching, as they fight its cause.

Thrush often develops as a reaction to antibiotics, stress, malnutrition.