Author\'s ethical misconduct.
\r\n\tKey Features:
\r\n\t*Reviews the basics of plating technology including electroless and immersion technologies
\r\n\t*Covers microjoining and nanojoining processes in various device applications
\r\n\t*Examines applications of microjoining such as the wafer level packaging, biomedical research, medical implants etc.
Ethics in medical sciences research may not always translate into ethical publications. As peer pressure rises the ethics of conducting medical research and subsequent writing scientific papers and publications gradually erodes in the last couple of years. This phenomenon so much deeply penetrates into the medical researchers that various professional bodies, universities and governments are forced to press panic button against unethical medical research and publications [1]. Ethical violations in conducting medical research always promote unethical scientific publications. The most important outcome of any research is its findings and observations and definitely improper research or scientific misconduct will lead to unethical publications. The research misconduct that promotes unethical publication impacts badly on other researchers who follow the steps shown in unethical scientific publications and resulting wrong practices or applications on patients [2]. Scientific and research misconduct is defined very clearly by the Royal College of Physicians at Edinburgh—‘as any behaviour by a researcher, whether intentional or not, that fails to scrupulously respect high scientific and ethical standards. Various types of research misconduct include fabrication or falsification of data, plagiarism, problematic data presentation or analysis, failure to obtain ethical approval by the Research Ethics Committee or to obtain the subject\'s informed consent, inappropriate claims of authorship, duplicate publication and undisclosed conflict of interest (COI)’ [1]. The statement specifically mentioned that research misconduct does not end at the research works level but also extends to the publication level. One must note that research misconduct either is done intentionally or unintentionally—hardly it matters on its impact to the society that includes fellow researchers, authors, reviewers, editors, institutes, universities, nations and above all future students of medicine, professionals and patients as a whole. In the era of ‘publish or perish’ medical fraternity should not focus only on his/her career advancement but also consider the professional ethics including research and publication ethics seriously [3]. How serious a research misconduct may be the story of South Korean stem cell scientist Woo Suk Hwang is enough to speak to that! Dr. Hwang\'s revolutionary work on stem cells published in Science (2004 and 2005) and later found that both the papers are fakes [4].
\nAccording to Fanelli, research misconduct should be redefined as ‘any omission or misrepresentation of the information necessary and sufficient to evaluate the validity and significance of research, at the level appropriate to the context in which the research is communicated’ [5]. Faneli also stated that ‘scientific knowledge is reliable not because scientists are more clever, objective or honest than other people, but because their claims are exposed to criticism and replication’ [5].
\nThe consequence of research misconduct not only tarnishes the image of the spirit of science but also collaterally damages many things like:\n
Society and humanity: Wrong procedures, false and fabricated data bring out products, which may be considered unsafe for humanity. Here comes the publication ethics regulation, which perhaps control or prevent these danger.
Fellow researchers: Published data and knowledge derived from research misconduct in medical sciences will mislead fellow medical researchers and that will lead to huge loss of money, funds, times and reputations.
Medical practitioners and students: Medical practitioner also suffers a lot due to unethical research publications as many wrong diagnostic and therapeutic published guidelines lead to professional disaster for them. Medical students might be taught subjects and understanding based on false and fabricated data which will jeopardize the career of future doctors.
Public trust and Government policies: Research misconduct and subsequent unethical publications may destroy public trust on science. Such false information and data may misguide government and lead to implement some erroneous health policies and laws. The ultimate sufferers are common man and society.
Hence, we can say that all the stakeholders from researchers, institutions/universities, government agencies, medical journals or book publishers are going to be devastated by research misconduct, which may also be considered as the most serious scientific assault on human health sciences.
\nWhile conducting medical research, researchers are usually careful and take all the precautions against any sort of ethical violation either in human or in animal research as per the guidelines of various apex professional bodies. Institutional Regulatory Body/Institutional Ethical Committee of all the countries function near similar pattern which strictly follow Declaration of Helsinki and other international guidelines. In general, all the institutional ethics committee critically obey all the ethical principles as per the Declaration of Helsinki by World Medical Association (WMA), National Institute of Health (NIH), the Food and Drug Administration (FDA), Environmental Protection Agency (EPA), Singapore statement of research integrity, ICMR guidelines, etc. In a nutshell, American Psychological Association comes out with five principles for research ethics: (i) discuss intellectual property frankly, (ii) be conscious of multiple roles, (iii) follow informed consent rules, (iv) respect confidentiality and privacy and (v) tap into ethics resources [6]. NIH also summarizes the principles of ‘Codes and Policies for Research ethics’ as the following: (i) honesty, (ii) objectivity, (iii) integrity, (iv) carefulness, (v) openness, (vi) respect for intellectual property, (vii) confidentiality, (viii) responsible publication, (ix) responsible mentoring, (x) respect for colleagues, (xi) social responsibility, (xii) nondiscrimination, (xiii) competence, (xiv) legality, (xv) animal care and (xvi) human subject protection [7]. Unfortunately, such strong and mandatory authority is unavailable in case of research publications.
\nThis review is undertaken to discuss how medical publications might have abused various ethical norms not only while conducting research but also during the publication process. The review also discusses the possible preventive measures against unethical practices of research and publications.
\nThere are several ways in which ethical violation in medical research are noticed, namely altering instrumentation or research procedure, nonreplicable findings, copying ideas, copying results, false study design, inadequate data, falsifying ethical consent, image manipulations, plagiarism, duplicate publication, etc. These unethical practices are taken place at each of the steps in research, that is performing works to disseminating knowledge through scientific publications [8, 9]. The most common research misconduct, which is manifested through publications, is falsifications and fabrication of data. As per NIH, ‘fabrication’ means ‘the intentional act of making up data or results and recording or reporting them’ whereas ‘falsification’ is manipulating research materials, equipment or processes, or changing or omitting/suppressing data or results without scientific or statistical justification, such that the research is not accurately represented in the research record [10]. It is noticed that ‘figures’ and ‘graphics’ where maximum fabrications or falsification take place. The graphical manipulations are mainly through Photoshop and journal editors are struggling hard to fight against these hi-tech manipulations on research data [11, 12]. Overall, we can say that research misconduct manifestation is multidimensional. These may be classified as (1) General research misconduct, (2) Research application misconduct, (3) Data generation misconduct, (4) Financial misconduct, (5) Behavioural misconduct and (6) Publication misconduct.
\nThe foremost important manifestation is general research misconduct, which includes fabrication, falsification and plagiarism. These three unethical research practices are very serious offences as it makes research either misrepresented by the facts or underrepresented by the truth. Usually, such unethical practices in research are due to peer pressure and personal gains and pressure from research sponsors. Research application misconduct usually occurs while adopting wrong or poor research design or technical errors during experimental, computational and statistical analysis. Improper uses of human subjects, patients or animals also lead to research misconduct and result in ethical violations. Data generation misconduct includes false data generation, not including real data in research, not sharing true data with colleagues’ especially multicentre studies. Financial misconduct in research usually includes misuse of research funds like unauthorized purchase procedures, use of research funds for personal reasons, disclosure of conflict of interest, etc. Behavioural misconduct covers inappropriate behaviours towards colleagues, research scholars and gender and religious insensitivities on students, colleagues, patients and subjects. Usually, publication misconduct occurs due to authorship dispute, ghost and gifted authorship, plagiarism, duplicate publication and suspicious clinical trials. Study on misconduct in clinical trials found that the most serious forms of research misconduct in clinical trials are selective and biased reporting [12, 13].
\nVarious factors actually induce research misconduct like:\n
Publish or Perish pressure.
Severe competition for funds.
Promotion or career advancement policies.
Pressure from research sponsors to obtain desired results.
Lack of knowledge on research ethics.
Desire to ‘go ahead’.
Personal characters.
In most of the cases, research misconduct is suspected, identified and reported by colleagues. Usually, researchers who work alone and never allow others to observe his or her research works or researchers who are self centric and do not have an attitude to work in a team are primarily prone to do research misconducts. Research findings in medical sciences should be always repetitive at any place and anytime. Failure to repeat research results by one\'s own laboratory or external laboratories definitely suspect misconduct.
\nThese are some criteria which are not direct research misconduct but definitely raise suspicion:\n
Failing to retain significant research data for a reasonable period.
Maintaining inadequate research records, especially for results that are published or are relied on by others.
Conferring or requesting authorship on the basis of a specialized service or contribution that is not significantly related to the research reported in the paper.
Refusing to give peers reasonable access to unique research materials or data that could support published papers.
Using inappropriate statistical or other methods of measurement to enhance the significance of research findings.
Inadequately supervising research subordinates or exploiting them.
Misrepresenting speculations as fact or releasing preliminary research results, especially in the public media, without providing sufficient data to allow peers to judge the validity of the results or to reproduce the experiments.
The reasons for questionable research practices may be due to poor supervision, excessive workloads, poor training in research, lack of interest of researchers and being over ambitious. These can be found in principal investigators, study coordinators, research scholars, administrative staff, technicians and even the research subjects themselves.
\nThe following are some examples of questionable research misconduct [14]:\n
Dates misrepresented.
Duplicate X-rays: different names.
Blank laboratory reports to fill in.
Fake subjects: obituary names.
Analysis done after subjects died.
Same subject different names.
Nonexistent subjects created.
Dates changed in records to match washout periods.
Consent not signed before entering the study.
Unqualified staff doing research.
Inadequate records.
Failure to get IEC/IRB approval.
Failure to report changes in research.
Bogus laboratory results reported.
Samples study from only a few subjects.
Subjects received prohibited medication while on study.
Failure to report adverse events.
Hence, we can say that from knowledge generation (ethical research) to knowledge dissemination (ethical practices and publications) – medical ethics is a common component of research integrity and medical science research cannot afford to lose this integrity for the interest of the humanity (Figure 1).
\nResearch integrity through ethical research, practice and publication.
Graf et al. [15] said that academic publishing depends mainly on ‘trust’. In the system of research publication procedure, editor trusts reviewers, authors trust editors by expecting fair reviewing processes and finally readers trust authors, reviewers and editors for providing honest sciences. In general, common public outside of research community considers physicians and scientists are just demigod with high morale and integrity. ‘Scientists are generally perceived as well-intentioned seekers of truth; universities, as cathedrals of learning and as producers of knowledge vital to the health and welfare of society’ [16]. Unfortunately, reports of unethical research publications shake the public confidence on medical scientists. Although medical practitioners, teachers and researchers can recognize publication misconduct and ignore that to some extent, chances of un detection of mistakes and doubtful observations are also may lead to serious consequences. Thorough understanding of publication ethics in medical research is need of the hour. World Association of Medical Editors (WAME), International Committee of Medical Journal Editors (ICMJE) and Committee on Publication Ethics (COPE) are the guiding force to interpret ethical publication appropriately [14]. They have provided guidelines on the publication ethics policies for medical journals on various issues such as study design, authorship, peer review, editorial decisions and plagiarism and also further guided the procedural guidelines to tackle those publication misconduct. These bodies also enlighten editors on various issues such as conflict of interest, authorship disputes, redundant publications, fabrication of data, plagiarism and human and animal rights [17].
\nPublished research influences other researchers and establishes credibility for individual or journal. Honest scientific reports build trust among peers and within scientific community. Publication ethics is not confined to one country—it is global by approach and is commonly held throughout the world. Author\'s seven deadly sin: Table 1 depicts unethical practices of authors.
\n\nIn the era of copy and paste, an excessive dependence on search engine make plagiarism a universally popular among the medical scientists who like to prefer a short cut for the way of success in publication. Plagiarism is defined as ‘to copy ideas and passages of text from someone else\'s work and use them as if they were one\'s own’ [18]. The word plagiarism may be further extended to unreferenced use of the ideas of others submitted as a ‘new’ paper by a different author! One must know plagiarism may not be considered always as accidental. The most vulnerable part for plagiarism in any research publication is ‘methods’.
\n\n\nAnother form of plagiarism is self-plagiarism where author copy and paste from his/her previous publications including results, tables and figures without providing copyright clearance certificate from publishers. Self-plagiarism is also an equal crime or research misconduct like simple plagiarism. Fortunately, due to the availability of many anti-plagiarism softwares, this menace has cut down notably. Editor must make his/her peer reviewers alert and possibly train them on this issue. Universities, medical institutes and funding authorities should also sensitize its medical researchers and practitioners on it. The best way to avoid plagiarism is to cite other\'s work always in the research articles, put the cited words in quotation marks and seek permission from appropriate authorities for references to cite tables, figures, etc. COPE has given a very useful guideline through flow chart on plagiarism for both submitted manuscripts and published manuscripts [18]. The Committee on Publication Ethics (COPE) is a UK-based charitable organization (established 1997) working mainly on research and publication misconduct. COPE has provided some very authentic guidelines addressing publication ethics from authors, reviewers, editors and publishers’ point of views. COPE defines the good practices in publication of research articles, which are really very helpful for authors, readers, editors, peer reviewers, editorial board members and journal and book publishers. COPE is the first organization, which advocates accountability of research institutions for its employee scientist\'s misdeed [19]. ICMJE also directs authors and editors to follow COPE guidelines in case of suspected unethical practices on publications or any ethical dispute [20].
\nSl. no. | \nSin | \nExample | \n
---|---|---|
1 | \nCarelessness | \nCitation bias, understatement, negligence | \n
2 | \nRedundant publication | \nSame tables or literature review reported without noting prior source | \n
3 | \nUndeclared conflict of interest | \nFailure to cite funding source | \n
4 | \nUnfair authorship | \nFailure to include eligible authors, honorary authors | \n
5 | \nHuman/animal subjects violations | \nNo approval from review board or ethics committee | \n
6 | \nPlagiarism | \nReproducing others’ work or ideas without as one’s own | \n
7 | \nOther fraudulences | \nFabrication or falsification of data, misappropriation of other ideas or plans given in confidence | \n
Author\'s ethical misconduct.
Redundant or duplicate publication is another serious issue pertaining to ethical publications. It is often revealed by reviewers and readers. In the modern era of Internet, it is relatively easy to find out such unethical publication in the form of duplicate publication. Many times, it happens without the knowledge of co-authors or the group of researchers who published it in previous journal. This unethical publication actually causes serious damage on humanity [21]. It makes waste of time of peer reviewers and editors, waste journal print pages unnecessarily. Redundant publication sometimes assault on academic reward system. It also violates copyright acts and inflated number of publications that injure society as a whole. Below, the facts that make redundant or duplicate publications are mentioned:\n
Data in conference abstract? – No
Same data, different journal? – Yes
Data on website? – May be
Data included in review article? – No if permission is taken
Expansion of published data set? – Yes
There are certain norms that may help clarify further on duplicate publications like if one takes an approval from both the journals and subsequently publishes, it may not be considered as ‘duplicate’. Secondary version for paper intended to different language readers with appropriate permission may not be taken as ‘duplicate’. But in any case secondary version faithfully reflects data and interpretations of the primary version with a clear message that it is the secondary publication for journal ‘y’ based on previously published article (primary) in journal ‘x’ in ‘z’ language. COPE has given some useful guidelines on how to handle suspected redundant (duplicate) publications, especially for journal editors. COPE instructed that at the beginning editor must verify whether it is the case of major or minor redundancy. Major redundancy is always considered with evidence of deliberate duplication such as changes of title and data sheet with identical findings. Minor redundancy is something ‘salami publication’ types with looks of extended follow-up of previously published article. Whatever it may be, editor must contact corresponding author and ask explanation, if satisfied, do not take any action. If it is not found satisfactory, editor has many choices such as inform the incidence to author\'s superior organizational authority/employer or prompt rejection of manuscript or notice of retraction immediately [22].
\nProbably, one of the most discussed and complex ethical violation in publication in medicine is authorship disputes and ethical misconducts. The difference between ‘disputes’ and ‘misconduct’ may be proclaimed as follows:
\nDisputes—‘Question of interpretation’ like whether ‘contribution’ by the authors was substantial? Whether authorship criteria were discussed when research was planned ? Or it was decided before submission of manuscript?
\nMisconduct—Authorship is unethical like ‘gift’ or ‘ghost’ authorship.
\nRegarding authorship issue, International Committee of Medical Journal Editors (ICMJE) guidelines states ‘anyone who has made a substantial contribution to the conception, design or acquisition of data or analysis and interpretation of data, drafting or revising the article for intellectual contents, or participated in the final approval of the version to be published is entitled to be an author’ [23]. The studies revealed that ‘gift authorship’ is prevalent among authorship misconducts. Gift authorship is usually taken place when research or administrative hierarchy comes in to the picture or because of a colleague with whom we have a personal relationship like son/daughter or husband/wife/relatives etc [24]. But senior researchers or administrative boss who have substantial contribution on the subject at any point like writing manuscript, editing manuscript, reviewing manuscript and providing additional knowledge with high intellectual input on writing science are not considered as ‘gifted’. One must clearly remember that simply helping research by way of logistic supports such as sample collections, patients supply, chemicals and reagents supply, helping data collections or providing research funds are not the criteria to become an author [1, 25]. Another unethical authorship dispute is ‘ghost authorship’. Ghost authors are the researchers who writes the research article without acknowledgement. This is very common for many cases where researcher drafts an article at the behest of pharmaceutical company. Here, the real author\'s name never comes in domain of publication. The problem of the ghost author is that whatever they write may not always be correct interpretation and may be biased; hence, it badly affects the researcher community. COPE, ICMJE and WAME have given certain guidelines to tackle this publication misconduct issue. Following are the summarized form of guidelines:\n
Journals must have clear authorship criteria.
Authors should disclose all contributors, regardless of author status and their specific individual contributions and affiliations.
Authors must sign about their contributions details.
Authors should disclose any of his/her conflict of interest and a statement whether they have received any support from medical writers [26].
Hence to be précise, it may be stated that as per ICMJE guidelines, the three important mechanics of authorship are ‘intellectual input in research, contribution in writing and final written approval of the manuscript’ [23, 27]. ICMJE also specifies that authorship criteria should be based only on:\n
Substantial contributions to conception and design, or acquisition of data, or analysis and interpretation of data.
Drafting the article or revising it critically for important intellectual content.
Examples of publication misconduct are authorship disputes and misconducts, which are very common in the medical professionals. Various studies in this regard showed the nature and execution of such unethical practices among medical professional. Works of Dhingra and Mishra [3] revealed that majority of respondent on questionnaires confirm publication misconduct especially authorship disputes among Indian biomedical researchers. Another study of Das et al. [25] observed clear authorship misconduct among medical faculty members of India. In their study, they have found that around 81.4% respondents from medical faculty members confessed authorship disputes in any form among themselves. Further, a comparative study with pharmacy faculty members the dispute level was found to be 29.2%, which further indicates that medical researchers are more vulnerable to authorship misconduct. The study also showed that 74.07% of medical and 68.29% of pharmacy faculty members did not have any discussion on authorship issues at any time before they actually started drafting article for publication. About 88.88% of medical and 36.5% of pharmacy faculty members also mentioned that their professors and head of the departments were included as author although they do not have any contributions or they do not fit in ICMJE authorship criteria. About 81.4% of medical and 29.26% of pharmacy faculty members also mentioned in questionnaires that senior research colleagues interfered while writing manuscript to include their names in the drafted manuscripts. Das et al. further elaborated that even though pharmacy faculty members are better practioners of ethical authorship as compared to their medical counterparts still more sensitization is needed for them to realize ethical authorship [25]. To regulate authorship disputes and misconduct the role of corresponding author should be considered the most important one although other co-authors are also accountable. Every author must have substantial research contribution to justify their inclusion as author. All authors must take their responsibility on manuscript\'s every pros and cons. The accuracy of all the data, conflict of interest, disclosure of funding authority and get manuscript checked by all the co-authors are the responsibilities must be put on corresponding or principal author\'s shoulder [9].
\nOne of the important but less admitted examples of publication misconduct is nondisclosure of conflict of interest. It may be financial (industry sponsor research) or others like personal interest like employment interest, promotion or career advancement interest, patents, personal believes, grant providing, relationship, academic competition or intellectual passion, etc [23, 28]. Most of the journals make disclosure of potential conflict of interest mandatory and do not publish articles even after acceptance if COI is not disclosed. It has been reported in a study on five leading medical journals like Annals of Internal Medicine, BMJ, Lancet, JAMA, New England Journal of Medicine that only 52 of total 3642 articles disclosed their potential COI, that is only 1.4% of total [29]. Another study also showed that one in three lead authors had financial interests in their research by patents, shares or payments for being on advisory boards or as a director, etc [30]. A study conducted by Das et al. [31] on awareness of COI among medical scientists/researchers from India showed that only 12% authors understand COI issues correctly and 19 % of medical authors just heard about it. Very interestingly, the authors who had clear knowledge on COI confessed that hardly they provide COI statement to the journal. The study also found that knowledge of COI is equally poor even among peer reviewers (30%) and editorial board members (25%) too! Some peer reviewers even stated that they are biased toward articles submitted by their known colleagues from medical sciences [31]. Another study also showed that there are no clear guidelines for institution and industries are other cause of COI-related issues [32]. In the complex scenario of COI issues among medical publications, editor of the journals, peer reviewers, research institutions or universities and grant providers must pay more attention to tackle this unethical issue in publications [32]. Das suggested COI case comes out even after publication, in which, the publisher and editor may apologize and issue a formal correction and subsequently retract the article [33].
\nFabrication means cooking up data or results (fictitious by nature) as per the hypothesis of research and publishes it in a journal whereas falsification is simply manipulating data or results. It also includes figures or graph distortions. Fabrication also covers selective reporting where authors just report a small number of significant values of the study but hide large number of insignificant observations. Such biasness completely destroys the spirit of science. Normally, both fabrication and falsification of research observations are common for clinical trials (pressure from sponsors) and research activities of medical researchers who have a tendency to go alone instead of working as a research team [1]. In an interest meta-analysis study, Fanelli [9] reported that around 2% of studied medical scientists confessed that they had fabricated or falsified research data. Nearly, one-third of the said study group also confessed that they allowed many publication malpractices including ‘dropping data’ results of a study in response to pressures from a funding source [9]. The issues on fabrication and falsification of data are very serious by nature, and unfortunately, even the world\'s top medical research institute faculties are also involved in it. Story of John Long, a pathologist at Harvard Medical School was compelled to resign after publication of his false and fake results on molecular immune complexes related to Hodgkin\'s disease [34]. Similarly, one Dr. Vijay Soman of Yale University was found an offender on publication ethics because of fabrication and falsification of data from his colleague [35]. This problem is not only restricted on medical researcher/author, but it is even extended to editor also. Malcolm Pearce who was an Assistant Editor of British Journal of Obstetrics and Gynaecology was found to be a publication ethics defaulter. His false case report based on a patient who had gone under successful delivery after reimplanting an ectopic pregnancy was actually nonexisting. Later, his all papers were retracted from various journals [36]. One of the classic example of data fabrication is the story of Ram B. Singh between India. Dr. Singh submitted nine papers from 1992 to 1996 on his research on diet and myocardial infarction. The then Editor of BMJ Professor Richard Smith suspected on Dr. Singh\'s work and asked him to produce raw data. Dr. R. B. Singh failed to produce that and insisted that data were ‘eaten by termites’. It was also found that the institution where he did his research was owned by his family members. BMJ initiated an independent inquiry and published his story [37].
\nBased on ICMJE and COPE guidelines for publishers, editors, peer reviewers and authors must practice and train themselves against publication misconduct. One of the most important things to promote ethical publication is to encourage research integrity among medical researchers. COPE advocated for a research integrity officer in each of the research institution to monitor and guide various issues pertaining to research ethics including publication ethics [18]. Research Institutions share a responsibility with all of its researchers to preserve scientific integrity in research. They bear the primary responsibility for promoting a culture of good scientific conduct among researchers and students and for the prevention, investigation and punishment of scientific misconduct in their midst. One must remember that research integrity requires the highest professional standards by a critical, open-minded approach, frankness and fairness with absolute honesty.
\nAn editor must take into consideration some important points before sending manuscript for reviewing like whether competing interests are cited by authors or reviewers, ensures that reviewer is adequately qualified and can keep confidentiality and also protects the whistle blower in case of reports on publication misconduct. It is suggested that journal editors must provide a link to WAME or COPE or ICMJE for authors, readers or reviewers to get first-hand information on ethics in publication. Editors should encourage peer reviewers to consider ethical issues on research manuscripts while reviewing and may also ask additional information from authors if need arises. Journals editors and publishers must protect confidentiality of research that includes identity of subjects/patients, etc besides identity of reviewers. Editors may also verify institutional review board clearance on each of the research manuscript in medical journal [15]. Ethical publication also includes timely peer reviewing and publication of the manuscript which is the responsibility of editor and publisher. Authors’ especially medical authors always should be sensitized by editors, publishers and institutions that medicine is a profession based on ‘absolute trust, philanthropy and altruism’. For ethical publication, the great role of peer reviewers must also to be remembered. Reviewer should be competent enough to review the content of manuscript; he/she should not be in hurry, no COI issues, have knowledge on publication ethics. One more important point on best practice for editors is to remain cultural and gender sensitive on any article. They should carefully observe whether any cultural offence is in the content of manuscripts. Language of the authors should not offend anyone among the readers [15].
\nTo regulate appropriately on the issues of ethical publications, institutions or universities should be accountable by the journal publishers for any unethical publication practices authored by the researchers belong to that institution. COPE or ICMJE have given some guidelines but that do not make institutions of author as accountable for any publication misconduct. Institution must have clear and transparent functioning on not only ethical research policy but also on ethical publications. Institution of authors and journal must take a special attention on the clinical trial-based publications. A Strong peer-reviewing system, uses of latest technological support, strong publication ethics policies, active monitoring, protection of whistle blowers and more liaisons between journals and research institutions or universities possibly prevent publication misconduct effectively.
\nIn a summary, we may say that the following points may be considered to prevent publication misconduct:\n
Better education on publication guidelines and ethics.
Introduction of registers for planned and ongoing clinical trials.
Change criteria from quantity to quality when papers are used for assessment of posts or grants.
Punish the culprits but be careful that innocent is not victimized.
The authors thank Professor B.G. Mulimani, Chief Adviser and former Vice Chancellor of BLDE University, Vijayapura, India, for his encouragement on ethical practices in all the aspects of life in BLDE University.
\nUTI affects approximately 150 million people worldwide, which is most common infection with female predominance [1]. Around 15–25% hospitalized patients receiving indwelling urinary catheter develops CAUTI with prolonged catheterization and in among 40% nosocomial UTI, 80% is due to CAUTI [2]. CAUTI causes about 20% of episodes of health-care acquired bacteraemia in intensive care facilities and over 50% in long term care facilities [3]. The microbiology of biofilm on an indwelling catheter is dynamic with continuing turnover of organisms in the biofilm. Patients continue to acquire new organisms at a rate of about 3–7%/day. In long term catheterization that is by the end of 30 days CAUTI develops in 100% patients usually with 2 or more symptoms or clinical sign of haematuria, fever, suprapubic or loin pain, visible biofilm in character or catheter tube and acute confusion all state [4]. In CAUTI the incidence of infection is Escherichia coli in 24%, Candida in 24%, Enterococcus in 14% Pseudomonas in 10%, Klebsiella in 10% and remaining part with other organisms [5]. Bacteraemia occurs in 2–4% of CAUTI patients where case fatality is three times higher than nonbacteremic patients [6]. Adhesions in bacteria initiate attachment by recognizing host cell receptors on surfaces of host cell or catheter. Adhesins initiate adherence by overcoming the electrostatic repulsion observed between bacterial cell membranes and surfaces to allow intimate interactions to occur [7]. A biofilm is an aggregate of micro-organisms in which cells adhere to each other on a surface embedded within a self-produced matrix of extracellular polymeric substance [8]. In biofilm micro-organisms growing in colonies within an extra-cellular mucopolysaccharide substance which they produce. Tamm-Horsfall protein and magnesium and calcium ions are incorporated into this material. Immediately after catheter insertion, biofilm starts to form and organisms adhere to a conditioning film of host proteins along the catheter surface. Both the inner and outer surfaces of catheter are involved. In CAUTI biofilms are initially formed by one organism but in prolonged Catheterization multiple bacteria’s are present. In biofilm main mass is formed by extra cellular polymeric substance (EPS) within which organisms live. So there are three layers in biofilm, where deeper layer is abiotic, than environmental zone and on surface biotic zone [9]. Growth of bacteria in biofilms on the inner surface of catheters promotes encrustation and may protect bacteria from antimicrobial agents and the consequence is more drug resistance of biofilm organisms. When antibiotic treatment ends the biofilm can again shed bacteria, resulting recurrent acute infection. The patients may present as asymptomatic bacteriuria or symptomatic. In symptomatic bacteriuria patient present with fever, suprapubic or costovertebral angle tenderness, and systemic symptoms such as altered mentation, hypotension, or evidence of a systemic inflammatory response syndrome. In asymptomatic CAUTI diagnosis is made with presence of 105 cfu/mL of one bacterial species in a single catheter urine specimen [10]. In symptomatic CAUTI bacteriological criteria is present with clinical symptoms.
It is recommended that urine specimens be obtained through the catheter port using aseptic technique or, if a port is not present, puncturing the catheter tubing with a needle and syringe in patients with short term catheterization [11]. In long term indwelling catheterization, the ideal method of obtaining urine for culture is to replace the catheter and collect the specimen from the freshly placed catheter. In a symptomatic patient, this should be done immediately prior to initiating antimicrobial therapy. Culture specimens from the urine beg should not be obtained [10, 12]. Urine sample can be collected from suprapubic puncture also. Biofilm can be cultured from the catheter, for this swab is taken from inner side of catheter.
Catheter Associated Asymptomatic Bacteriuria (CA-ASB) is diagnosed when one or more organisms are present at quantitative counts ≥105 cfu/mL from an appropriately collected urine specimen in a patient with no symptoms [13]. Lower quantitative counts may be isolated from urine specimens prior to ≥105 cfu/mL being present, but these lower counts likely reflect the presence of organisms in biofilm forming along the catheter, rather than bladder bacteriuria [14]. Thus, it is recommended that the catheter be removed and a new catheter inserted, with specimen collection from the freshly placed catheter, before antimicrobial therapy is initiated for symptomatic infection [13]. In biofilm culture, most biofilm contains mixed bacterial communities meaning polymicrobial colonization.
Patients who remain catheterized without having antimicrobial therapy and who have colony counts ≥10 2 cfu/mL (or even lower colony counts), the level of bacteriuria or candiduria uniformly increases to >105 cfu/mL within 24–48 h [14]. Given that colony counts in bladder urine as low as 102 cfu/mL are associated with symptomatic UTI in non-catheterized patients [15], untreated catheterized patients and those who have colony counts ≥102 cfu/mL or even lower, the level of bacteriuria or candiduria uniformly increases to >105 cfu/mL within 24–48 h [10, 16]. Colony counts as low as 102 cfu/mL in bladder urine may be associated with symptomatic UTI in non-catheterized patients. Whereas low colony counts in catheter urine specimens are likely to be contaminated by periurethral flora, and the colony counts will increase rapidly if untreated. Low colony counts in catheter urine specimens are also reflective of significant bacteriuria in patients with intermittent catheterization [14].
Pyuria is usually present in CA-UTI, as well as in CA-ASB. The sensitivity of pyuria for detecting infections due to enterococci or yeasts appears to be lower than that for gram-negative bacilli. Dipstick testing for nitrites and leukocyte esterase was also shown to be unhelpful in establishing a diagnosis in catheterized patients hospitalized in the ICU [17].
It is the most common cause of CAUTI in 24–60% patients [5, 18]. In CAUTI the source of this organism is usually patients own colonic flora. E. coli is large and diverse group of bacteria found in environment, foods and intestine of human and animal. Among many species of E. coli only a few causes disease in human being. It is beneficial in that it prevents the growth and proliferation of other harmful species of bacteria. Even it plays an important role in current biological engineering.
E. coli was discovered in 1885 by Theodor Escherich, German bacteriologist, is gram negative rod, lactose fermenter, composed of one circular chromosome which is common facultative anaerobes in colon and farces of human. Distribution is diverse and most of them are harmless belonging to genus Escherichia. Harmful species causes infection of urinary tract, gastrointestinal tract, respiratory system and rarely bacteraemia and septicemia. Phylogenetic analysis of E. coli showed majority of the strains responsible for UTI belongs to the phylogenetic group B2 and D, while in smaller percentage belong to A and B1 [19].
It has three antigens O-cell was antigen, H- flagella antigen and k- Capsular antigen. It has pili—a capsule, fimbriae, endotoxins and exotoxins also. Uropathogenic E. coli use P fimbriae (pyelonephritis-associated pili) to bind urinary tract endothelial cells. Vast majority of catheter-colonizing cells (up to 88%) express type 1 fimbriae and around 73% in E. coli causing CAUTI [20]. In UPEC fimbrial genes are ygiL, yadN, yfcV, and c2395 [21]. Pathogenesis of CAUTI initiated with UPEC colonization in periurethral and vaginal areas. Then it ascends to bladder lumen and grows as planktonic cells in urine. Sequentially adherence to bladder epithelium, then biofilm formation and invasion with replication and kidney colonization and finally bacteremia [22] (Figure 1).
Gram stain picture and morphology of E. coli. Adapted from CCBC faculty web. BIOL 230 Lab Manual: gram stain of E. coli and infection landscapes: Escherichia coli. http://faculty.ccbcmd.edu/courses/bio141/labmanua/lab16/gramstain/gnrod.html.
Diagnosis of E. coli infection is simple, by isolation and laboratory identification of bacterium from urine or biofilm. Laboratory diagnosis by culture of specimen—urine or catheter biofilm in blood agar, MacConkey’s agar or eosin-methylene blue agar (which reveal lactose fermentation). Immunomagnetic separation and specific ELISA, latex agglutination tests, colony immunoblot assays, and other immunological-based detection methods are other ways for diagnosis of E. coli.
Proteus species, member of the Enterobacteriaceae family of gram-negative bacilli are distinguishable from most other genera by their ability to swarm across an agar surface [23, 24]. Proteus species are most widely distributed in environment and as other enterobacteriaceae, this bacteria is part of intestinal flora of human being [25, 26]. Proteus also found in multiple environmental habitats, including long-term care facilities and hospitals. In hospital setting, it is not unusual for proteus species to colonize both the skin and mucosa of hospitalized patient and causing opportunistic nosocomial infections. It is one of the common causes of UTI in hospitalized patients undergoing urinary catheterization [26, 27].
UTIs are the most common manifestation of Proteus infection. Proteus infection accounts for 1–2% of UTIs in healthy women and 5% of hospital acquired UTIs. Catheters associated UTI have a prevalence of 20–45%. Proteus mirabilis causes 90% of proteus infection and proteus vulgaris and proteus penneri also isolated from long-term care facilities and hospital and from patients with underlying disease or specialized care. Most common age group is 20–50 years. More common in female group and the ratio between male female begins to decline after 50 years. UTI in men younger than 50 are usually caused by urologic abnormalities. Patients with recurrent infections, those with structural abnormalities of the urinary tract, those who have had urethral instrumentation or catheterization have an increase frequency of infection caused by proteus species [28].
Proteus mirabilis produces an acidic capsular polysaccharide which was shown from glycose analysis, carboxyl reduction, methylation, periodate oxidation and the application high resolution nuclear magnetic resonance techniques. Proteus species possess an extracytoplasmic outer membrane, a common feature shared with other gram-negative bacteria. Infection depends upon the interacting organism and the host defense mechanism. Various component of the membrane interplay with the host to determine virulence. Virulence factors associated with adhesion, motility, biofilm formation, immunoavoidance, nutrient acquisition and as well as factors that cause damage to the host [29, 30] (Figure 2).
Gram stain picture and morphology of Proteus. Adapted from CCBC faculty web. BIOL 230 Lab Manual: gram stain of Proteus mirabilis and Proteus vulgaris bacteria (SEM) | Macro & Micro: Up Close and Personal | Pinterest | Microbiology, Bacteria shapes and Fungi. https://www.pinterest.com › pin.
Certain virulence factors such as adhesin, motility and biofilm formation have been identified in Proteus species that has a positive correlation with risk of infection. After attachment of Proteus with urothelial cells, interleukin 6 and interleukin 8 secreted from the urothelial cells causes apoptosis and mucosal endothelial cell desquamation. Urease production of proteus also augments the risk of UTI. Urease production, together with the presence of bacterial motility and fimbriae or pili, as well as adhesins anchored directly within bacterial cell membrane may favor the upper urinary tract infection. Once firmly attached on the uroepithelium or catheter surface, bacteria begin to phenotypically change, producing exopolysaccharides that entrap and protect bacteria. These attached bacteria replicate and form microcolonies that eventually mature into biofilms [31, 32]. Once established, biofilms inherently protect uropathogens from antibiotic and the host immune response [33, 34]. Proteus mirabilis as with other uropathogens is capable of adapting to the urinary tract environment and acquiring nutrients. And this is accomplished by the production of degradative enzymes such urease and proteases, toxins such as Haemolysin Hpm A and iron nutrient acquisition proteins.
The infection with Proteus can be diagnosed by taking a urine sample for microscopy and culture which is sufficient in most of the cases except in few cases where advanced diagnostic tools are used. If the urine is alkaline, it is suggestive of infection with Proteus sp. The diagnosis of Proteus is made on swarming motility on media, unable to metabolized lactose and has a distinct fishy door. Ultrasound or CT scan to identify renal stone (Struvite stone) or to visualized kidneys or surrounding structures. It will allow to exclude other possible problems, mimicking symptoms of urinary tract infection [35, 36].
Pseudomonas is a gram-negative bacteria belonging to the family Pseudomonadaceae and containing 191 validly described species [37]. Because of their widespread occurrence in water and plant seeds, the pseudomonas was observed in early history of microbiology. Pseudomonas is flagellated, motile, aerobic organism with Catalase and oxidase-positive. Pseudomonas may be the most common nuclear or of ice crystals in clouds, thereby being of utmost importance to the formation of snow and rain around the world [38]. All species of Pseudomonas are strict aerobes, and a significant number of organisms can produce exopolysaccharides associated with biofilm formation [39]. Pseudomonas is an opportunistic human pathogen that is especially adept at forming surface associated biofilms. Pseudomonas causes catheter associated urinary tract infection(CAUTIs) through biofilm formation on the surface of indwelling catheters, and biofilm mediated infection including ventilator associated pneumonia, infections related to mechanical heart valves, stents, grafts, sutures, and contract lens associated corneal infection [40].
Pseudomonas is third ranking causes nosocomial UTI about 12%, where E. coli remain on the top [41]. CAUTI is directly associated with duration of catheterization. Within 2–4 days of catheterization 15–25% patients develop bacteriuria [42].
Pseudomonas aeruginosa is a gram-negative, rod shaped, asporogenous and monoflagellated, noncapsular bacterium but many strains have a mucoid slime layer. Pseudomonas has an incredible nutritional versatility. Pseudomonas can catabolize a wide range of organic molecule including organic compounds such as benzoate. This, then make Pseudomonas a very ubiquitous microorganism and Pseudomonas is the most abundant organism on earth [43] (Figure 3).
Gram stain picture and morphology of Pseudomonas aeroginosa. Adapted from Science News. A new antibiotic uses sneaky tactics to kill drug-resistant Pseudomonas aeruginosa illustration and Pseudomonas Aeruginosa Stock Photos & Pseudomonas Aeruginosa Stock Images—Alams. https://www.alamy.com › stock-photo.
Pseudomonas is widely distributed in nature and is commonly present in moist environment of hospitals. It is pathogenic only when introduce into areas devoid of normal defense such as disruption of mucous membrane and skin, usage of intravenous or urinary catheters and neutropenia due to cancer or in cancer therapy. Its pathogenic activity depends on its antigenic structure, enzymes and toxins [44]. Among the enzymes Catalase, Pyocyanin, Proteases, elastase, haemolysin, Phospholipase C, exoenzyme S and T and endotoxin and endotoxin A play role in disease process and as well as immunosuppression. Pseudomonas can infect almost any organ or external site. Pseudomonas in invasive and toxigenic. It attached to and colonized the mucous membrane of skin. Pseudomonas can invade locally to produce systemic disease and septicemia. Pseudomonal UTs are usually hospital acquired and are associated with catheterization, instrumentation and surgery. These infections can involve the urinary tract through an ascending infection or through bacteriuria spread. These UTIs may be a source of bacteraemia or septicemia [45].
Identification of bacterium with microscopy is simple method of identification of pseudomonas. Culture and antibiotic sensitivity pattern can be done in most laboratory media commonly on blood agar or eosin-methylthionine blue agar. Pseudomonas has inability to ferment lactose and has a positive oxidase reaction. Fluorescence under UV light is helpful in early identification of colonies. Fluorescence is also used to suggest the presence of pseudomonas in wounds [46].
Urinary catheters are standard medical devices utilized in both hospital and nursing home settings are associated with a high frequency of catheter-associated urinary tract infections (CAUTI). The contribution of Klebsiella spp. in CAUTI is near about 7.7% [47].
Klebsiella pneumoniae is a gram-negative pathogenic bacterium, is part of the Enterobacteriaceae family. It has got polysaccharide capsule attached to the bacterial outer membrane, and it ferments lactose. Klebsiella species are found ubiquitously in nature, including in plants, animals, and humans. They are the causative agent of several types of infections in humans. It has a large accessory genome of plasmids and chromosomal gene loci. This accessory genome divides K. pneumoniae strains into opportunistic, hyper virulent, and multidrug-resistant groups [48] (Figure 4).
Gram stain picture and morphology of Klebsiella pneumonie. Adapted from studyblue.com. Microbio Lab Practical I—Microbiology 101 with Johnson at University of Vermont—StudyBlue. Study 368 Microbio Lab Practical I flashcards from Tess H. on StudyBlue and Klebsiella Pneumoniae Stock Photos and Pictures. Getty Images https://www.gettyimages.com › photos.
The source of Klebsiella causing CAUTI can be endogenous typically via meatal, rectal, or vaginal colonization or exogenous, such as via equipment or contaminated hands of healthcare personnel. They typically migrate along the outer surface of the indwelling urethral catheter, until they enter the urethra.
Migration of the Klebsiella along the inner surface of the indwelling urethral catheter occurs much less frequently, compared with along the outer surface Internal (intraluminal) bacterial ascension occurs by Klebsiella tend to be introduced when opening the otherwise closed urinary drainage system, ascend from the urine collection bag into the bladder via reflux, biofilm formation occurs.
A critical step in progression to CAUTI by Klebsiella is to adhere to host surfaces, which is frequently achieved using pili (fimbriae) [49]. Pili are filamentous structures extending from the surface of Klebsiella. They can be as long as 10 μm and between 1 and 11 nm in diameter. Among the two types of pili—type 1 (fim) pili and type 3 (mrk) pili, type 1 aids virulence by their ability to adhere with mucosal surfaces and type 3 pili strongly associated with biofilm production [50]. Both fim and mrk pili are considered part of the core genome [51]. It is thought that both types of pili play a role in colonization of urinary catheters, leading to CAUTI [52]. In addition to fim and mrk pili, a number of additional usher-type pili have been identified in Klebsiella with an average of ~8 pili clusters per strain. Based on varying gene frequencies, some of these appear to be part of the accessory genome. Immediately after catheterization Klebsiella starts biofilm production on the inner as well as outer surface of the catheter and on urothelium. Biofilm augments migration of Klebsiella into urethra and urinary bladder. Biofilm formation on the catheter surface by Klebsiella pneumoniae causes severe problem. Type 1 and type 3 fimbriae expressed by K. pneumoniae enhance biofilm formation on urinary catheters in a catheterized bladder model that mirrors the physicochemical conditions present in catheterized patients. These two fimbrial types does not is expressed when cells are grown planktonically. Interestingly, during biofilm formation on catheters, both fimbrial types are expressed, suggesting that they are both important in promoting biofilm formation on catheters [53]. The biofilm life cycle illustrated in three steps: initial attachment events with inert surfaces type 1 and type 3 fimbriae encoded by the mrk ABCDF gene cluster within K. pneumoniae promotes biofilm formation [54, 55]. Detachment events by clumps of Klebsiella or by a ‘swarming’ phenomenon within the interior of bacterial clusters, resulting in so-called ‘seeding dispersal’.
Modifiable risk factor are prolonged catheterization, lack of adherence to aseptic catheter care, insertion of the indwelling urethral catheter in a location other than an operating room, presence of a urethral stent, feecal incontinence. Non-modifiable risk factor—renal disease (i.e., serum creatinine >2 mg/dL), diabetes mellitus, older age (i.e., age > 50 years old), female sex, malnutrition and severe underlying illness [53]. For infection several virulence factors such as surface factors (fimbriae, adhesins, and P and type 1 pili) and extracellular factors toxins, siderophores, enzymes, and polysaccharide coatings are necessary for initial adhesion with colonization of host mucosal surfaces for tissue invasion overcoming the host defense mechanisms, and causing chronic infections [55].
Diagnosis of klebsiella infection is by isolation and laboratory identification of bacterium from urine or biofilm. Laboratory diagnosis can be done by culture of specimen—urine or catheter biofilm in blood agar, MacConkey’s agar. Specific ELISA, latex agglutination tests, PCR and other immunological-based detection methods are sophisticated alternatives for diagnosis of klebsiella. Determination of a gene on capsule of Klebsiella is rapid and simple method for the determination of the K types of most K. pneumoniae clinical isolates [56].
Enterobacter species, particularly Enterobacter cloacae and Enterobacter aerogenes, are important nosocomial pathogens responsible for about 1.9–9% CAUTI, rarely causes bacteremia [57, 58]. Enterobacter cloacae exhibited the highest biofilm production (87.5%) among isolated pathogens [53].
Enterobacter bacteria are motile, rod-shaped cells, facultative anaerobic, non-spore-forming, some of which are encapsulated belonging to the family Enterobacteriaceae. They are important opportunistic and multi-resistant bacterial pathogens. As facultative anaerobes, some Enterobacter bacteria ferment both glucose and lactose as a carbon source, presence of ornithine decarboxylase (ODC) activity and the lack of urease activity. In biofilms they secrete various cytotoxins (enterotoxins, hemolysins, pore-forming toxins. Though it is microflora in the intestine of humans, it is pathogens in plants and insects. Amp C β-lactamase production by E. cloacae is responsible for cephalosporin resistance. They possess peritrichous, amphitrichous, lophotrichous, polar flagella. E. aerogenes flagellar genes and its assembly system have been acquired in bloc from the Serratia genus [59] (Figure 5).
Gram stain picture and morphology of Enterobacter species. Adapted from Gram Stain Kit | Microorganism Stain | abcam.comAdwww.abcam.com/ and Science Prof Online. Gram-negative Bacteria Images: photos of Escherichia coli, Salmonella & Enterobacter and Enterobacter aerogenes | Gram-negative microorganism—HPV Decontamination | Hydrogen Peroxide Vapour—Bioquellhealthcare.bioquell.com › microbiology.
The most important test to document Enterobacter infections is culture. Direct gram staining of the specimen is also useful. In the laboratory, growth of Enterobacter isolates is occurs in 24 h or less; Enterobacter species grow rapidly on selective (i.e., MacConkey) and nonselective (i.e., sheep blood) agars.
Enterococci are gram-positive facultative anaerobic cocci, two species are common commensal organisms in the intestines of humans: Enterococcus faecalis (90–95%) and Enterococcus faecium (5–10%) [60]. Though normally a gut commensal, these organisms are commonly responsible for nosocomial infection of urinary tract, biliary tract and blood, particularly in intensive care units (ICU) [61]. E. coli is usually the most frequent species isolated from bacteremic catheter associated urinary tract infections (CAUTI). However, Enterococcus spp. (28.4%) and Candida spp. (19.7%) were also reported to be most common [62]. In another study, E. coli was found the commonest (36%) followed by Enterococcus spp. (25%), Klebsiella species (20%) and Pseudomonas spp. (5%) [63].
The most important cause of bacteriuria is the formation of biofilm along the catheter surface [64]. Enterococcus is gram positive bacteria often found in pairs or short chains. Broadly, Enterococcus is in two groups—faecalis and non-faecalis (E. gallinarum and E. casseliflavus). Enterococcus faecalis formerly classified as part of the group D Streptococcus is a gram-positive, commensal bacterium inhabiting the gastrointestinal tracts of humans and other mammals, survive harsh environmental conditions including drying, high temperatures, and exposure to some antiseptics [65]. E. faecalis has the important characteristics of complex set of biochemical reactions, including fermentation of carbohydrates, hydrolysis of arginine, tolerance to tellurite, and motility and pigmentation. Presence of the catheter itself is essential for E. faecalis persistence in the bladder, E. faecalis depends on the catheter implant for persistence via an unknown mechanism that more than likely involves its ability to produce biofilms on the silicone tubing and immune-suppression [66].
E. faecalis produce a heteropolymeric extracellular hair-like fimbrial structure called the endocarditis- and biofilm-associated pilus-Ebp, having three components the organelle (EbpC), a minor subunit that forms the base of the structure (EbpB) and a tip-located adhesin (EbpA) [67]. EbpA is responsible for adhesion in urothelial and catheter surface for biofilm production (Figure 6).
Morphology of Enterococcus. Adapted from Science Photo Library/Alamy Stock Photo Image ID: F6YBC3.
Urine sample and biofilm microscopy can identify this gram positive organism. Culture yields the growth of E. faecalis in appropriate media. Advanced diagnostic methods like immunological-based detection methods and PCR are rarely needed for diagnosis.
One of the common causes of catheter associated urinary tract infection is fungal infection. Bacterial infections are accounted for 70.9% of catheter associated urinary infection. E. coli is the most commonly isolated organism (41.6%) whereas fungal infections are accounted for 16.6% and mixed fungal and bacterial infections accounted for 12.5% [68]. The National nosocomial infections surveillance (NNIS) data indicated that C. albicans caused 21% of catheter-associated urinary tract infections, in contrast to 13% of non-catheter-associated infections [69]. In one study 24% of the cases showing fungal yeast growth. Candida spp. was the commonest. Non-albicans Candida (86%) isolated more commonly than Candida albicans (14%) [70]. Candida are commensals, and to be pathogenic, interruption of normal host defenses is crucial which is facilitated in conditions like immunocompromised states as AIDS, diabetes mellitus, prolonged broad spectrum antibiotic use, indwelling devices, intravenous drug use and hyperalimentation fluids [71]. Diabetes mellitus has been reported as the most common risk factor for fungal infection [72, 73]. The duration of catheterization is also an important risk factor as the duration increases the incidence of fungal infection is increased [74].
Candida albicans is an oval, budding yeast, which is a member of the normal flora of mucocutaneous membrane. Twenty species of Candida yeasts can cause in human infection but most common is Candida albicans. Sometimes it can gain predominance and can produce disease. Other candida species that can cause disease occasionally are Candida parapsilosis, Candida tropicalis and Candida krusei [75]. Although Candida albicans are common isolates in CAUTI, Candida tropicalis is increasingly reported in CAUTI [76]. The majority of Candida albicans infections are associated with biofilm formation on host or abiotic surfaces such as indwelling medical devices, which carry high morbidity and mortality [63, 77]. Several factors and activities contribute to the pathogenesis of this fungus which mediate adhesion to and invasion into host cells, which are in sequences are the secretion of hydrolases, the yeast-to-hypha transition, contact sensing and thigmotropism, biofilm formation, phenotypic switching and a range of fitness attributes [78] (Figure 7).
Morphology of Candida albicans. Adapted from biomedik8888, Aug 24, 2011. http://www.BioMedik.com.au3.
Urine and materials removed from catheter are needed. Microscopic examinations of gram-stained specimen showed pseudohyphae and budding cells. Culture on Sabouraud’s agar at room temperature and at 37°C showed typical colonies and budding pseudomycelia [79].
It is facultative anaerobic bacilli gram-negative rod of Enterobacteriaceae family considered opportunistic human pathogen but not a component of human facial flora. It is capable of producing a pigment called prodigiosin, which ranges in color from dark red to pale pink. It is ubiquitously spent in nature and has preference for damp conditions. Though previously known as nonpathogenic, but since 1970s it is associated with multi drug resistant infection due to presence of R factor—a plasmid. A study in Japan showed 6.8% incidence of UTI with this organism [80]. It also causes bacteraemia rarely. Diagnosis is confirmed by culture of the urine specimen or catheter biofilm. Automated bacterial identification systems and Matrix-Assisted Laser Desorption Ionization-Time of Flight Mass Spectrometry (MALDI-TOF MS) is the other modality for diagnosis of serratia as well as other enterobacteriaceae [81].
This non-fermentative gram-negative rod discovered as plant growth-promoting bacterium and potential biocontrol agent against plant pathogens. Infection with this uncommon organism in CAUTI occurs in combination with commonest bacteria E. coli, Klebsiella pneumoniae and Pseudomonas aeruginosa. D. tsuruhatensis and E. coli coexist and tend to co-aggregate over time and also cooperate synergistically [82]. D. tsuruhatensis metabolized citric acid more rapidly leaving more uric acid available in the medium to be used by E. coli for dynamic growth of both organisms. Identification of this organism is not confirmatory with culture, so molecular methods are more reliable [83].
Achromobacter denitrificans is gram negative bacterium formerly known as Alcaligenes denitrificans. Infection with this organism predominantly observed in elderly patients with predisposing factors as urological abnormalities, malignancies and immune-suppression. Rarely it causes bacteraemia. This bacterium has high level of antibiotic resistance [84].
In polymicrobial biofilm, Achromobacter xylosoxidans cohabits with common organisms E. coli, Pseudomonas aeruginosa and Klebsiella pneumoniae. Diagnosis is by bacterial culture and molecular methods.
Staphylococci (methicillin-sensitive Staphylococcus aureus [MSSA] and methicillin-resistant S. aureus [MRSA], Staphylococcus saprophyticus. These are the common gram positive bacteria usually responsible for skin and soft tissue infections but rarely cause CAUTI and bacteraemia [85].
The incidence of Staphylococcal UTI as well as CAUTI is increasing and the organisms carry wide variety of multidrug-resistant genes on plasmids, which augment spread of resistance among other species [86].
Diagnosis is easy, gram stain of the sample, culture is sufficient. Advanced techniques rarely needed (Figure 8).
Morphology of Staphylococcus aureus. Adapted from abcam.comAdwww.abcam.com/ pharmacist-driven intervention improves care of patients with S aureus Bacteremia/Staph aureus. Nebraska Medicine https://asap.nebraskamed.com.
CAUTI is one of the most nosocomial Infection worldwide resulting from rational as well as sometimes irrational use of indwelling urinary catheter. Cause of CAUTI is formation of pathogenic biofilm commonly due to UPEC, Proteus, Klebsiella, Pseudomonas, Enterobacter rarely Candida and other uncommon opportunistic organisms. CAUTI has got high impact on morbidity and mortality as biofilm producing organisms are more antibiotic resistant. Antibiotic resistance is a global problem. Early detection of CAUTI is simple by examination of urine and catheter biofilm with microscopy as well as culture with antibiogram. It is easy and cost effective with early diagnosis and treatment for good clinical outcome. Advanced and sophisticated methods like Immunomagnetic separation, specific ELISA, colony immunoblot assays and PCR for diagnosis of CAUTI is seldom necessary.
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