Microbiology Current Characterization of Cystic Fibrosis Review Article

User Generated

Km3mb

Science

Description

I.Assessment Requirements

You should produce a review article of approximately 3000 words (absolute maximum is 3300 words excluding references, abstract, boxes and figures/tables) on the topic outlined below. The review should give sufficient background and context, critically cover recent advances in the field, be clear and easy to follow even for non-experts, progress logically with clear signposting, and include a concluding section. Your article should be appropriately referenced and formatted in the style of a professional journal, Trends in Microbiology. You should format your


review article as if it were a published paper in this journal (see pdf versions of recent papers from this journal to view the style; examples are available in the Resource List).

In your review, you should include a title and authors (in this case just yourself), an abstract, the main body of the review and two additional boxes, the 'Highlights' box and the 'Outstanding Questions' box, which are given in all Trends in Microbiology papers. You may add further optional boxes if you wish, following the guidelines provided in the Trends in Microbiology Instructions to Authors Note that the abstract, boxes and reference list do not count towards the 3000-word limit (however, in-text citations do).

You are encouraged to use Figures and Tables to help explain complex ideas in your review article. Figures should have a title and a legend allowing the figure to be understood independently from the main text. However, all figures and tables should be called out in the main text of the review. If using a figure from some other publication, the source of the figure must be cited. Use high-quality images with sufficient resolution, so the images do not appear pixelated or blurry in the final paper. Most scientific journals allow downloading high-resolution images and using them for educational purposes if the source publication is cited. You can also prepare your own figures. A particularly useful programme is

Biorender (www.biorender.com), which allows making professionallooking figures quickly and easily. This programme is free to use for educational purposes. Tables should have a title and possible explanatory notes and should be formatted according to the journal style. Tables and figure legends do not count towards the 3000-word limit.

You should cover the topic as described below. However, you are free to choose a title and focus on a particular aspect of the topic, so long as all the points noted in the specifications below are covered. You should base your work on the latest primary research literature. You can also cite other review articles or reputable online sources (e.g. the websites of Public Health England, the World Health Organization, the Centers for Disease Control and Prevention etc.), but most of your references should be recent original research articles. Avoid using online sources such as Wikipedia as your only references. Wikipedia is a good starting point to get an overview of a subject, but it should not be referenced in a scientific context as the content can be edited in a non-controlled way. The citation style should be as in Trends for Microbiology.


When preparing your review article, it is highly recommended that you use a reference manager. offers RefWorks - see the for further information.

Note that the article is limited, so you probably cannot include all the information you have found. You will therefore have to select which information to include to make a clear, balanced, engaging and up-to-date review article.

Some examples of excellent coursework are provided in the learning room on NOW.

Unformatted Attachment Preview

1 COURSEWORK ASSESSMENT SPECIFICATION (PG) Details of Module and Team What Learning Outcomes are assessed? What are my Deadlines and how much does this assessment contribute to my Module Grade? What am I required to do in the assessment? What are my assessment criteria? (What do I have to achieve for each grade?) Can I get formative feedback before submitting ? If so, how? What extra support could I look for myself? How and when do I submit this assessment? How and when will I get summative feedback? What skills might this work evidence to employers? MODULE CODE BIOL40472 MODULE TITLE Medical Microbiology COURSEWORK TITLE Review article 2 LEARNING OUTCOMES ASSESSED Kl: Relate theory to the clinical and laboratory aspects of Medical Microbiology investigations; K2: Demonstrate a critical understanding of the role of the microbiology laboratory in the diagnosis of disease; K3: Demonstrate a thorough understanding of the causes of infection and evaluate appropriate methods of prevention, detection and treatment. K4: Demonstrate a thorough understanding of the principles and methodologies of the techniques used in medical microbiology. Sl: Critically evaluate research and development work; S2: Present work in written form to a standard appropriate at Masters level; S3: Collect, collate and critically report on scientific literature; S4: Show evidence of continued learning by independent study; 3 4 Work handed in up to five working days late will be given a maximum Grade of Low Pass whilst work that arrives more than five working days will be given a mark of Zero. Work will only be accepted beyond the five working day deadline if satisfactory evidence, for example, an NEC is provided. Any issues requiring NEC https:/(ntu.ac.uk/current students/ resources/ student handbook/ app eals/index.html The University views plagiarism and collusion as serious academic irregularities and there are a number of different penalties which may be applied to such offences. The Student Handbook has a section on Academic Irregularities, which outlines the penalties and states that plagiarism includes: 'The incorporation of material (including text, graph, diagrams, videos etc.) derived from the work (published or unpublished) of another, by unacknowledged quotation, paraphrased imitation or other device in any work submitted for progression towards or for the completion of an award, which in any way suggests that it is the student's own original work. Such work may include printed material in textbooks, journals and material accessible electronically for example from web pages.' Whereas collusion includes: "Unauthorised and unacknowledged copying or use of material prepared by another person for use in submitted work. This may be with or without their consent or agreement to the copying or use of their work." If copied with the agreement of the other candidate both parties are considered guilty of Academic Irregularity. Penalties for Academic irregularities range from capped marks and zero marks to dismissal from the course and termination of studies. To help you avoid plagiarism and collusion, you are permitted to submit your work once to a separate drop box entitled "Draft report" to view both the matching score and look at what areas are affected. It is then down to you to make any changes needed. 5 6 Turnitin cannot say if something has been plagiarised or not. Instead it highlights matches between your text and other Turnitin content. There is no Good or Bad score , it depends on the piece of work If you find your text matching there may be a problem, see the examples below. 7 1) The reference section is highlighted. This may mean you have referenced correctly and this has been matched with other well referenced documents online. 2) A table containing class data is highlighted. This is acceptable as long as any text accompanying the table is not similar picked up as identical 3) Paragraphs of text in the introduction or conclusion sections are highlighted. This may mean they have been copied exactly from another source. Even if this source is referenced this is bad practice, see advice below 4) A sentence, or part of a sentence is highlighted. Sometimes there are few ways to write a sentence, especially straightforward ones. As long as this does not occur throughout a paragraph this may be acceptable. There will be occasions where a few words within a sentence produce a match. This is acceptable but ensure that this not a common occurrence or a patchwork of copied statements from different sources. Overall when you look at the work, put yourself in the place of the marker. Is a lot of the work highlighted so it does not really look like the author's work? If so, then you need to work on it some more For help, do not contact the setter of the work, but use these links (Plagiarism Support and Turnitin support) to book time with staff and students to help with I. Assessment Requirements You should produce a review article of approximately 3000 words (absolute maximum is 3300 words excluding references, abstract, boxes and figures/tables) on the topic outlined below. The review should give sufficient background and context, critically cover recent advances in the field, be clear and easy to follow even for non-experts, progress logically with clear signposting, and include a concluding section. Your article should be appropriately referenced and formatted in the style of a professional journal, Trends in Microbiology. You should format your 8 review article as if it were a published paper in this journal (see pdf versions of recent papers from this journal to view the style; examples are available in the Resource List). In your review, you should include a title and authors (in this case just yourself), an abstract, the main body of the review and two additional boxes, the 'Highlights' box and the 'Outstanding Questions' box, which are given in all Trends in Microbiology papers. You may add further optional boxes if you wish, following the guidelines provided in the Trends in Microbiology Instructions to Authors Note that the abstract, boxes and reference list do not count towards the 3000-word limit (however, in-text citations do). You are encouraged to use Figures and Tables to help explain complex ideas in your review article. Figures should have a title and a legend allowing the figure to be understood independently from the main text. However, all figures and tables should be called out in the main text of the review. If using a figure from some other publication, the source of the figure must be cited. Use high-quality images with sufficient resolution, so the images do not appear pixelated or blurry in the final paper. Most scientific journals allow downloading highresolution images and using them for educational purposes if the source publication is cited. You can also prepare your own figures. A particularly useful programme is Biorender (www.biorender.com), which allows making professionallooking figures quickly and easily. This programme is free to use for educational purposes. Tables should have a title and possible explanatory notes and should be formatted according to the journal style. Tables and figure legends do not count towards the 3000-word limit. You should cover the topic as described below. However, you are free to choose a title and focus on a particular aspect of the topic, so long as all the points noted in the specifications below are covered. You should base your work on the latest primary research literature. You can also cite other review articles or reputable online sources (e.g. the websites of Public Health England, the World Health Organization, the Centers for Disease Control and Prevention etc.), but most of your references should be recent original research articles. Avoid using online sources such as Wikipedia as your only references. Wikipedia is a good starting point to get an overview of a subject, but it should not be referenced in a scientific context as the content can be edited in a non-controlled way. The citation style should be as in Trends for Microbiology. 9 When preparing your review article, it is highly recommended that you use a reference manager. offers RefWorks - see the for further information. Note that the article is limited, so you probably cannot include all the information you have found. You will therefore have to select which information to include to make a clear, balanced, engaging and up-todate review article. Some examples of excellent coursework are provided in the learning room on NOW. The library also offers support with referencing and various other aspects of writing; see The Language Centre offers support with academic English: https://www.ntu.ac.uk/studyandcourses/courses/ourschools/hum/english- classes You should submit your article as a single pdf to the dropbox on NOW by Friday 4th December (Week 19). You may also submit the original Word document file in addition to the pdf. Topic for coursework: Lung infections in cystic fibrosis patients Introduce the condition of cystic fibrosis, the pathogens associated with the condition, discuss disease symptoms and progression of the disease, epidemiology, diagnosis, and treatment and control options. You are free to give the review a title of your choice and focus on a specific aspect of the topic, as long as the review covers all the points noted above. 幫 岳 늠c ℃ 그 C0 O= 0 0 E 그℃ 흐픈셛 Exceptionally well- fully orofessional standard. Article is fully in the suggested journals. papers and reputable data sources. Cited sources are highly relevant to the topic and of high quality. 10 Ill. Feedback Opportunities Formative (Whilst you're working on the coursework) You will have an opportunity for peer feedback on a draft of your work during Week 17. You can also join the online tutorials during Weeks 15 and 17 for support. Queries can be posted on the discussion forums in the NOW learning room. Summative (After you've submitted the coursework) You will receive specific feedback regarding your coursework submission together with your awarded grade when it is returned to you. Clearly, feedback provided with your coursework is only for developmental purposes so that you can improve for the next assessment or subjectrelated module. IV. Resources that may be useful Referencing styles: please use the journal-specific style as detailed here. Guide to planning your time here and an automated planner here. Further guidance on avoiding cheating is here. Remember to use Outlook or physical calendars to block out time between lectures and labs to work on this coursework. V. Moderation The Moderation Process All assessments are subject to a two-stage moderation process. Firstly, any details related to the assessment (e.g., clarity of information and the assessment criteria) are considered by an independent person (usually a member of the module team). Secondly, the grades awarded are considered by the module team to check for consistency and fairness across the cohort for the piece of work submitted. VI. Aspects for Professional Development The report itself covers examples of: Writing a scientific-style report Researching existing literature Referencing appropriately Construction and proper labelling of figures Many of these are useful transferable skills for employment applications or your Skills Portfolio. Similarly, the practical class protocols provide several examples appropriate for use in the Skills Portfolio as bioscience (i.e. subjectspecific) skills. Candida infections Zoe Taylor The Candida genus has over 200 species in it, however only few of these species are pathogenic. The main 5 clinically important are discussed in this review: Candida tropicalis, Candida krusei, Candida glabrata, Candida parapsilosis and Candida albicans. Superficial and invasive Infections are most commonly found in the immunocompromised. Cases of superficial infection usually influence the mucosal membranes, whereas invasive infections are seen all over the body’s organs. In this review, we cover the main and emerging pathogens, epidemiology, symptoms, diagnosis and treatment of these significant Candida species, while introducing the worrying challenges antifungal resistance poses to the at-risk populations. Pathogenic Candida species cause problems for immunocompromised The genus Candida boasts over 150-200 recognised species; this review will focus on distinct pathogenic species, adapted to survive in the human host as commensal bacteria and behave opportunistically when the hosts immune and antimicrobial defences are compensated. Candida albicans is most common species of the Candida genus and where most research is focused [1]. Candida bacteria are the cause of most fungal infections and around 90% of these are due to five species, Candida tropicalis, Candida krusei, Candida glabrata, Candida parapsilosis and the most common, Candida albicans. Candida fungus can cause mucosal and cutaneous infections as well as systemic [2]. They pose a serious health risk to the immunocompromised and hospitalised, with the source of around 8% of nosocomial bloodstream infections being Candida species [3]. The incidence of Candida infections is rising, and many factors contribute to the risk of catching opportunistic fungi infections, including the increase in immunocompromised patients with mucosal or cutaneous barrier disruption and neutrophil defects, an aging population and the escalated use of broad-spectrum antibiotics, transplants and chemotherapeutics [2]. Main and emerging human pathogens Candida albicans Candida albicans colonizes a multitude of locations in the body, including the gastrointestinal and genitourinary tracts of healthy people. It is the most common fungal species found in human microbiota. Adjustments in host immunity, resident microbiota, stress and other circumstances provokes C. albicans to overgrow, causing two main types of infections in humans: superficial candidiasis in the vaginal and oral regions, and life-threatening disseminated candidiasis [4]. To successfully infect the host, C. albicans depends on an array of virulence factors (Figure 1); the ability to morphologically convert between yeast and hyphal forms, the compilation of biofilms, thigmotropism, phenotypic switching and then expression of adhesins and invasins on the cell surface are a few pathogenicity mechanisms [5]. Highlights Candida species such as C. albicans transition from commensal to opportunistic pathogens frequently in immunocompromised hosts. Mucosal and invasive infections are the consequence of this transition and are a major cause of mortality. Optimal diagnosis and treatment options are needed to improve these mortality rates, as well as tacking growing antifungal resistance. Key Figure Pathogenicity mechanisms in Candida species. Figure 1. An outline of the different mechanisms of pathogenicity used by Candida species. (A) Expression of adhesins allows yeast cells to adhere to cell surface membranes. (B-C) When the yeast cells come into contact with the cell surface membrane, it triggers the yeast cell to transform into hyphae and directed growth by thigmotropism. (D) Switching (phenotypic plasticity) is thought to influence antigenicity and biofilm formation. (E) In medical devices (specifically catheters), biofilms can form, usually with yeast cells on device and hyphae cells on top of the biofilm. (F) Fitness traits can influence fungal pathogenicity as well as virulence factors. These include heat shock proteins (Hsps) in the response to stress, the uptake of amino acids, excretion of NH₃ can cause yeast cells to turn into hyphae, the uptake of compounds such as carbon and nitrogen and fundamental metals iron, zinc, copper and magnesium [5]. With the increase of opportunistic fungal infections and the rise in use of antifungals for prophylaxis in patients, CNA species colonization has become more prevalent in the immunocompromised populations. C. tropicalis has emerged as the second most virulent Candida species to C. albicans. It is known for its ability to form true hyphae like C.albicans, to produce strong biofilms and have properties which make it highly adherent to epithelial and endothelial cells [6]. C. tropicalis is frequently found in neutropenic hosts, specifically those with cancers such as leukaemia. It poses a great threat to these patients due to the ability of it to move through the bloodstream to peripheral organs [7]. Another emerging Candida pathogen is Candida krusei, especially among patients suffering from acute leukaemia and other haematological malignancies. Naturally it is resistant to fluconazole, a standard antifungal agent. It is therefore found most commonly in patients who have previously been treated with fluconazole. The mortality rate for Candida krusei infections is higher than C.albicans and other Candida species [8]. The widespread use of immunosuppressive therapy and antimycotic therapy has led to Candida glabrata infections to rise significantly. It was previously a nonpathogenic commensal fungus, but now is the third most common cause of candidiasis. Like C.albicans it can cause systemic and mucosal infections in immunocompromised hosts. Despite these similarities, C.glabrata is not dimorphic and is found as blastoconidia in both pathogenic and non-pathogenic form. Like C. krusei, C.glabrata infections are difficult to treat and have a high mortality rate [9]. The frequency of Candida parapsilosis infections has drastically increased over the past decade and is a leading cause of invasive Candida disease. High risk patients include neonates and those in intensive care. The fungus is strongly associated with hyperalimentation solution, indwelling catheters and prosthetic devices. It is able to form biofilms on catheters and other implanted devices, as well as adhere to prosthetics and secrete hydrolytic enzymes, allowing them to persist in the hospital environment [10]. Epidemiology Candida species have become the most common cause of significant fungal infections. C.albicans has historically accounted for 70-80% of Candida infection isolates while CNA species, C.tropicalis and C.glabrata accounted for around 5-8% of isolates. Epidemiological studies from recent years have highlighted a mycological shift where Candida species such as C.glabrata, C.tropicalis, C. krusei and C.parapsilosis are becoming more common [11]. Table 1 shows the global estimates of Candida infections; however, these figures are now 3 years out of date, therefore population distribution may have changed. Table 1. Annual incidence of the different types of Candida infections in 2016 [Taken from 12,13]. Risk factors of invasive candidiasis IC infections have been rising since the 1980s, specifically in immunocompromised populations and in patients who have been hospitalized with underlying conditions [14]. It is a leading cause of mortality, with candidemia being the most frequent clinical presentation of IC. Factors contributing to the increased incidence include the expanded use of broad spectrum anti-fungal agents, the number of immunocompromised patients using intravenous catheters, a rise in the number of invasive procedures, use of therapeutic drugs and transplantation [15]. Glossary Invasive candidiasis: A critical Candida infection that can affect many organs in the body, including the blood, eyes and brain. Candida non-albicans species: Candida species that does not include the most common type, Candida albicans Candidemia: The existence of Candida in the blood stream. Vulvovaginal candidiasis: A condition affecting over 75% of women in their lifetime. Caused by an overgrowth of Candida yeast in the vagina and vulva. Oral candidiasis: The overgrowth of Candida in the mucosal membranes of the mouth. Species distribution Candida is now the fourth most common organism found in blood cultures in patients who have been hospitalized. In patients with AIDS, the most common fungal infection is Candida [14]. The difference in distribution of Candida species in patients can be related to varying factors. Candida parapsilosis is commonly identified in neonates with candidemia and usually originates exogenously, contaminating medical devices and subsequently leading to central venous catheter-associated candidemia’s [15]. Other NAC species like Candida glabrata, Candida tropicalis and Candida krusei are found in blood cultures from patients who are 65 and over. These patients present with risk factors including solid tumours, abdominal surgery, haematological malignancies, transplants and corticoid steroid treatments [16]. Geographically, C. albicans accounts for over half of the incidences of candidaemia in Europe. Incidence rates for NAC infections showed C.glabrata and C.parapsilosis at 14%, C.tropicalis at 7% and C.krusei at 2% [17]. In North America, despite C.albicans being the most prevalent species, C. glabrata and other NAC species are emerging [18]. C. parapsilosis is prevalent in Latin America, Australia and the Mediterranean. In Chile, there is progressive expansion of NAC infections, with C.parapsilosis overtaking C.albicans as the most abundant species, followed by C. tropicalis and C.glabrata[19]. In Brazil, 20.9% of cases were C. tropicalis, 40.9% C.albicans, 20.5% C.parapsilosis and 4.9% C.glabrata [20]. Symptoms Oral Oral candidiasis (OC) has a variety of clinical manifestations. Classically, it presents as acute pseudomembranous, acute and chronic erythematous (atrophic) and chronic hyperplastic variants [21]. Other Candida-associated lesions include median rhomboid glossitis, angular cheilitis and linear gingival erythema, although the latter’s microbial aetiology is poorly understood. Oral pseudomembranous candidiasis (thrush) is distinguished by white pseudomembranes, formed of desquamated epithelial cells, fungal hyphae and fibrin. The white patches can be found on the hard and soft pallet, surface of the labial and buccal mucosa, tongue, oropharynx and periodontal tissues. Other conditions can also present with these symptoms, such as lichen panus and squamous cell carcinoma, therefore it is imperative that clinicians look at patient history and identify any underlying diseases. However, pseudomembranous candidiasis accounts for one third of oropharyngeal candidiasis cases, and because it is so common it is straightforward to diagnose [22]. Vulvovaginal Vulvovaginal candidiasis (VVC) can be categorized as either sporadic or recurrent, depending on how frequent episodes of infection are. Clinically it is vital to distinguish between these two categories in order to manage them effectively. Symptoms include irritation, vulvovaginal pruritus, dyspareunia, white ‘cheesy’ discharge and burning when urinating. Unfortunately, both individually and collectively, none of these symptoms are pathognomonic [23]. Invasive Invasive candidiasis (IC) incorporates a myriad of different clinical conditions, the most common being candidaemia. This is associated with a high mortality rate and long stays in hospital. Another, deep-seated candidiasis causes various syndromes which involve the liver, heart, eyes, spleen , kidney, mengies, bone, peritoneum and lungs. This can be with or without concomitant candidaemia [24]. Invasive candidiasis has non-specific symptoms and is usually a nosocomial infection, with many risk factors contributing to the different symptoms exhibited by patients (Table 2) [25]. As there are no disease specific symptoms or clinical signs of IC, research presents a variety of different manifestations seen by patients. Most have found that patients presenting with persistent fever which is unresponsive to broad spectrum antibiotics is indicative of IC. It is also reported that some patients (19% of cases) developed septic shock, found in a point prevalence study [26]. Another study has shown a higher incidence of renal and hepatic failure and lower lactate dehydrogenase levels in patients with septic shock caused by Candida species than the bacterial septic shock [27]. Table 2. The risk factors involved in invasive Candidiasis and the subsequent range of symptoms observed [Taken from 25]. Diagnosis Oral Diagnosis of OC is usually started by taking patient history and a thorough examination of the mouth. This involves examining the hard and soft pallet and buccal mucosa (for those with dentures) [28]. Correct diagnosis for acute pseudomembranous and chronic atrophic candidiasis is made by identifying a characteristic lesion and its response to antifungal therapy. There diagnosis can be made clinically, however if anti-fungal treatment fails, subsequent culture and sensitivity testing should be carried out. This includes imprint cultures using Sabouraud’s broth. Sterile foam pads are dipped in the broth and then placed on the lesion for 30 seconds. They are then cultured in Sabouraud’s agar with chloramphenicol for an hour and then incubated. A biopsy is recommended for acute atrophic and chronic hyperplastic forms on top of this, as these presentations may mimic other diseases such as squamous cell carcinoma [22]. Vulvovaginal As VVC is not pathognomonic, an accurate diagnosis cannot be made from a patient’s history and physical examination alone. Laboratory tests are needed to reliably diagnose patients due to the wide range of other causes for these nonspecific symptoms. Despite this, VVC is commonly diagnosed from only a physical examination and self-diagnosis, leading to over-the-counter purchase of antifungal medication [29]. Methods used in the laboratory are summarised in figure 2. These include microscopy using saline solution to detect yeast blastospores or pseudohyphae or using 10% potassium hydroxide. The potassium hydroxide test has a higher sensitivity out of the two, however one third of cases produce a negative result [30]. Microscopy with saline solution poses difficulty in recognising blastospores which don’t form hyphae or pseudohyphae from nonalbicans strains. Still, these two tests in amalgamation with a normal vaginal pH reading is usually indicative of vulvovaginal candidiasis and excludes other sources [31]. Key Figure Diagnosis of vulvovaginal candidiasis Figure 2. Investigation and laboratory diagnosis of vulvovaginal candidiasis in patients showing signs and symptoms[23]. Invasive IC is hard to diagnose due to the most common manifestation being candidaemia which is largely asymptomatic. There is also a lack of disease specific symptoms, like vulvovaginal candidiasis [32]. Therefore, there are a variety of diagnostic methods used. IC can be diagnosed using direct, such as blood cultures and indirect detection, using PCR assays and surrogate markers. A number of diagnostic tests must be used as no laboratory test is 100% accurate in diagnosis of IC. Blood cultures Blood cultures are used to detect Candida which resides in the bloodstream. Despite only having 50-70% sensitivity (reported in autopsy studies), they are the gold standard technique when diagnosing candidaemia [33]. The sensitivity of modern blood culture techniques is reduced by intermittent shedding of organisms from the blood stream, non-viable organisms and also through blood volumes having low pathogen numbers therefore it is recommended to sample frequently [34]. Deep-seated candidiasis is diagnosed by the growth of positive cultures from collected sterile tissue samples, however these are hard to obtain [33]. Other drawbacks of blood cultures include slow turnaround times and that positive results may only be seen in late stages of the disease. If a blood culture returns positive, immediate treatment should be given [35]. Molecular techniques Molecular tests for diagnosis of IC include the β-D-glucan assay and Candida mannan antigens and antimannan antibodies (table 2). β-D-glucan is component of the cell wall of different important fungi [36]. It can detect candidaemia and intraabdominal candidiasis, however it has low sensitivity and specificity, which is sometimes overestimated due to studies using healthy and mildly ill patients. Other limitations include false positive results in patients with high risk of IC due to a high rate of contamination. Nonetheless, β-D-glucan has a negative predictive value for invasive candidiasis in places where IC has a low to moderate prevalence. For these reasons, these tests are not commonly used in many European laboratories [37,38]. PCR assays also exists to diagnose IC. A Nguyen et al. study found an 89% sensitivity for deep-seated candidiasis that wasn’t detected on blood cultures. Two commercial PCR methods have been marketed in recent years; SeptiFast in 2015 and T2Candida Panel which has been recently tested one clinical trial, showing encouraging results (table 2) [39]. Another commercial whole-blood multiplex PCR assay that detects 5 of the most medically significant Candida species has reported a 94% sensitivity [40]. An automated PCR based method named a T2 magnetic resonance assay has found to be encouraging in rapid diagnosis of IC [41]. These detection methods do have disadvantages, they have restricted validation and standardization, which has halted their implementation and progression into laboratories [42]. Other ways for diagnosing IC include MALDI-TOF, which has been promising in accelerating the right identification of Candida spp. [43]. In diagnosis of endophthalmitis, patients with visual disturbance are recommended to receive a dilated fundoscopy [44]. When Candida species are found in urine or respiratory isolates, the fungi have colonized, although if neutropenic patients have symptomatic candiduria this can indicate to the presence of Candida cystitis and needs treatment [45]. Table 3. The different types of laboratory-based tests used to diagnose IC. CSF denotes cerebrospinal fluid, CNS central nervous system, IQR interquartile range. A spiked sample is a negative sample where Candida has been added [Taken from 24]. Treatment Treatment is given on suspicion of Candida infection, even in absence of clinical symptoms. There are four main classes of anti-fungal drugs with treat mucosal and invasive Candida infections. These are as follows; azoles, echinocandins, polyenes and nucleoside analogues (figure 3) [46]. Key Figure Antifungal treatments for Candida Figure 3. The different classes of treatment for Candida infections and their mode of action [Taken from 76]. Azoles As seen in figure 3, azoles are the largest group of antifungal drugs. They work by inhibiting lanosterol 14-α-demethylase, causing disturbance in the cell membrane [47]. Lanosterol 14-α-demethylase is an enzyme which is required for the biosynthesis of ergosterol, the biggest sterol element of the cell membrane in funguses. There is no cross reactivity with host cells as ergosterol differs structurally to cholesterol found in human cell membranes. Azoles can be used both topically and for therapy in IC. Drugs in this category include imidazole’s, triazoles and posaconazoles [47,49]. An example of when azoles are used is in vulvovaginal candidiasis. Fluconazole, ketoconazole and itraconazole are highly effective when treating uncomplicated versions of the disease [50]. Fluconazole has particular advantages in singledosages as it is still secreted from vaginal tissue in therapeutic concentrations after 72 hours. Studies have shown that all three drugs are clinically and mycologically equivalent (single-dose fluconazole, single-day itraconazole) [51]. However, in complicated vulvovaginal candidiasis, studies have compared single-dose fluconazole with multidose 7-day treatments of miconazole or clotrimazole. Patients with a history of recurrent VVC showed a reduced response to both therapies, highlighting the need for it to be treated longer with anti-fungal therapy [52]. Studies are ongoing to find the correct oral treatment regime. In severe infection, the 7-day multidose treatment worked better than the single-dose of fluconazole [53]. Polyenes Polyenes also bind to ergosterol (figure 3), disrupting the cell membrane and leading to the production of aqueous pores. This causes the cells permeability to alter, cytosolic components leak, and the cell to die. Drugs in this family include nystatin and amphotericin B [54]. Polyenes are used in the treatment of IC, and amphotericin B has a low minimum inhibitory concentration resistance patterns and broad activity throughout most Candida species [55]. It has been the first line treatment for severe Candida infections for 5 decades, however it has toxic adverse effects, including infusion reactions and kidney damage. Other therapies have been proposed for IC; a Duarte et al study compared caspofungin with amphotericin B, reporting significantly less drug-related adverse effects in the caspofungin group [56]. Echinocandins Echinocandins are a relatively new antifungal agent. They inhibit the synthesis of the fungal wall by blocking (1,3)-β-D-glucan synthase non-competitively (figure 3)[57]. This causes the cell walls to have a damaged structure, leading to osmotic lysis. Echinocandins include the drugs caspofungin, micafungin and anidulafungin and the all have concentration-dependent anti-fungal activity against most Candida species [58]. They are used in treatment of oesophageal candidiasis, IC and candidaemia. They have a lower incidence of infusion related unpleasant effects and their nephrotoxicity is lower than amphotericin B [59]. Despite this, they have an adverse effect of hepatoxicity and therefore liver function needs to be monitored. The drug is also more expensive than azole therapies and therefore their use may be limited to cases where azole resistance is found [60]. Nucleoside Analogues Nucleoside Analogues inhibit DNA and RNA synthesis (figure 3) by inhibiting thymidylate synthase [61]. Therapies in this family include flucytosine, and it is commonly used together with amphotericin B for treatment of CNS candidiasis. Studies have shown that flucytosine is effective in small doses at frequent time intervals. Bone marrow toxicity is a side effect linked to large concentrations [62]. Antifungal resistance The extensive use of some of the drugs mentioned in treatments has encouraged selection pressure and subsequent antifungal resistance [63]. Resistant C.albicans strains have been seen frequently in people with HIV and oropharyngeal candidiasis [64]. Despite this, NAC species are more frequently showing resistance, most significantly in C.glabrata and C.parapsilosis [65]. Azole resistance Around 7% of bloodstream Candida infections show resistance to fluconazole, the most used drug for C.albicans infections [66]. The rise in infection from NAC species is thought to be due to their intrinsic azole resistance. This ability for Candida species to have high levels of azole resistance is well documented, with research showing C. glabrata with the highest. Patients with oropharyngeal candidiasis have shown higher levels of fluconazole resistance depending on whether they have been previously treated with the drug [67]. Resistance arises through a multitude of mechanisms; decreasing the concentration of azole inside the cell via the upregulation of efflux pumps, decreasing the drugs target affinity and counterbalancing the drugs effect [68]. Polyene resistance It is rare for antifungal resistance to develop in polyenes such as amphotericin B, even though it has been around for over 30 years. However, as there has been an increase in infections caused by NAC species, resistance to amphotericin B resistance has recently risen [69]. Studies have shown C.glabrata and C.krusei have higher minimum inhibitory concentrations to polyenes than C.albicans, meaning that larger doses of amphotericin B are needed, and more antifungal resistance has been reported in these species [70]. Resistance occurs because of a decrease in ergosterol in cell membranes. Studies have shown that isolates of Candida species that are resistant to polyenes have lower ergosterol levels than susceptible species [71]. Echinocandin resistance Despite resistance in polyenes being rare, echinocandin resistance is a serious problem due to their critical importance in the treatment of invasive candidiasis. Resistance is most frequent in C.glabrata, with a 7.4% increase from 2001-2010 [72]. In even more worrying statistics, species are emerging with resistance to echinocandins and azoles [73]. Resistance arises due to point mutations in genes which code for (1,3)-β-D-glucan synthase, causing reduced target processivity for the drug [74]. Even with the treatments discussed in this review, therapy for Candida infections is limited, and the evolvement of antifungal resistance, new treatments are needed. Studies have shown that antifungal treatments that intervene early are important in effective treatment of IC . Once an effective approach has been defined, mortality rates should decline [24]. Conclusion and future perspectives Pathogenic Candida species have been an emerging threat to at risk populations for decades. Excluding fairly common infections such as vulvovaginal and oral candidiasis, IC is now the most common fungal disease found in hospital patients and it poses serious danger to those at most risk, causing up to 40% mortality [75]. Fortunately, its management has improved vastly in the past 10 years. Patients are able to receive intervention in the early stages of disease thanks to new laboratory methods such as PCR assays and antigen tests. However, more research is needed into non-culture-based tests to fully validate their ability to strongly diagnose IC. Even with the treatments discussed in this review, therapy for Candida infections is limited, and the evolvement of antifungal resistance, new treatments are needed. Studies have shown that antifungal treatments that intervene early are important in effective treatment of IC . Once an effective approach has been defined, mortality rates should decline [24]. References 1. ODDS, F.C., 1987. Candida Infections: An Overview. Critical Reviews in Microbiology, 15 (1), 1-5. 2. TURNER, S.A. and BUTLER, G., 2014. The Candida Pathogenic Species Complex. Cold Spring Harbor Perspectives in Medicine, 4 (9), a019778. 3. M. A. PFALLER and D. J. DIEKEMA, 2007. Epidemiology of Invasive Candidiasis: a Persistent Public Health Problem. Clinical Microbiology Reviews, 20 (1), 133-163. 4. NOBILE, C.J. and JOHNSON, A.D., 2015. Candida albicans Biofilms and Human Disease. Annual Review of Microbiology, 69, 71-92. 5. MAYER, F.L., WILSON, D. and HUBE, B., 2013. Candida albicans pathogenicity mechanisms. Virulence, 4 (2), 119128. 6. MARCOS-ZAMBRANO, L.J., et al., 2014. Production of biofilm by Candida and non- Candida spp. isolates causing fungemia: Comparison of biomass production and metabolic activity and development of cut-off points. International Journal of Medical Microbiology, 304 (8), 11921198. 7. KOTHAVADE, R.J., et al., 2010. Candida tropicalis: its prevalence, pathogenicity and increasing resistance to fluconazole. Journal of Medical Microbiology, 59 (Pt 8), 873880. 8 M. A. PFALLER, et al., 2008. Candida krusei, a Multidrug-Resistant Opportunistic Fungal Pathogen: Geographic and Temporal Trends from the ARTEMIS DISK Antifungal Surveillance Program, 2001 to 2005. Journal of Clinical Microbiology, 46 (2), 515-521. Outstanding Questions What early treatment interventions could be developed to decrease mortality rates in invasive candidiasis? What non-culture diagnostic tests could build on the current available ones for the most specific and sensitive diagnosis of Candia infections? What can be done to avoid the ever-emerging antifungal resistant strains of Candida species? 11. BANERJEE, S.N., et al., 1991. Secular trends in nosocomial primary bloodstream infections in the United States, 1980–1989. The American Journal of Medicine, 91 (3), S86-S89. 12. BROWN, G.D., et al., 2012. Hidden killers : human fungal infections. Science Translational Medicine, 4 (165), 165rv13. 13.VOS, T., Prof, et al., 2012. Years lived with disability (YLDs) for 1160 sequelae of 289 diseases and injuries 1990–2010: a systematic analysis for the Global Burden of Disease Study 2010. Lancet, The, 380 (9859), 21632196. 14.MAIKEN CAVLING ARENDRUP, et al., 2005. Seminational Surveillance of Fungemia in Denmark: Notably High Rates of Fungemia and Numbers of Isolates with Reduced Azole Susceptibility. Journal of Clinical Microbiology, 43 (9), 4434-4440.. 15. ANA ESPINEL-INGROFF, et al., 2009. Comparison of 24-Hour and 48Hour Voriconazole MICs as Determined by the Clinical and Laboratory Standards Institute Broth Microdilution Method (M27-A3 Document) in Three Laboratories: Results Obtained with 2,162 Clinical Isolates of Candida spp. and Other Yeasts. Journal of Clinical Microbiology, 47 (9), 2766-2771. 16. QUINDÓS, G., 2013. Epidemiology of candidaemia and invasive candidiasis. A changing face. Revista Iberoamericana De Micologia, 31 (1), 42-48. 17. TORTORANO, A.M., et al., 2006. Candidaemia in Europe: epidemiology and resistance. International Journal of Antimicrobial Agents, 27 (5), 359366. 17. TORTORANO, A.M., et al., 2006. Candidaemia in Europe: epidemiology and resistance. International Journal of Antimicrobial Agents, 27 (5), 359366. 18. DAVID L. HORN, et al., 2009. Epidemiology and Outcomes of Candidemia in 2019 Patients: Data from the Prospective Antifungal Therapy Alliance Registry. Clinical Infectious Diseases, 48 (12), 16951703. 19. Ajenjo H, M. C., Aquevedo S, A., Guzmán D, A. M., Poggi M, H., Calvo A, M., Castillo V, C., . . . Labarca L, J. (2011). Epidemiologial profile of invasive candidiasis in intensive care units at a university hospital. Revista chilena de infectologia : organo oficial de la Sociedad Chilena de Infectologia, 28(2), 118. Retrieved from https://www.ncbi.nlm.nih.gov/ pubmed/21720690. 20. NUCCI, M., et al., 1998. Fungemia in cancer patients in Brazil: Predominance of non-albicans species. Mycopathologia, 141 (2), 6568. 21. Akpan, A. and Morgan, R., 2002. Oral candidiasis. Postgraduate medical journal, 78(922), pp.455-459. 22. MILLSOP, J.W. and FAZEL, N., 2016. Oral candidiasis. Clinics in Dermatology, 34 (4), 487-494. 23. SOBEL, J.D., et al., 1998. Vulvovaginal candidiasis: Epidemiologic, diagnostic, and therapeutic considerations. American Journal of Obstetrics and Gynecology, 178 (2), 203-211. 24. KULLBERG, B.J. and ARENDRUP, M.C., 2015. Invasive Candidiasis. The New England Journal of Medicine, 373 (15), 1445-1456. 25. MAARTENS, G. and WOOD, M.J., 1991. The clinical presentation and diagnosis of invasive fungal infections. The Journal of Antimicrobial Chemotherapy, 28 Suppl A (suppl A), 13-22. 26. VINCENT, J., et al., 2009. International Study of the Prevalence and Outcomes of Infection in Intensive Care Units. JAMA: The Journal of the American Medical Association, 302 (21), 2323-2329. 27. HADLEY, S., et al., 2002. Candidemia as a cause of septic shock and multiple organ failure in no immunocompromised patients. Critical Care Medicine, 30 (8), 1808-1814. 28. ABU-ELTEEN, K.H. and ABUALTEEN, R.M., 1998. The prevalence of Candida albicans populations in the mouths of complete denture wearers. The New Microbiologica, 21 (1), 41. 29. FERRIS, D.G., et al., 2002. Overthe-counter antifungal drug misuse associated with patient-diagnosed vulvovaginal candidiasis. Obstetrics & Gynaecology, 99 (3), 419-425. 30. SCHAAF, V.M., 1990. The limited value of symptoms and signs in the diagnosis of vaginal infections. Archives of Internal Medicine, 150 (9), 1929-1933. 31. ILKIT, M. and GUZEL, A.B., 2011. The epidemiology, pathogenesis, and diagnosis of vulvovaginal candidosis: A mycological perspective. Critical Reviews in Microbiology, 37 (3), 250261. 32. CUENCA-ESTRELLA, M., et al., 2012. ESCMID guideline for the diagnosis and management of Candida diseases 2012:diagnostic procedures. Clinical Microbiology and Infection, 18, 9-18. Diagnostics Will Improve Understanding of Disease Spectrum and Transform Patient Care. Clinical Infectious Diseases, 56 (9), 12841292. 34. CUENCA-ESTRELLA, M., et al., 2012. ESCMID guideline for the diagnosis and management of Candida diseases 2012:diagnostic procedures. Clinical Microbiology and Infection, 18, 9-18. 35. PETER G. PAPPAS, et al., 2009. Clinical Practice Guidelines for the Management of Candidiasis: 2009 Update by the Infectious Diseases Society of America. Clinical Infectious Diseases, 48 (5), 503-535. 36 LUIS OSTROSKY-ZEICHNER, et al., 2005. Multicenter Clinical Evaluation of the (1→3) β-D-Glucan Assay as an Aid to Diagnosis of Fungal Infections in Humans. Clinical Infectious Diseases, 41 (5), 654-659. 37. TISSOT, F., et al., 2013. β-Glucan Antigenemia Anticipates Diagnosis of Blood Culture–Negative Intraabdominal Candidiasis. American Journal of Respiratory and Critical Care Medicine, 188 (9), 1100-1109. 38. MARTÍNEZ-JIMÉNEZ, M.C., et al., 2015. Candida biomarkers in patients with candidaemia and bacteraemia. The Journal of Antimicrobial Chemotherapy, 70 (8), 2354-2361. 39. CHANG, S., et al., 2013. Multiplex PCR System for Rapid Detection of Pathogens in Patients with Presumed Sepsis – A Systemic Review and MetaAnalysis. PLoS ONE, 8 (5), e62323. 40. BARBARA LUCIGNANO, et al., 2011. Multiplex PCR Allows Rapid and Accurate Diagnosis of Bloodstream Infections in Newborns and Children with Suspected Sepsis. Journal of Clinical Microbiology, 49 (6), 22522258. 41. MYLONAKIS, E., et al., 2015. T2 Magnetic Resonance Assay for the Rapid Diagnosis of Candidemia in Whole Blood: A Clinical Trial. Clinical Infectious Diseases : An Official Publication of the Infectious Diseases Society of America, 60 (6), 892-899. 42. TOMER AVNI, LEONARD LEIBOVICI and MICAL PAUL, 2011. PCR Diagnosis of Invasive Candidiasis: Systematic Review and Meta-Analysis. Journal of Clinical Microbiology, 49 (2), 665-670. 43. LACROIX, C., et al., 2014. Evaluation of two matrix-assisted laser desorption ionization-time of flight mass spectrometry (MALDI-TOF MS) systems for the identification of Candida species. Clinical Microbiology and Infection, 20 (2), 153-158. 44. VINIKOOR, M.J., et al., 2013. Do all candidemic patients need an ophthalmic examination? International Journal of Infectious Diseases, 17 (3), e146e148. 45. RELLO, J., et al., 1998. The Role of Candida sp Isolated from Bronchoscopic Samples in Nonneutropenic Patients. Chest, 114 (1), 146-149. 46. MATHEW, B. and NATH, M., 2009. Recent Approaches to Antifungal Therapy for Invasive Mycoses. ChemMedChem, 4 (3), 310323. 47. KATSAMBAS, A., et al., 2015. European Handbook of Dermatological Treatments. Third edition. ed. Berlin, Heidelberg: Springer. 48. H. Hof, “A new, broad-spectrum azole antifungal: posaconazole— mechanisms of action and resistance, spectrum of activity,” Mycoses, vol. 49, no. 1, pp. 2–6, 2006. 49. R. Hay, “Antifungal drugs,” in European Handbook of Dermatological Treatments, A. Katsambas and T. Lotti, Eds., pp. 700– 710, Springer, Berlin, Germany, 2003. 50. SUSAN E. REEF, et al., 1995. Treatment Options for Vulvovaginal Candidiasis, 1993. Clinical Infectious Diseases, 20 (Supplement_1), S80S90. 51. SOBEL, J.D., et al., 1995. Single oral dose fluconazole compared with conventional clotrimazole topical therapy of Candida vaginitis. American Journal of Obstetrics and Gynaecology, 172 (4), 1263-1268. 52. Houang ET, Chappatte O, Byrne D, Macrae P~ Thorpe JE. Fluconazole levels in plasma and vaginal secretions of patients after a 150miUigram single oral dose and rate of eradication of infection in vaginal candidiasis. Antimicrob Agents Chemother 1990;34:909-10. 53. MARTIN, M.V., 1999. The use of fluconazole and itraconazole in the treatment of Candida albicans infections: a review. The Journal of Antimicrobial Chemotherapy, 44 (4), 429-437. 54. D. Sanglard and F. C. Odds, “Resistance of Candida species to antifungal agents: molecular mechanisms and clinical consequences,” The Lancet Infectious Diseases, vol. 2, no. 2, pp. 73–85, 2002. 55. CORONADO-CASTELLOTE, L. and JIMÉNEZ-SORIANO, Y., 2013. Clinical and microbiological diagnosis of oral candidiasis. Journal of Clinical and Experimental Dentistry, 5 (5), 279. 56. MORA-DUARTE, J., et al., 2002. Comparison of Caspofungin and Amphotericin B for Invasive Candidiasis. The New England Journal of Medicine, 347 (25), 2020-2029. 64. J. Peman, E. Can’t ´ on, and A. Espinel-Ingroff, “Antifungal drug ´ resistance mechanisms,” Expert Review of Anti-Infective Therapy, vol. 7, no. 4, pp. 453–460, 2009. 57. ] N. Grover, “Echinocandins: a ray of hope in antifungal drug therapy,” Indian Journal of Pharmacology, vol. 42, no. 1, pp. 9–11, 2010. 65. D. S. Perlin, “Antifungal drug resistance: do molecular methods provide a way forward?” Current Opinion in Infectious Diseases, vol. 22, no. 6, pp. 568–573, 2009. 58. D. Cappelletty and K. EiselsteinMcKitrick, “The echinocandins,” Pharmacotherapy, vol. 27, no. 3, pp. 369–388, 2007. 59. KEATING, G.M. and FIGGITT, D.P., 2003. Caspofungin: A Review of its Use in Oesophageal Candidiasis, Invasive Candidiasis and Invasive Aspergillosis. Drugs, 63 (20), 22352263. 60. GROVER, N.D., 2010. Echinocandins: A ray of hope in antifungal drug therapy. Indian Journal of Pharmacology, 42 (1), 9-11. 61. ] A. Vermes, H.-J. Guchelaar, and J. Dankert, “Flucytosine: a review of its pharmacology, clinical indications, pharmacokinetics, toxicity and drug interactions,” Journal of Antimicrobial Chemotherapy, vol. 46, no. 2, pp. 171–179, 2000 62. PEA, F. and LEWIS, R.E., 2018. Overview of antifungal dosing in invasive candidiasis. The Journal of Antimicrobial Chemotherapy, 73 (suppl_1), i33-i43. 63. A. Espinel-Ingroff, “Novel antifungal agents, targets or therapeutic strategies for the treatment of invasive fungal diseases: a review of the literature (2005– 2009),” Revista Iberoamericana de Micologia, vol. 26, no. 1, pp. 15–22, 2009. 66. WHALEY, S.G., et al., 2016. Azole Antifungal Resistance in Candida albicans and Emerging Non-albicans Candida Species. Frontiers in Microbiology, 7, 2173. 67. ] T. Noel, “The cellular and molecular defense mechanisms of ¨ the Candida yeasts against azole antifungal drugs,” Journal de Mycologie Medicale ´ , vol. 22, pp. 173–178, 2012. 68. ] R. D. Cannon, E. Lamping, A. R. Holmes et al., “Efflux-mediated antifungal drug resistance,” Clinical Microbiology Reviews, vol. 22, no. 2, pp. 291–321, 2009. 69. KAITLYN C. GRAY, et al., 2012. Amphotericin primarily kills yeast by simply binding ergosterol. Proceedings of the National Academy of Sciences of the United States of America, 109 (7), 2234-2239. 70. ] J. H. Rex, T. J.Walsh, J. D. Sobel et al., “Practice guidelines for the treatment of candidiasis, ”Clinical Infectious Diseases, vol. 30, no. 4, pp. 662–678, 2000. 71. ] A. Espinel-Ingroff, “Mechanisms of resistance to antifungal agents: yeasts and filamentous fungi,” Revista Iberoamericana de Micologia, vol. 25, no. 2, pp. 101–106, 2008. 72. ] B. Alexander, M. Johnson, C. Pfeiffer et al., “Increasing echinocandin resistance in Candida glabrata: clinical failure correlates with presence of FKS mutations and elevated minimum inhibitory concentrations,” Clinical Infectious Diseases, vol. 56, pp. 1724–1732, 2013.#73. 73. ARENDRUP, M. and PERLIN, D., 2014. Echinocandin resistance: an emerging clinical problem? Current Opinion in Infectious Diseases, 27 (6), 484-492. 74. ] J. N. Kahn, G. Garcia-Effron, M.-J. Hsu, S. Park, K. A. Marr, and D. S. Perlin, “Acquired echinocandin resistance in a Candida krusei isolate due to modification of glucan synthase,” Antimicrobial Agents and Chemotherapy, vol. 51, no. 5, pp. 1876–1878, 2007 75. M. A. PFALLER and D. J. DIEKEMA, 2007. Epidemiology of Invasive Candidiasis: a Persistent Public Health Problem. Clinical Microbiology Reviews, 20 (1), 133-163. 76. CLAUDIA SPAMPINATO and DARÍO LEONARDI, 2013. Candida Infections, Causes, Targets, and Resistance Mechanisms: Traditional and Alternative Antifungal Agents. BioMed Research International, 2013, 204237. Candida: Epidemiology, Pathogenesis, Diagnosis, and Treatment. Highlights Introduction Candida species such as Candida albicans, Candida infections are considered one of the most Candida glabrata, Candida parapsilosis, prevalent kinds of opportunistic yeast infection [1,2]. They responsible for causing fungal infection in the Candida krusei, and Candida tropicalis are constitute a lethal form of infection that can affect the human body. organs but are commonly identified by yeast growth in C. albicans is considered as one of the most bloodstream samples. The number of Candida infections has been increasing dramatically all over the world because of the increased number of immunocompromised patients [3,4,5]. The cases of Candida species are responsible for causing fungal infection, with Candida albicans, Candida glabrata, Candida prevalent kinds of Candida species. The pathogenic Candida species are capable of causing local and superficial infections in the vagina, intrauterine device, anal, and oral cavity. Candida infections are known to be a major threat to global public health. C. albicans is the most predominant and parapsilosis, Candida krusei, and Candida tropicalis being widespread species in UK and China. identified Diagnostic approaches that can be used for as the most prevalent [6,7,8,33]. The pathogenicity of the Candida species has been linked to various virulence factors, including the ability to evade the candidiasis detection include: examination, c direct - -D- Glucan method, and Polymerase Chain defence systems of the host, biofilmformation, adherence, Reaction (PCR) techniques. and the production of hydrolytic enzymes that damage The primary therapeutic agents for Candida tissues [5,10]. Even though C. albicans are the key cause alternative of Candida infections in humans, they are known to form infections are antifungal treatments can drugs, also help with candidiasis management. an important component of the commensal flora among a large percentage of the healthy population [1,10,11,12,33]. Studies have shown that colonisation by C. albicans is beneficial to individuals because it hinders the growth and multiplication of pathogenic fungi and enhances the proper functioning of the immune system [1,2]. The opportunistic fungi within the Candida genus can become pathogenic when the immune system is weakened. It has been observed that the pathogenic Candida species cause high rates of morbidity and mortality globally, and thus represent a significant threat to public health [6,13,14]. The Candida species are responsible for 1 causing various superficial and systemic infections [15]. It is recommended that individuals with invasive candidiasis receive early and effective treatment because delayed initiation of therapy is linked with increased mortality [16,17]. Another significant challenge associated with some Candida species is the development of resistance to the various systemic antifungals and their capacity to spread fast within healthcare institutions [16,17,18]. The development of new drugs with novel targets and efficient antifungal properties has contributed to improving the control of Candida infections [20,21,22]. This review will discuss Candida infections by focusing on the characteristics of the pathogenic organisms in the genus Candida, the symptoms of the disease and epidemiology, diagnosis, and treatment. Characteristics of Candida genus The organisms that belong to the genus Candida are mainly yeasts, and occur in the unicellular form. They are small in size (46µm) and have a thin wall, as well as an ovoid aspect referred to as blastospheres [29]. Most of the organisms under the genus Candida are reproduced by budding. The available evidence indicates that there are over 200 species of Candida, but only a few species have harmful effects on humans [12,31]. The characteristics of the common pathogenic Candida species are summarised in Table 1. The Candida genus forms part of the human microbiota and resides in the Candida species Characteristics Candida albicans The first most commonly found fungal pathogen globally. It is responsible for various infections, including oropharyngeal thrush, esophagitis, genital candidiasis, cutaneous candidiasis, and deep candidiasis [19,49,52]. Candida Causes systemic candidiasis and candidemia tropicalis in immunosuppressed individuals. Candidemia can be linked to severe myalgia and myositis [19,61]. Candida glabrata Second most common cause of candida infections after C. albican. Causes systemic candidiasis, urinary tract infections, and candidaemia [19,29,49]. Candida Linked with deep-seated infections related to parapsilosis implanted devices. Infections also linked to contaminated solution [19,49]. Candida krusei Linked with candidaemia, diarrhoea in infants, and endophthalmitis [19,61]. Candida Associated with endocarditis in drug abusers, guillermondii as well as systemic candida [19]. Candida Causes oropharyngeal infections in patients dubliniensis with HIV [19,49]. Table 1. Characteristics of the Candida species that are frequently found in human disease. human mucosae as well as the skin [3,24]. The genus can also occur in fruits, vegetables, the ground, animals, and in hospital environments. Despite occurring in hospitals, the Candida genus is not considered a laboratory contaminant [29]. The Candida genus is classified as an endogenous microbe because approximately 70% of individuals can 2 have it in the mucosal epithelium, particularly in the genital and gastrointestinal tracts [26]. C. albicans, which constitute the common species in the gastrointestinal and genitourinary tracts also cause vaginal infections in women, and are linked to mucocutaneous and mouth infections [3,27,46]. They are characterised by polymorphism, which is the capacity to occur in many forms, including blastospores, pseudohyphae, true hyphae, germ tubes, and chlamydospores [25,27,46]. The ability of C. albicans and other pathogenic species within the Candida genus to switch from one form of growth to another depends on the environmental conditions, which facilitate colonisation and invasion of the host organs [28,46]. C. albicans have a high degree of flexibility and are able to grow under diverse environmental conditions with regard to nutrient availability, pH, amount of oxygen available, temperature variation, and osmolarity [6,23]. Candida Infections The pathogenic Candida species have the capacity to cause local and superficial infections. Various classes of Candida infections have been identified over the years and they include: Vaginal candidiasis Vaginal infections, also known as vulvovaginal candidiasis (VVC), are very common. It is estimated that approximately 70% of women develop VVC at a certain period in their lifetime [32,34]. Further, over 80% of VVC is linked to C. albicans, with only 20% being caused by other species, usually C. glabrata [34,35]. This infection occurs mostly among pregnant women, especially during the final trimester of pregnancy [1,32,35]. This can be attributed to the fact that diabetes causes immune dysfunction. Other risk factors for VVC infection include antibiotic therapies, use of oral contraceptives, engaging in sexual activities that involve oral-genital contact, and having immunosuppressed immunity [1,32,35]. Although it is not a significant threat to life, VVC is challenging and unpleasant, causing a variable degree of itching and abnormal whitish discharge. Other common symptoms include development of rash 3 around the vagina, a burning feeling when urinating or having sex, and redness or swelling around the vagina [1]. Intrauterine candidiasis Despite the reported high incidence of VVC, intrauterine candidiasis is considered a rare infection [37]. This forms if infection occurs during pregnancy. The occurrence of this type of infection should be avoided, especially during the final few weeks of pregnancy, because of its capacity to extend to the uterus and cause complications, and even infect the child before birth [1,38]. The common symptoms of intrauterine candidiasis include: the presence of a widespread rash and maculopapular or pustular-vesicular. Anal candidiasis Anal candidiasis is characterised by pruritis or intense itching, accompanied by localised erythmia or a burning sensation around the anus [1,39,40]. The skin usually appears macerated with circumscribed lesions. Anal candidiasis occurs commonly among children and women. Its occurrence in women is associated with the use of hormonal contraceptives, practice of oral and anal sex, and use of intimate hygiene products [1]. Oral candidiasis This is the most common form of candida infection within the oral cavity, and is mainly caused by the invasion of Candida species, especially C. albicans [41,43]. Other species of Candida which cause oral candidiasis include C. tropicalis, C. glabrata, and C. krusei [43]. Oral candidiasis commonly occurs in the extremes of age [41,44]. Approximately 7% of infants are at risk of developing oral candidiasis. The prevalence of oral candidiasis is approximately 9-30% in AIDS patients and about 20% in those with cancer. Further, oral candidiasis is known to affect individuals with immune system disorders and those with dental prostheses. Healthy individuals also face the risk of developing oral infection, with approximately 30-45% of the healthy adults being carriers of candida organisms [44]. The common symptoms associated with this infection include the presence of whitish papules or small spots on the tongue or in the inner region of the cheeks, a painful or 4 burning sensation in the mouth, difficulty eating or swallowing, and redness in the mouth [1]. Mucocutaneous candidiasis Mucocutaneous candidiasis can be classified into genitourinary disease and nongenitourinary disease. Oropharyngeal manifestations are common among individuals with nongenitourinary candidiasis, and are usually diagnosed in immunocompromised patients [46]. Areas of the body that are moist, warm, or sweaty serve as good environments for the growth of yeast. These areas include the skin between toes and fingers, armpits, the region under the breasts, and the groin [1]. The key risk factors associated with the development of mucocutaneous candidiasis include: poor hygiene, wearing tight undergarments, having diabetes, antibiotic use, and having a weakened immune system. The symptoms associated with Candida skin infection include the development of a red rash in the affected part and the formation of blister-like lesions [1]. Epidemiology of Candida Infections The available evidence indicates that over 17 types of Candida species have been identified as key causative agents of Candida infections [5,28,51]. The National Nosocomial Infections Surveillance System (NNISS), and most recent studies, have shown that Candida species is the fourth most commonly isolated pathogen in US hospitals [9,12]. Candida infections are known to be a significant threat to public health globally. C. albicans colonises approximately 90% of the total human population, but in most cases does not cause infection or any health issues [5,12]. The incidence of invasive candida is reported to be lower in Europe and the US compared to other regions of the world. However, the incidence rates experienced an increase in the two regions from the 1970s to the 1990s before the situation was stabilised [51,53]. In Europe, the highest incidence has been reported in Denmark (10.4 cases per 100,000 individuals) [53]. The UK was reported to have an overall rate of 3.6 cases per 100,000 individuals in 2016 and 2017. During this period, the three Candida species frequently identified from blood samples were C. albicans (42%), C. glabrata (23%), and C. parapsilosis (11%) [72]. In the US, the average incidence of candidiasis between 2013 and 2017 was approximately 9 per 100,000 individuals [54]. In china, as illustrated in 5 the (Figure 1), C. albicans is the most predominant and widespread species (46.4%). Other prevalent Candida species include C. parapsilosis at 19.5%, C. glabrata (15.9%), C. tropicalis (14.6%), and C. dubliniensis, C. guillier-mondii, and Candia spp each at 1.2% [55]. Figure 1. Illustration of the distribution of Candida species responsible for causing Candida in China [55]. Diagnosis Diagnosis is important not only for the confirmation of infection, but also for the identification and initiation of the appropriate treatment. Diagnosis of candidiasis has been reported to be difficult due to the non-specific nature of clinical presentation. Some of the key diagnostic approaches that can be employed for diagnosis of candidiasis include: Direct examination Direct microscopic examination is a rapid and cost-effective method that can be used to diagnose candidiasis [27,28,48]. It is carried out using wet mount preparation. This 6 approach involves swabbing or scraping the infected area and placing the obtained swab on a microscopic slide. 10% potassium hydroxide (KOH) solution is then added so as to dissolve the skin cells without interfering with the integrity of the Candida cells. The KOH solution aids in digesting the proteinaceous debris. This is important for enabling complete visualisation of the pseudohyphae and the yeast cells of the various Candida species [27,28,47]. The appearance in direct microscopy of mycelial forms of Candida is a diagnostic marker of candidiasis; however, in the C. glabrata situation, a major cause of VVC cannot be diagnosed with microscopic examination, only because this species of Candida is haploid and does not develop hyphae or pseudohyphae invitro [28,36]. Culture method The media most widely employed for the isolation of Candida species is Sabouraud dextrose agar (SDA), as shown in the (Figure 2) [27,28,30]. Its low pH value allows Candida to grow while inhibiting the reproduction of other bacteria [27]. For the isolation of Candida, a sterile swab is rubbed onto the area that is infected and the swab is then stroked across the SDA medium [30]. Because SDA is not a differential medium, it is difficult to distinguish the colonies of varying yeast species developed on this agar. Chromogenic agars and Pagano-Levin agars are therefore sometimes utilised. Yeast infections can thus be diagnosed much more quickly, as the Candida species can be differentiated through the colour of their colonies, as shown in the (Figures 3,4) [28,30]. Some species of Candida (such as C. krusei, C. parapsilosis and C. tropicalis) are sensitive to cycloheximide; SDA with cycloheximide should not be used as a single isolation of the Candida species [28,36]. Improvements in blood culturing techniques have also contributed to improving sensitivity and lowering the time required to detect a positive blood culture. One of the culture methods that is commonly used is the comprehensive digestive stool analysis (CDSA). This method aids in determining the existence of digestive disturbances as well as the functional and clinical status of the gastrointestinal tract, which may be one of the major causes of Candida's overgrowth [1]. 7 Figure2. Colonies of Candida spp on SDA [28]. Figure 3. Different morphotypes of Candida albicans on Pagano-Levin agar [28]. Figure 4. Differentiation of Candida spp. on CHROM agar [28]. 8 - -D-Glucan method - -D-Glucan assay is a chromogenic, quantitative enzyme immunoassay (EIA) [57]. The cell walls of all the Candida - -D-glucan (BDG) as a structural component [27,28,45,57]. Given that this polysaccharide does not occur in other organisms such as viruses, bacteria, or mammals, its detection in the circulation of patients can be used to indicate the presence of Candida infections [27]. BDG can help to diagnose Candida infections in their early stages. The levels of BDG may also be a valuable tool for monitoring how a patient is responding to therapy. [45].The interpretation of the test results must take into account the possibility of false positivity and false negativity. Researchers have reported a number of factors that can cause a false positive BDG result, such as abdominal surgery, haemodialysis and being treated with -lactam antibiotics [28,45]. False positive results can also be caused by receiving blood products, albumin, immunoglobulin, coagulation factors, or plasma protein that has been fraction filtered through BDG-containing filters. This is also true for high triglycerides, haemoglobin (hemolysed samples) and bilirubin [45]. Polymerase Chain Reaction (PCR) techniques Various PCR techniques have been developed to aid in the identification of Candida species. The sensitivity of PCR-based techniques enhances the possibility of detecting infections during the early stages, when it is relatively easy to treat or prevent their clinical manifestation [58,59,60,63]. PCR is an amplification method that provides rapid and objective identification of Candida species. Prior to amplification, primers are selected according to the appropriate target sequences. Studies have shown that the sensitivity of PCR assays depends mainly on various aspects including sample preparation, DNA target selection, extraction of DNA, and efficiency of amplification [64,65]. Before conducting PCR, it is recommended to obtain DNA from appropriate samples. In most cases, serums or whole blood samples from individuals with Candida infections are used [65,66,67]. Appropriate target nucleic acid is critical for the success of PCR. As a result, species-specific sequences are often used so as to produce better diagnostic results. 9 Treatment of Candida Infections Treatments aimed at managing Candida infections are often based on the anatomic status, the type of species responsible for the infection, and the susceptibility of the Candida species to antifungal agents [27,44]. Antifungal drugs have been widely used for the clinical treatment of Candida infections [44]. Even though there are numerous types of antifungal drugs, only a few classes are available to treat systemic infections associated with Candida species, as shown in (Figure 5). Azoles inhibit Lanestrol 14- -Demethylase Azoles form the largest class of antifungal drugs. Azoles mainly disrupt the cell membrane by binding and inhibiting the lanosterol 14- -demethylase enzyme [3,62] which is involved in the generation of ergosterol, as shown in (Figure 5). Ergosterol has been identified as the largest sterol component of fungal cell membranes. Most of the azoles are effective when used topically or when used as prophylaxis of invasive of Candida infections [3,16]. The common drugs found within the azole family include: imidazoles, triazoles, and posaconazole [3]. Echinocandins Inhibit glucan synthesis Echinocandins are lipopeptidic antifungal drugs that function by inhibiting the synthesis of the fungal wall. This is achieved by inhibiting the (1, 3)- -D-glucan synthase enzyme, as illustrated in (Figure 5) [3,12]. The inhibition of the enzyme activity results in the formation of fungal cell walls that have poor structural integrity, and this results in the vulnerability of the cells to osmotic lysis [14]. The common echinocandins include: micafungin, caspofungin, and anidulafungin. All these types of drugs exhibit concentration-dependent activity against the various Candida species [3]. Polyenes Bind ergosterol Polyenes function by binding to ergosterol and consequently disrupt the lipidic component of the fungal cell membrane [3,12]. This leads to the formation of aqueous spores. Moreover, the permeability of the cells is altered, thus leading to the leakage 10 of cytosolic components and eventually the death of the invasive Candida species [56]. Examples of polyenes include nystatin and amphotericin B [12]. Nucleoside analogues Inhibit DNA/RNA synthesis Nucleoside analogues such as flucytosine are transported into the cells of the invasive Candida by cytosine permeases. The members of this group of drugs are then deaminated to 5-fluorouracil and subsequently phosphorylated to 5-fluorodeoxyuridine monophosphate. The fluorinated nucleotide functions by inhibiting thymidylate synthase, and in the process interferes with the DNA formation. The 5fluorodeoxyuridine monophosphate can undergo further phosphorylation and be integrated into RNA, thus affecting both RNA and protein synthesis [12,42]. Allylamines Disrupt cell membrane Allylamines inhibit squalene epoxidase and in the process disrupt the cell membrane. Allylamines have been shown to be effective against various fungal agents such as the azole-resistant Candida species [3,12]. Treatment with allylamines results in the accumulation of squalene in cells while ergosterol is reduced. The subsequent steps in the ergosterol biosynthetic pathway also become blocked. Allylamines cause the death of fungal cells through accumulation of squalene, which in turn alters the plasma membrane and interferes with membrane organisation [3,44,50]. This causes increased permeability of the membrane and eventually cell death. Examples of allylamines include terbinafine and naftifine. 11 Figure 5. The common antifungal classes and their modes of action [12]. Alternative treatment Studies have shown that certain factors, such as high sugar diets, antibiotic therapies, allergies and other factors, can interfere with the normal balance of the intestinal environment, thus killing the beneficial bacteria and stimulating the overgrowth of pathogenic microbes [1,68]. Complementary treatment mechanisms can therefore be employed to reduce and control the levels of Candida. The key alternative treatment approaches that can be taken into consideration include: 12 Nutrition and diet Dietary factors can affect and enhance the overgrowth of the Candida species. Therefore, adhering to a special diet as a form of treatment for candidiasis may be beneficial. Given that C. albicans grow in environments rich in sugar, there is a need to avoid refined sugars including sucrose, sweetened foods, and fruit juice. In addition, it is necessary to avoid diets with high content of yeast or fungi, such as alcoholic beverages, bread, and fermented food products [1,27]. Milk and other daily products can also be avoided because they contain high levels of lactose that promote overgrowth of Candida and are also considered the most common food allergens. The presence of traces of antibiotics in milk and dairy products can disrupt the gastrointestinal bacterial flora [44,96,70]. Enhancing the immune system A weakened immune system allows rapid growth of C. albicans and other invasive Candida species [1,52,71]. Therefore, restoring optimal functioning of the immune system can aid in the management of candidiasis. Various strategies can be employed to enhance the immune system, including: effective management of stress, nutritional supplementation, diet restriction, use of plant-based medicines, exercise, and glandular therapy [1]. Conclusion Every individual is exposed to the various candidiasis predisposing factors, and as such it is almost impossible to avoid the risk factors. Candida infections can affect different parts of the body, including the gastrointestinal tract, vagina, and the skin. Candida infections are considered a significant public health issue. The past few decades have witnessed an increase in Candida infections globally due to the rising population of immunocompromised patients. C. albicans constitute the most common Candida species and are responsible for causing more than 60% of all the Candida infections in humans. The common Candida infections which have been outlined include genital candidiasis, intrauterine candidiasis, anal candidiasis, mucocutaneous candidiasis, and oral candidiasis. Proper diagnosis is important for the identification 13 and confirmation of the infections and for facilitating the initiation of appropriate treatment. The key diagnostic approaches that can be used with individuals suspected - D-glucan method, and Polymerase Chain Reaction (PCR) techniques. Antifungal drugs are the primary treatment agents for Candida infections. The antifungal drugs have been placed into various classes depending on their mechanisms of action, including: azoles, achinocandins, polyenes, nucleoside analogues, and allylamines. In addition to the use of pharmaceutical agents, alternative treatments can aid in the management of candidiasis, with the common approaches being: adherence to a special diet and improving the immune system. References 1. Martins, N. et al. (2014) Candidiasis: Predisposing Factors, Prevention, Diagnosis and Alternative Treatment. Mycopathologia. 177, 223-240. 2. Vázquez-González, D. et al. (2013). Opportunistic yeast infections: candidiasis, cryptococcosis, trichosporonosis and geotrichosis. JDDG: Journal der Deutschen Dermatologischen Gesellschaft. 11, 381-394. 3. Kabir, M. and Ahmad, Z. (2013) Candida Infections and Their Prevention. ISRN Preventive Medicine. 2013, 1-13. 4. Kothavade, R. et al. (2010) Candida tropicalis: its prevalence, pathogenicity and increasing resistance to fluconazole. Journal of Medical Microbiology. 59, 873-880. 5. Sardi, J. et al. (2013) Candida species: current epidemiology, pathogenicity, biofilm formation, natural antifungal products and new therapeutic options. Journal of Medical Microbiology. 62, 10-24. 6. De Oliveira Santos, GC. et al. (2018) Candida infections and therapeutic strategies: mechanisms of action for traditional and alternative agents. Frontiers in microbiology. 9, 1351. 7. Pfaller, M. et al. (2010) Results from the ARTEMIS DISK Global Antifungal Surveillance Study, 1997 to 2007: a 10.5-Year Analysis of Susceptibilities of Candida Species to Fluconazole and Voriconazole as Determined by CLSI Standardized Disk Diffusion. Journal of Clinical Microbiology. 48, 1366-1377. 14 8. Turner, S. and Butler, G. (2014) The Candida Pathogenic Species Complex. Cold Spring Harbor Perspectives in Medicine. 4, 019778-019778. 9. Ramage, G. et al. (2001) Characteristics of biofilm formation by Candida albicans. Revista iberoamericana de micología. 18, 163-70. 10. Silva, S. et al. (2011) Adherence and biofilm formation of non-Candida albicans Candida species. Trends in Microbiology. 19, 241-247. 11. Rosenbach, A. et al. (2010) Adaptations of Candida albicans for Growth in the Mammalian Intestinal Tract. Eukaryotic Cell. 9, 1075-1086. 12. Spampinato, C. and Leonardi, D. (2013) Candida Infections, Causes, Targets, and Resistance Mechanisms: Traditional and Alternative Antifungal Agents. BioMed Research International. 2013, 1-13. 13. Matthaiou, DK. et al. (2015) How to treat fungal infections in ICU patients. BMC infectious diseases. 15, 205. 14. Pappas, PG. et al. (2015) Clinical practice guideline for the management of candidiasis: 2016 update by the Infectious Diseases Society of America. Clinical Infectious Diseases. 62, 1-50. 15. Tsui, C. et al. (2016) Pathogenesis of Candida albicans biofilm. Pathogens and Disease. 74, 018. 16. Ben-Ami, R. (2018) Treatment of Invasive Candidiasis: A Narrative Review. Journal of Fungi. 4, 97. 17. Van De Veerdonk, F. et al. (2010) Novel strategies for the prevention and treatment of Candida infections: the potential of immunotherapy. FEMS Microbiology Reviews. 34, 1063-1075. 18. Ku, TS. et al. (2018) Candida auris: disinfectants and implications for infection control. Frontiers in microbiology. 9, 726. 19. Eggimann, P. et al. (2003) Epidemiology of Candida species infections in critically ill non-immunosuppressed patients. The Lancet Infectious Diseases. 3, 685-702. 20. Lee, H. and Lee, D. (2018) Novel Approaches for Efficient Antifungal Drug Action. Journal of Microbiology and Biotechnology. 28, 1771-1781. 15 21. Li, Y. et al. (2018) Promising antifungal targets against Candida albicans based on ion homeostasis. Frontiers in cellular and infection microbiology. 8. 22. Parente-Rocha, J. et al. (2017) Antifungal Resistance, Metabolic Routes as Drug Targets, and New Antifungal Agents: An Overview about Endemic Dimorphic Fungi. Mediators of Inflammation. 2017, 1-16. 23. Dühring, S. et al. (2015) Host-pathogen interactions between the human innate immune system and Candida albicans understanding and modeling defense and evasion strategies. Frontiers in Microbiology. 6. 24. Krüger, W. et al. (2019) Fungal-Bacterial Interactions in Health and Disease. Pathogens. 8, 70. 25. Neville, BA. et al. (2015) Candida albicans commensalism in the gastrointestinal tract. FEMS yeast research. 15. 26. Raimondi, S. et al. (2019) Longitudinal Survey of Fungi in the Human Gut: ITS Profiling, Phenotyping, and Colonization. Frontiers in Microbiology.10. 27. Hani, U. et al. (2015) Candidiasis: A Fungal Infection- Current Challenges and Progress in Prevention and Treatment. Infectious Disorders - Drug Targets.15, 42-52. 28. Deorukhkar, SC. And Saini,S. (2014) Laboratory approach for diagnosis of candidiasis through ages. International Journal of Current Microbiology and Applied Sciences. 3, 206-18. 29. Cortes, J. and Corrales, I. (2018) Invasive Candidiasis: Epidemiology and Risk Factors. In Fungal Infection (Loreto, E. and Tondolo, J.), 1-25, IntechOpen. 30. Ilkit, M. and Guzel, A. (2011) The epidemiology, pathogenesis, and diagnosis of vulvovaginal candidosis: A mycological perspective. Critical Reviews in Microbiology. 37, 250-261. 31. Tsai, P. et al. (2013) Study of Candida albicans and its interactions with the host: A mini review. BioMedicine. 3, 51-64. 32. Jeanmonod, R. and Jeanmonod, D. (2018) Candidiasis, Vaginal (Vulvovaginal Candidiasis). InStatPearls (Internet), 1-11, StatPearls Publishing. 16 33. Mahmoudi Rad, M. et al. (2011) The epidemiology of Candida species associated with vulvovaginal candidiasis in an Iranian patient population. European Journal of Obstetrics & Gynecology and Reproductive Biology. 155,199-203. 34. Zeng, X. et al. (2018) Risk Factors of Vulvovaginal Candidiasis among Women of Reprodu -Sectional Study. BioMed Research International. 2018,1-8. 35. Sobel, J. (2007) Vulvovaginal candidosis. The Lancet. 369, 1961-1971. 36. Chakravarthi, S. and Haleagrahara, N. (2011) A comprehensive review of the occurrence and management of systemic candidiasis as an opportunistic infection. Microbiol J. 1, 1-7. 37. Meizoso, T. et al. (2008) Intrauterine candidiasis: report of four cases. Archives of Gynecology and Obstetrics. 278, 173-176. 38. Kemp, MW. (2014) Preterm birth, intrauterine infection, and fetal inflammation. Frontiers in immunology. 5. 39. De Wet, P. et al. (1999) Perianal candidosis-a comparative study with mupirocin and nystatin. International Journal of Dermatology. 38, 618-622. 40. McGirt, L. and Martins, C. (2004) Dermatologic Diagnoses in the Perianal Area. Clinics in Colon and Rectal Surgery. 17, 241-245. 41. Akpan, A. and Morgan, R. (2002) Oral candidiasis. Postgraduate medical journal. 78, 55-9. 42. Rodrigues, ME. et al. (2016) Novel strategies to fight Candida species infection. Critical reviews in microbiology. 42, 594-606. 43. Taylor, M. and Raja, A. (2019) Oral Candidiasis (Thrush). InStatPearls (Internet), 1-12, StatPearls Publishing. 44. Patil, S. et al. (2015) Clinical appearance of oral Candida infection and therapeutic strategies. Frontiers in microbiology. 6. 45. Tran, T. and Beal, SG. (2016) Application of the 1, 3- -d-glucan (Fungitell) assay in the diagnosis of invasive fungal infections. Archives of pathology & laboratory medicine. 140, 181-5. 17 46. Achkar, J. and Fries, B. (2010) Candida Infections of the Genitourinary Tract. Clinical Microbiology Reviews. 23, 253-273. 47. Sobel, J. (2014) Genital candidiasis. Medicine. 42, 364-368. 48. Schelenz, S. et al. (2015) British Society for Medical Mycology best practice recommendations for the diagnosis of serious fungal diseases. The Lancet Infectious Diseases. 15, 461-474. 49. Yang, B. and Rao, R. (2018) Emerging Pathogens of the Candida Species. In Candida albicans (Sandai, E.), 1-18. IntechOpen. 50. Campoy, S. and Adrio, J. (2017) Antifungals. Biochemical Pharmacology. 133, 86-96. 51. Yapar, N. (2014) Epidemiology and risk factors for invasive candidiasis. Therapeutics and Clinical Risk Management. 95. 52. Nobile, C. and Johnson, A. (2015) Candida albicans Biofilms and Human Disease. Annual Review of Microbiology. 69, 71-92. 53. Lass-Flör,l C. (2009) The changing face of epidemiology of invasive fungal disease in Europe. Mycoses. 52,197-205. 54. Centers for Disease Control and Prevention. Invasive Candidiasis Statistics. Available https://www.cdc.gov/fungal/diseases/candidiasis/invasive/statistics.html from: [accessed 27th November 2019]. 55. Xiao, Z. et al. (2019) Epidemiology, species distribution, antifungal susceptibility and mortality risk factors of candidemia among critically ill patients: a retrospective study from 2011 to 2017 in a teaching hospital in China. Antimicrobial Resistance & Infection Control. 8, 89. 56. Bondaryk, M. et al. (2013) Antifungal agents commonly used in the superficial and mucosal candidiasis treatment: mode of action and resistance development. Advances in Dermatology and Allergology. 5, 293-301. 18 57. Theel, E. and Doern, C. (2013) Point- -d-Glucan Testing Is Important for Diagnosis of Invasive Fungal Infections. Journal of Clinical Microbiology. 51, 3478-3483. 58. Arvanitis, M. et al. (2014) Molecular and Nonmolecular Diagnostic Methods for Invasive Fungal Infections. Clinical Microbiology Reviews. 27, 490-526. 59. Dendis, M. et al. (2003) PCR-RFLP detection and species identification of fungal pathogens in patients with febrile neutropenia. Clinical Microbiology and Infection. 9, 1191-1202. 60. Maaroufi, Y. et al. (2004) Early Detection and Identification of Commonly Encountered Candida Species from Simulated Blood Cultures by Using a Real-Time PCR-Based Assay. The Journal of Molecular Diagnostics. 6, 108-114. 61. Safavieh, M. et al. (2017) Advances in Candida detection platforms for clinical and point-of-care applications. Critical reviews in biotechnology. 37, 441-58. 62. Hof, H. (2006) A new, broad spectrum azole antifungal: posaconazole mechanisms of action and resistance, spectrum of activity. Mycoses. 49, 2-6. 63. Springer, J. et al. (2012) Molecular techniques in the diagnosis of deep and systemic mycosis. Clinics in Dermatology. 30, 651-656. 64. Bretagne, S and Costa, J. (2005) Towards a molecular diagnosis of invasive aspergillosis and disseminated candidosis. FEMS Immunology & Medical Microbiology. 45, 361-368. 65. Chen, X. et al. (2011) Development of molecular assays in the diagnosis of Candida albicans infections. Annals of microbiology. 61, 403-9. 66. Kasai, M. et al. (2006) Use of quantitative real-time PCR to study the kinetics of extracellular DNA released from Candida albicans, with implications for diagnosis of invasive candidiasis. Journal of clinical microbiology. 44, 143-50. 67. Estran, C. et al. (2008) Testing the LightCycler Candida Kit M GRADE in artificiallycontaminated whole blood and serum: Consequences for the diagnosis of invasive candidiasis. Journal de Mycologie Médicale. 18, 36-38. 68. Langdon, A. et al. (2016) The effects of antibiotics on the microbiome throughout development and alternative approaches for therapeutic modulation. Genome Medicine. 8, 39. 19
Purchase answer to see full attachment
User generated content is uploaded by users for the purposes of learning and should be used following Studypool's honor code & terms of service.

Explanation & Answer

Please cheack and let me know if you have a question

Cystic Fibrosis and Respiratory Infections

Background
Cystic fibrosis (CF) began to be described clinically in 1905

Highlights

when Landsteiner conducted a study with patients with lung
infection related to pancreatic disease [1]. However, by this

been observed as a series of systemic clinical syndromes.

Dorothy Andersen described
for the first time the clinical
symptoms of CF differentiating
it from other diseases.

In 1936 Guido Fanconi used the term "Cystic Fibrosis" for the

It is as an autosomal recessive
genetic disease.

time cystic fibrosis was not recognized as a disease, it had only

first time to describe the association of exocrine pancreatic
insufficiency and chronic lung disease in children, but his
studies were not taken into account [2]. And two years later
Dorothy Andersen carried out a study and published the
clinical data of patients describing more fully the disease and
the histological changes of the pancreas, its correlation with

Mutations in CFTR gene
encoded the defective protein
product that causes CF.
Cystic fibrosis mainly affects
the pancreas, digestive and
respiratory tracts.

certain pathological symptoms of the respiratory system, she

Patients produce salty sweat.

called it the fibrocystic disease of the pancreas or

Cystic fibrosis has no cure.

mucoviscidosis, differentiating that of other digestive diseases
with similar symptoms, such as celiac disease [3]. This

Respiratory Infections are the
leading cause of death.

researcher also classified CF as an autosomal recessive
genetic disease [4].

Later in 1952, Paul di Sant'Agnese discovered that the disease

P. aeruginosa and S. aureus
are the most reported
pathogens
in
respiratory
disease.

was related to an electrolyte deficiency in sweat [5], and then a sweat test was standardized as a
diagnostic method and is still used.

And finally, in the 1980s it was identified that mutations in the transmembrane conductance
regulator (CFTR) gene encoded the defective protein product that causes CF. The ∆F508 variant
was also discovered [6, 7], which is currently known to be the most frequent, despite the fact that
more than 1800 mutations related to this disease have already been described.

Cystic Fibrosis Condition
The CF is a genetic disease caused by the by the presence of mutations in both copies of the
CFTR gene, which results in a defective function of the CFTR protein, which is responsible for
the transport of chloride anions and is present in different organs of the body, mainly in the

respiratory tract, gastrointestinal tract, pancreas, and liver, so it also translates into defective
function or tissue damage of these organs [8]. CFTR is associated with the production of sweat,
digestive fluids, and mucus, and when it stops working these secretions become thicker [9, 10].

In the respiratory tract, when this protein fails, secretions become denser and cannot be
eliminated by the mucociliary system, generating accumulations of mucus that can obstruct the
respiratory tract, giving an advantage to certain microorganisms to colonize and produce a chronic
infection, where an uncontrolled inflammatory response is activated. The accumulation of
cytokines and waste causes lung damage and bronchiectasis [11, 12].

Symptoms and Progression of the Disease
CF is characterized by presenting various symptoms that appear from childhood and last
throughout life, of which salty sweat, poor growth and little weight gain, fatty stool, clubbing of the
fingers and toes, accumulation of thick secretions, recurrent respiratory infections, cough, and
hypoxia stand out. In addition, it usually causes male infertility, due to the congenital absence of
the vas deferens. On some occasions, newborns suffer from intestinal obstruction due to
meconium ileus. Rarer cases can present coagulation problems and deficiency in the absorption
of vitamin K [13-17].

Figure 1. Health conditions related to Cystic Fibrosis [18].

Respiratory tract infections are associated with decreased lung function that progresses to
respiratory failure, which is the leading cause of death in CF patients [19].

Pathogens associated with the condition
People with CF are prone to developing recurrent respiratory infections from birth. Colonizing
microorganisms vary according to the age of the host individual. The figure 2 shows the most
frequent pathogenic microorganisms in patients of various age groups, it can be seen that S.
aureus is more commonly found at an early age and after 10 years, contrary to P. aeruginosa,
Achromobacter s., S maltophilia, and species of the Burkholderia cepaccia complex that appears
in adolescents and adults. Pulmonary infection most commonly occurs because a bacterial strain
mutates into a mucoid strain that produces a biofilm in the lung epithelium, allowing it to be
persistent [8, 20].

Figure 2. Prevalence of common respiratory pathogens in CF by age cutoff. (MDR-PA:
multidrug-resistant P. aeruginosa) [20].

Despite the fact that these bacteria are the classic pathogens in CF lung infection, the
development of improved culture methods and culture-independent approaches, where mass
sequencing technologies stand out, has allowed the identification of the complete microbiome
that makes life in the airways of each CF patient, which are chronically colonized with complex
polymicrobial infections [21]. Although CF is a monogenic disease, it is also multifactorial and the
genotype and microbiome profiles act simultaneously in the progression of the disease [22].

After knowing the microbiome, and its multiple domains, the real challenge lies in recognizing
which are the pathogens. When conducting this analysis, Filkins & O'Toole (2015) found that the
emerging pathogens or microorganisms that contribute to the progression of CF and poor
prognosis are bacteria (Streptococcus milleri group s., Non-tuberculous mycobacteria), fungi
(Trichosporon s.) and viruses (rhinovirus). Whereas, other organisms that were previously
considered pathogens are now considered normal microbiota and unlikely pathogens, such as
Stenotrophomonas maltophilia, Achromobacter s., Ralstonia s, Burkholderia gladioli, and
Streptococcus pneumoniae. [21, 23].

On the other hand, the accumulation of dense secretions in the lungs, makes this organ go from
having a completely aerobic microenvironment to having anaerobic zones with hypoxic or anoxic
conditions. This heterogeneity has a major impact on host-microbe interactions and indirectly on
disease progression. This is because the colonizing microbes must be equied to survive the host's
various conditions, in this case, low or varying oxygen concentrations. In which P. aeruginosa
stands out, which is traditionally considered aerobic, it can also survive and grow with little or no
oxygen, it can breathe nitrate and nitrite, and it has multiple oxidases that suort aerobic respiration
in low-oxygen conditions. This species can also ferment arginine and pyruvate as a form of
maintenance energy. In addition, such hypoxic or anoxic environments confer on the
microorganism a greater tolerance to antibiotics, to which coinfection with viruses contributes.
Mixed infections of bacteria, viruses, and / or fungi further increase the pro-inflammatory response
[24-27].

In some cases, other diseases can occur due to chronic respiratory tract infections such as
allergic bronchopulmonary aspergillosis (caused by Aspergillus fumigatus) that causes a
worsening of respiratory difficulties. Another serious disease causes lung damage and does not
respond to the usual antibiotics (caused by Mycobacterium avium). In addition, individuals with
CF are prone to pneumothorax [28].

Epidemiology
Cystic fibrosis (CF) is the autosomal recessive disease with the highest incidence in the
Caucasian population, of these approximately 1 in 3000 are born with this condition, and 12 out
of 30 are carriers of a mutation in the CFTR gene. In Latin Americans, it is less frequent and
occurs in 1 in 4,000 - 10,000. On the other hand, the Afro-Americans are affected in a proportion
of 1 in every 15,000 - 20,000. And it is even much less common in Asian Americans [29, 30].

According to data from the CF Foundation in the USA, at least 1,000 people are diagnosed with
this disease per year (Figure 3) [12].

Figure 3. The number of new diagnoses of CF and percentage of detected by newborn
screening (NBS) in the US per year [12].

It is known as a rare disease, and is categorized as one of the genetic diseases that shortens life
the most. It is very common in Western countries, where Finland stands out, in which one in every
80 people is a carrier of a mutation in the CFRT gene. The World Health Organization states that
in the European Union, one in every 2500 newborns may have CF [31-32].

Diagnosis
If a CF patient is not treated, he can die at an early age, which is why the diagnosis in newborns
is important, and even more so when there is a suspicion of a family history. Although more
notable symptoms appear in middle age (chronic cough, low weight gain or complications due to
malnutrition), the mean age at the time of diagnosis can vary from months to years. Preventing
the progression and complications of lung disease is key. It is now known that neonatal CF
screening increases survival [33-36].

Neonatal screening for cystic fibrosis was previously performed with serum immune-reactive
trypsinogen in a drop of blood, but this strategy did not give consistent results. Therefore, it is
now accompanied by the detection of the most frequent CFTR mutations [36].

The positive result of the neonatal screening should be followed up and the diagnosis completed
with a positive sweat test (sweat chloride> 60 mmol / L) or the presence of two mutations in the
CFTR gene [37].

Molecular Biology tests are carried out (new generation sequencing - NGS) for the identification
of pathogenic microorganisms that cause lung disease in CF patients.

Treatment and control
Although no cure has been found, many methods are used to treat the disease. Advances in the
knowledge of the disease and its associations have allowed the progressive development of a
series of drugs to treat patients with CF (Figure 4). Such treatments go hand in hand with the
broad characterization of the pathology in each patient. The combination of these together with
follow-up has provided increased survival rates [36].

Figure 4. Advances in the development of treatment for patients with CF [36].

When the cause of death of the patients was found to be malnutrition due to pancreatic
insufficiency, enzyme supplements were developed, along with a high-fat diet to treat CF patients,
to improve digestion and nutritional status [36].

Later it was discovered that many individuals with CF died from chronic respiratory infections
(Staphylococcus aureus, Pseudomonas aeruginosa, among others). However, it took several
years to find treatments for the lung disease, of which there are now antibiotics, surfactant and
systemic drugs (to counteract slimy secretions and excessive inflammation) [36].

The most important factor in CF therapy is to prevent and treat lung damage caused by thick
mucus and infection. Antibiotic treatment and pulmonary replacement therapy must be constant,
in some untreated cases, patients lose respiratory capacity and lung transplantation is necessary.
Antibiotics can be administered intravenously, inhaled, and orally, and are dependent on the
results of microbiological tests. Levofloxacin is commonly used in the treatment of P. aeruginosa
infections [37, 38].

Survival has increased, and children survive into adulthood thanks to intensive follow-up and
combined treatment. In Western Europe (where the highest incidence has been found), adults
with CF outnumber children 4. But resource-poor countries like Eastern Europe still have a low
proportion of adults with CF [36].

The discovery of the CFTR gene also revealed that CF harbors a large number of clinical
syndromes. With this approach, gene modulator therapies targeting the CFTR gene, such as
Elexacaftor / ivacaftor / tezacaftor, have been developed [37]. Patients also need supplements
such as vitamins (A, E, D and K) to counteract the deficiencies caused by the disease.

In others hands, some patients have late-onset symptoms or have only one symptom. Although
symptoms are slow to appear, patients can develop respiratory failure, and treatment of
symptomatic CF greatly improves the outcome [36, 39-41].

Other therapies to treat CF are still under study, such as the genetic edition that has not yet been
approved for human studies, and on the other hand, phage treatments against multi-resistant
bacteria for patients with respiratory infections of this type [42-44].

Conclusions
Cystic fibrosis is a disease rat, of genetic origin, that is inherited in an autosomal recessive way.
This disease is due to the defective function of the CFTR protein, which plays an important role
in the production of secretions. CF is characterized by being multifactorial and affects several
organs, of which the respiratory tract and gastrointestinal system are most affected.

The abnormal secretion of mucus in the airways allows the establishment of multiple organisms.
Among which can be found generally bacteria, and less frequently viruses and fungi. Among
which can be found generally bacteria, and less frequently viruses and fungi. These can be
pathogenic and cause chronic respiratory infections, the main cause of death in this disease.

Over the years, the findings on the characteristics of the disease have allowed the development
of new early detection techniques and the creation of treatments, which has meant an
improvement in survival.

References
1. Landsteiner, K. (1905). Darmverschluss durch eingedicktes Meconium; pancreatitis.
Zentralbl. Allg. Pathol. Ser. U, 16: 903.
2. Wiedemann HR. (1979). Guido Fanconi (1892–1979) in memoriam. Eur. J. Pediatr., 132,
131-132.
3. Andersen, DH. (1938). Cystic fibrosis of the pancreas and its relation to celiac disease: a
clinical and pathologic study. Am. J. Dis. Child. 56:344-399.
4. Andersen, DH & Hodges, RC. (1946). Celiac syndrome. V. Genetics of cystic fibrosis of
the pancreas with consideration of the etiology. Am. J. Dis. Child, 72, 62-80.
5. Di Sant'Agnese P, et al. (1953). Abnormal electrolyte composition of sweat in cystic
fibrosis of the pancreas; clinical significance and relationship to the disease. Pediatrics. 12 (5):
549–63.
6. Tsui L, et al. (1985) Cystic fibrosis locus defined by a genetically linked polymorphic DNA
marker. Science, 230, 1054-1057.

7. Rommens, J. et al. (1989). Identification of the cystic fibrosis gene: chromosome walking
and jumping. Science, 245, 1059-1065.
8. Blanchard, A., & Waters, V. (2019). Microbiology of cystic fibrosis airway disease. In
Seminars in respiratory and critical care medicine. Theme Medical Publishers. 40(06): 727-736.
9. Buckingham L. (2012). Molecular Diagnostics: Fundamentals. Methods and Clinical
Alications (2). Philadelphia: F.A. Davis Co.
10. Yankaskas JR, et al. (2004). Cystic fibrosis adult care: consensus conference report.
Chest. 125 (1): 1S–39S.
11. Konstan MW, et al. (2007). Scientific Advisory Group and the Investigators and
Coordinators of the Epidemiologic Study of Cystic Fibrosis. Risk factors for rate of decline in
forced expiratory volume in one second in children and adolescents with cystic fibrosis. J. Pediatr.;
151(02): 134-139, 139.e1.
12. Gibson RL, et al. (2003) Pathophysiology and management of pulmonary infections in
cystic fibrosis. Am. J. Respir. Crit. Care Med.; 168 (08) 918-951.
13. Quinton PM. (2007). Cystic fibrosis: lessons from the sweat gland. Physiology. 22 (3):
212–25.
14. Hardin D. (2004). GH improves growth and clinical status in children with cystic fibrosis,
a review of published studies. European Journal of Endocrinology. 151(1): S81-5.
15. O'Malley C. (2009). Infection control in cystic fibrosis: cohorting, cross-contamination, and
the respiratory therapist. Respiratory Care. 54 (5): 641–57.
16. Makker K, et al. (2009). Oxidative stress & male infertility. The Indian Journal of Medical
Research. 129 (4): 357–67.
17. Blackman S, et al. (2006). Relative contribution of genetic and nongenetic modifiers to
intestinal obstruction in cystic fibrosis. Gastroenterology. 131 (4): 1030–9.
18. Blausen.com staff. (2014). Medical gallery of Blausen Medical 2014. WikiJournal of
Medicine 1 (2).
19. Liou T, et al. (2001). Predictive 5-year survivorship model of cystic fibrosis. Am J
Epidemiol; 153 (04) 345-352.
20. Cystic Fibrosis Foundation. 2020. Cystic Fibrosis Foundation Patient 2019 Registry
highlights. Bethesda, Maryland.
21. Filkins, L. & O’Toole G. (2015) Cystic Fibrosis Lung Infections: Polymicrobial, Complex,
and Hard to Treat. PLoS Pathog 11(12): e1005258.
22. Françoise, A., & Héry-Arnaud, G. (2020). The Microbiome in Cystic Fibrosis Pulmonary
Disease. Genes, 11(5), 536.
23. Gilligan PH (2014) Infections in patients with cystic fibrosis: diagnostic microbiology
update. Clin Lab Med 34: 197–217.
24. Worlitzsch D, et al. (2002) Effects of reduced mucus oxygen concentration in airway
Pseudomonas infections of cystic fibrosis patients. J Clin Invest, 109: 317–325.
25. Brown P, et al. (2014). Directly sampling the lung of a young child with cystic fibrosis
reveals diverse microbiota. Ann Am Thorac Soc 11: 1049–1055.

26. Alvarez-Ortega C & Harwood C. (2007). Responses of P. aeruginosa to low oxygen
indicate that growth in the CF lung is by aerobic respiration. Mol Microbiol 65: 153–165.
27. Schobert M, & Jahn D. (2010). Anaerobic physiology of Pseudomonas aeruginosa in the
cystic fibrosis lung. Int J Med Microbiol 300: 549–556.
28. Amin R, et al. (2012). "Chemical pleurodesis versus surgical intervention for persistent
and recurrent pneumothoraces in cystic fibrosis". The Cochrane Database of Systematic
Reviews. 12: CD007481.
29. Sanders, D. B., & Fink, A. K. (2016). Background and Epidemiology. Pediatric clinics of
North America, 63(4), 567–584.
30. O'Sullivan B, & Freedman S. (2009). Cystic fibrosis. Lancet. 373(9678):1891–1904.
31. Hytönen M, et al. (2001). Cystic fibrosis gene mutations deltaF508 and 394delTT in
patients with chronic sinusitis in Finland. Acta Oto-Laryngologica. 121 (8): 945–7.
32. "WHO | Genes and human disease". Who.int. 2010-12-07. Retrieved on November,
2020, from: https://www.who.int/genomics/public/geneticdiseases/en/index2.html

33. Sims EJ, et al. (2007). Cystic fibrosis diagnosed after 2 months of age leads to worse
outcomes and requires more therapy. Pediatrics. 119: 19‐ 28.
34. Dijk FN, et al. (2011). Improved survival in cystic fibrosis patients diagnosed by newborn
screening compared to a historical cohort from the same centre. Arch Dis Child. 2011; 96: 1118‐
1123.
35. De Boeck, K. (2020). Cystic fibrosis in the year 2020: a disease with a new face. Acta
Paediatrica, 109(5), 893-899.
36. Hayes D, et al. (2019). Home Oxygen Therapy for Children. An Official American Thoracic
Society Clinical Practice Guideline. American Journal of Respiratory and Critical Care Medicine.
199 (3): e5–e23.
37. European Medicines Agency. (2016). Quinsair (Levofloxacin).
38. Office of the Commissioner (2019). FDA approves new breakthrough therapy for cystic
fibrosis. FDA. UU. EE.
39. De Boeck K, et al. (2017). The diagnosis of cystic fibrosis. Presse Med. 46: e97‐ 108.
40. Simmonds NJ. (2013). Ageing in cystic fibrosis and long‐term survival. Paediatr Respir
Rev; 14: 6‐ 9.
41. Wagener J, et al. Lung function decline is delayed but not decreased in patients with
cystic fibrosis and the R117H gene mutation. J Cyst Fibros. 2018; 17: 503‐ 510.
42. Schwank G, et al. (2013). Functional repair of CFTR by CRISPR/Cas9 in intestinal stem
cell organoids of cystic fibrosis patients. Cell Stem Cell. 13 (6): 653–8.
43. Hraiech S, Brégeon F, Rolain JM (2015). Bacteriophage-based therapy in cystic fibrosisassociated Pseudomonas aeruginosa infections: rationale and current status. Drug Design,
Development and Therapy. 9: 3653–63.

44. Trend S, et al. (2017). The potential of phage therapy in cystic fibrosis: Essential humanbacterial-phage interactions and delivery considerations for use in Pseudomonas aeruginosainfected airways. Journal of Cystic Fibrosis. 16 (6): 663–670.


Outline Answer

Cystic Fibrosis and Respiratory Infections (Review): It is presented schematically as it´s shown
in the following:


Background and Highlights



Cystic Fibrosis Condition



Symptoms and Progression of the Disease



Pathogens associated with the condition



Epidemiology



Diagnosis



Treatment and control



Conclusions



References.

it`s done.. please check... sorry it take me a lot of time

Cystic F...


Anonymous
Super useful! Studypool never disappoints.

Studypool
4.7
Trustpilot
4.5
Sitejabber
4.4

Related Tags