By G. Armon. Briar Cliff University.

In order to under- depends on the ability of the phages to kill stand the pharmacology of phage therapy purchase discount pilex on line, we their target cells in situ: phages that are less must determine the pharmacokinetics (the efficient at killing their target cells will require fate of the administered agent in vivo) and larger numbers to sufficiently lyse host pharmacodynamics (the physiological and bacteria than would be needed when using therapeutic activity of the administered more efficient phages pilex 60caps without a prescription. Dosing parameters are agent) of phage therapeutics purchase cheap pilex, which discount pilex 60 caps with amex, due to particularly significant when considering both the complexity of phages and their ‘active’ versus ‘passive’ phage therapy. Active ability to self-replicate, are fundamentally phage therapy requires phage propagation in different in phage therapy compared with situ to bring about a therapeutic effect, chemotherapeutic approaches, a theme that whereas passive phage therapy uses higher has been explored at length by Curtright and doses of phages and further phage propa- Abedon (2011). It is therefore extremely gation is not required to generate therapeutic valuable to develop relevant, high-quality efficacy. This is discussed further by Abedon animal disease models to study the (Chapter 17, this volume). Phage pharmacology is in its infancy but We will now briefly discuss recent animal has been discussed in several studies and models of particular relevance to clinical theoretical papers (Geier et al. Perhaps most importantly, no correlation between antibiotic The ease with which blood-borne bacterial resistance and phage resistance has been infections can be induced in mouse models reported so far, suggesting that phage therapy has been exploited for many bacterial could prove especially useful in treating pathogens, and phage treatment is usually drug-resistant bacteria. Such models have especially in immunocompromised patients, been used for the treatment of bacterial represents a significant challenge clinically infections including E. Animal models therefore are highly assess phage treatment of cholera, again with useful to ascertain such limitations, as well as apparent success (Bhowmick et al. It is the potential of phage treatment of lung important to note that prophylactic use of infections. In some cases, therefore, non- infections, and phages can then be applied by pathogenic phage hosts present in the normal any route to determine treatment or flora could sustain phage numbers prior to prophylactic efficacy. This model has been pathogen challenge (see Letarov, Chapter 2, used to study phage treatment of K. A similar model of healthy animals, implying that prophylaxis Burkholderia cenocepacia infection also may be less useful for this type of infection. When essentially the same administered orally following neutralization model was used for P. More work is required to ascertain the from death compared with antibiotic-treated factors involved in phage treatment success or untreated animals. Such models also interesting to note that gastric do not appear to be difficult to work with, as neutralization may not always be necessary, the bacteria can be applied orally, as well as as some phages are able to survive the gastric the phage, although intragastric adminis- pH and reach the bowel in significant Phage Therapy of Non-wound Infections 209 numbers without this step (Chibani- increased approximately 100-fold. The need to be demonstrated on a phage-by- positive results of this work were sufficient to phage basis. This work demon- A brief list of human uses of phage therapy is strated that even temperate phages are given in Table 14. Ultimately, phage therapy capable of mitigating bacteraemia symptoms is unlikely to be accepted in the West until it in their model, especially when the phage satisfies the regulatory authorities by had been evolved to perform beter in vivo by demonstrating efficacy and safety in fully serial passage. While it has been suggested generally proscribed for therapy due to their that phage therapy warrants a loosening of potential to augment the pathogenicity of the regulatory standards (Verbeken et al. In addition, some large, multinational com- panies have expressed an interest in develop- Canine otitis ing and, ultimately, commercializing phage products for human use. In some cases, the While not all animal diseases are relevant to clinical research has focused on wound-care human disease, veterinary trials can still be applications, which are discussed by Loc- used to pave the way for human clinical trials Carrillo et al. Natural occur- Washington, New York-based company rences of canine otitis were used for a field Exponential Biotherapies Inc. Some details of other human applications, research and clinical trials and other studies are given by Häusler (2006) and Abedon (2011a,b). This table, however, illustrates some of the wide range of potential applications for phage therapy. A recent report described small-scale as a commercially supplied phage cocktail production of a purified phage preparation and standard-of-care treatments (htp:// for use in an as yet unreported clinical trial to clinicaltrials. While the trial was therapy has been carried out, using a cocktail for burn patients (a wound), the techniques of phages active against several bacterial and regulatory processes are of great species, in this case of chronically infected importance in paving the way for production wounds (Rhoads et al. No adverse of phage preparations for potentially any effects due to phage treatment were reported application, although more stringent afer topical administration of the cocktail requirements may be imposed for parenteral (see also Loc-Carrillo et al. A regulatory framework, it is unlikely that total of 24 patients were recruited with bespoke approaches will be acceptable, at chronic otitis of Pseudomonas aetiology. As mentioned above, it infecting bacteria were demonstrated to be has been suggested that in vitro phage susceptible to the cocktail prior to the activities may be poorly predictive of in vivo beginning of the trial. Debarbieux, assessments made on days 7, 21 and 42, Institut Pasteur, France, personal com- including microbiological analyses and munication) and some experimental work is physician and patient assessments. Both the emerging to corroborate these observations test and control groups received ear cleaning (Bull et al. If this at every visit and the results were the first is the case, we will need superior tools to human clinical data to demonstrate to predict the pharmacodynamic properties of Western regulators that phage therapy could therapeutic phages. The applications phage application led to bacterial titres falling discussed above used multiple ways to apply below the detection limit within 7 days and phages, and phages are partitioned differently remained undetectable up to 42 days post- depending on how they are applied (McVay treatment. Debarbieux reported the efficacy two whose bacterial infection had resolved, of phage treatment of P. In response to this potential need, research has been carried Additional issues out to find mechanisms to aerosolize phages as dried particulates for inhalational delivery Should phage therapy successfully complete into the deep lung space (Golshahi et al. It is likely the gold standard method of caesium chloride that bacteria will eventually become resistant density-gradient ultracentrifugation (Biswas et to any phage preparation, as they have to al. The degree of effective both geographically and temporally, purification may depend on the route of or instead should the focus be on development administration, presumably with parenteral of bespoke approaches that tailor phages for administration requiring far more highly individuals or small groups of patients? However, within the existing Western for a given bacterial pathogen, as is currently 212 B. Otherwise, unlikely that this approach would be used for addition of new phages to a formula to all but the most extreme circumstances (see maintain efficacy if bacteria become resistant Abedon, Chapter 17, this volume). As mentioned above, directed been shown to be safe for use can be modified evolution has been used successfully to alter combinatorially to expand their host range, the pharmacokinetic properties of then such requirements might be avoided. The huge global diversity Conclusions of phages, combined with phage-display technology (see Siegel, Chapter 8, this Phage therapy still has a long way to go volume) and other molecular approaches before it becomes a common or preferred raises the possibility that phages that target treatment modality for a large range of specific tissues or body compartments could bacterial diseases. Molecular techniques have Western regulatory approval, phage therapy also been used to augment phage antibiofilm will be used initially for refractory diseases. Ultimately, this may lead combined therapy, albeit at the cost of clinicians to prefer phages to current complicating the regulatory approval conventional treatments, even for some pathway (see also Goodridge, 2010, and Shen antibiotic-susceptible bacterial isolates (e. Advances in Applied host range of a single phage by creating a Microbiology 77, 1–40. Eliava Institute of Bacterio- work during the period from 1st January to 1st phages, Microbiology and Virology, Tbilisi, September 1929. Journal of the American dealing with reality, resistance and resistance to Medical Association 103, 1847–1853. Antimicrobial bacteriophage: its nature and its therapeutic Agents and Chemotherapy 50, 2912–2918. Archivum Immunologiae et Therapiae fibrosis strains: first steps towards treatment Experimentalis 32, 317–335. Archivum engineered virulent phage banks in the Immunologiae et Therapiae Experimentalis 33, detection and control of emergent pathogenic 219–240. Journal of General treatment of multidrug-resistant Pseudomonas Microbiology 128, 307–318. Journal of General Use of bacteriophage in the treatment of Microbiology 133, 1127–1135. The term ‘enzybiotic’ was coined by Vincent as the Gram-negative peptidoglycan is Fischeti’s group in 2001 to describe both the covered by a protective outer membrane that enzymatic and antibiotic properties of is not permeable to an exogenous enzyme bacteriophage-encoded endolysins (Nelson et under normal conditions. Endolysins are peptidoglycan enzybiotics encoded by Gram-positive phage hydrolases that function to lyse the bacterial represent an atractive therapeutic option cell wall for release of progeny virions during (Loessner, 2005; Borysowski et al. Significantly, in the absence of antibacterial or antifungal properties, holins or parental bacteriophage, these whether phage derived or not (Veiga-Crespo enzymes can be used exogenously to lyse the et al. Once the structural peptidoglycan is com- Autolysins are peptidoglycan hydrolases promised, internal turgor pressure, measured encoded by bacteria for growth, division and at 20–50 atmospheres for Gram-positive repair of the bacterial peptidoglycan. Like organisms (Whatmore and Reed, 1990; Doyle their phage-encoded endolysin counterparts, and Marquis, 1994; Arnoldi et al. For example, the major pneumo- endolysin enzybiotics, such as virion- coccal autolysin, LytA, was shown to effect a associated enzymes, have also been identified 5 log drop in bacterial counts 4 h afer (Takac and Blasi, 2005; Rodriguez et al. Likewise, fungal glucan- that has been used to describe a variety of ases and chitinases could be considered phenomena in which an extracellular agent autolysins with a potential for therapeutic destroys a bacterial cell envelope (Abedon, use (Veiga-Crespo and Villa, 2010). What is rarely the peptidoglycan of a different strain or mentioned in historical reviews, however, is species. One of the most-studied bacterial that Twort’s seminal manuscript also exolysins is lysostaphin, a peptidoglycan contained perhaps the first evidence for phage hydrolase secreted by Staphylococcus simulans endolysins.

Weaknesses Communication effects Included studies did not report sufficient detail on communication-based indicators of change to draw any inferences or conclusions on outcomes buy discount pilex 60 caps. Behavioural and other changes The studies included in the review highlight a need for more research on the nature and strength of association between behaviour and behavioural determinants quality pilex 60 caps. Many of the included individual-level and interpersonal-level theory based interventions targeted common intermediate variables but did not measure change order pilex american express. This represents a lost opportunity to pool evidence through meta-analysis or other methods to identify and measure treatment for purchase on line pilex, or effects size of, modifiable factors shared by the various theories and models (e. Application What has been applied into practice regarding the use of theories and models of behaviour change? European Fifteen per cent (n=9) of intervention studies captured by the review were from European settings [282, 286, 292, 301-302, 327, 330-331, 337]. Targeting including hard-to-reach populations • A wide range of target audiences, in particular a large body of evidence reporting on health professionals (n= 16) [282, 285-286, 289-290, 299-300, 302, 308, 312, 314, 317-318, 324, 337-340]. Weaknesses European There is an imbalance with relatively less evidence for lay persons (e. The reference numbering system used in this table does not stem from the completed review, published in the technical report series as: Angus K, Cairns G, Purves R, Bryce S, MacDonald L, Gordon R. Systematic literature review to examine the evidence for the effectiveness of interventions that use theories and models of behaviour change: towards the prevention and control of communicable diseases. The synthesis of evidence [1-9] highlights the most significant strengths and gaps in the European evidence base currently available for health communication in the prevention and control of communicable diseases. While there were many strengths and weaknesses evident, overall, it is apparent that there is a limited evidence base focusing on prevention and control of communicable diseases in a European context. Much of the evidence originated from North America and draws substantially on evidence from non-communicable diseases and other health issues. Therefore, the transferability of this knowledge, learning, expertise, and best practice should be explored in order to develop capacity. However, it is also evident that there is a lack of knowledge on how to use health communications to effectively engage and improve health outcomes for hard-to-reach groups [1-9], even though they carry the most significant burden of disease, have the poorest access to services and are found to be disproportionally affected during communicable disease outbreaks [7]. The reviews also indicated that within the current evidence base, there was: methodological variability, a lack of rigorous evaluation, inconsistent reporting, and lack of empirical studies and use of standardised measures, heterogeneity of interventions and evaluations. These limitations highlight the need for enhanced development and support of health communication research capacity in Europe. This is required in order to facilitate the development of a high-quality robust evidence base. Overall, while there is a limited European evidence base for health communication and communicable diseases, there is also evidence indicating some, albeit limited capacity across Europe. The implications of these findings, their relevance and suggested action areas for the future development of capacity for effective communication for the prevention and control of communicable diseases are discussed further in Chapter 3 of this report. Evidence review: social marketing for the prevention and control of communicable disease. A literature review on health information-seeking behaviour on the web: a health consumer and health professional perspective. A literature review of trust and reputation management in communicable disease public health. Health communication campaign evaluation with regard to the prevention and control of communicable diseases in Europe. A literature review on effective risk communication for the prevention and control of communicable diseases in Europe. Systematic literature review of the evidence for effective national immunisation schedule promotional communications. Systematic literature review to examine the evidence for the effectiveness of interventions that use theories and models of behaviour change: towards the prevention and control of communicable diseases. Barry Chapter 2 Opportunities and challenges: The consultation phases Introduction This chapter presents the evidence from the consultation phases of the Translating Health Communication Project. The matrices in this chapter, focusing on the identification of opportunities and challenges through primary data collection, complement those presented in Chapter 1, where the focus was on strengths and weaknesses of the evidence. The consultation comprised an e-survey and telephone interviews, and full information about the methodology used can be accessed in Doyle et al. The data from the e-survey was collected between October and December 2010, and 65 participants completed the survey. The semi-structured telephone interviews were designed to obtain more in-depth information on health communication activities. These were undertaken between October 2010 and March 2011, and 44 key informants participated. Using questions drawn from the findings of the e-survey, an expert consultation was conducted in Budapest, Hungary, on 21 March 2011. The protocol comprised of nine questions and covered domains such as health communication: examples, gaps, barriers, priorities, capacity and needs with regard to communicable diseases. The complete results of this consultation are presented in Doyle, Sixsmith and Barry, 2011 [2]. Data was gathered using asynchronous communication via a private electronic mailing list and supported by an interactive website/e-forum which provided access to project information and relevant resources, including 3 Participants identified what they would like to happen in the future for health communication. These participants had a wide range of public health and health communication expertise and were employed by a diversity of organisations. Primary information gathering Challenges and opportunities identified The first matrix presented in Table 2. The subsequent matrices in this chapter present the data collected through the e-forum [3]. Please note that for the twelve participants that took part in the online email consultation, personal identifiers were removed and replaced with participant numbers, thus any direct quotes from these participants will be labelled as such, for example ‘P1’. Opportunities To enhance collaborative working and strengthen partnerships and professional networks among those working in the area of health communication and communicable disease within countries and across all Member States. Opportunities • An opportunity exists to facilitate development of guidelines and tools to support health communication in a consistent way, for example developing health communication strategies and plans. European Antibiotic Awareness Day), especially among participants from those smaller countries, can be explored and built upon. Are there differences in health communication for communicable and non-communicable diseases? Challenges • It is reported that health communication for non-communicable diseases is more developed in terms of an evidence base than that for communicable diseases. Opportunities • To explore the transferability of expertise, capacity, information, best practice and lessons learned in health communication for non-communicable diseases to communicable diseases. Challenges • Many are reactive and undertaken during a crisis, leading to a perception of overreliance on crisis communication. Challenges • There appear to be some knowledge gaps in identifying credible sources of evidence for informing health communication activities and clearly defining the term ‘evidence’, e. Challenges • A reported lack of participation of key target audiences such as general public and community groups in the development of health communication activities. Challenges • Print media is widely used in practice while doubts of its effectiveness were expressed. Opportunities • To explore what are the most effective channels for dialogue with priority target audiences. Challenges • Limited cross-country use of health communication activities and resources. Opportunities • Facilitate the sharing of experiences with regard to: development, implementation and evaluation of health communication activities for communicable diseases between countries. It was also evident that in many instances responsibility for health communication work did not fall to a designated and/or trained health communication expert but usually formed part of a brief for an expert working in another area. Identified training needs included the areas of social media and evaluation and in public relations in order to be prepared for dealing with the media, particularly in emerging risk and crisis situations. Opportunities • In addition to outcome evaluation, there is an opportunity for investment in communication profiling and formative evaluation research. Formative evaluation research serves to answer key questions before the implementation of a behaviour change intervention/campaign. This means that evaluation requires active planning and implementation from programme inception to completion in order to contribute to programme success. In order to address the social determinants of health through health communication, future collaborations should be multi- disciplinary, not only should they involve the health sector or experts from the same field e. Coordination at national level • should be improved regardless of the many good health communication activities organised by local communities, regional public administration and national organisations.

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Write a description of what (“textural description”) the participants experienced with the phenomenon discount 60caps pilex amex, including verbatim examples purchase pilex 60caps without prescription. Combine the textural and structural descriptions into a composite depiction of the essence of the experience discount 60 caps pilex. The latter allows “opening up the codes to reflect the views of the participants in a traditional qualitative way” (Creswell buy pilex 60caps mastercard, 2007, p. I identified significant statements and themes based on the theoretical perspectives of feminism and social constructivism (a priori coding). More specifically, statements and themes related to the issues of (a) communication (gender differences; see Cheney & Ashcraft, 2007; Tannen, 2007), (b) culture (medical profession and education; see Kaiser, 2002; Thomas, 2001), and (c) diagnostic bias (see Hamberg et al. While it is known that the prevalence of thyroid disease is much higher in women than men across cultures (Canaris et al. Based upon my communications with 102 members of The Thyroid Support Group and current feminist literature, I had anticipated that themes will emerge in the following areas: (a) gender differences in communication (see Cheney & Ashcraft, 2007; Tannen, 2007), (b) culture of the medical profession (see Kaiser, 2002; Thomas, 2001), and (c) gender in diagnostic bias (see Hamberg et al. In addition, as the support group was international, it was possible that various patterns could emerge based on the participants’ culture, ethnicity, or both. In order to help validate the findings, I asked the participants to review the findings for accuracy and thoroughness. My colleague saved the participants’ interview transcripts and my interpretations onto a password-protected thumb drive. My colleague reviewed my interpretations of the data and provided me with feedback. I used my colleague’s feedback as a “reality check” to guard against my subjectivity as an individual with thyroid disease. Permission was also sought and obtained from the group owner-moderator of The Thyroid Support Group via a letter of cooperation (see Appendix B), after which members of The Thyroid Support Group were invited via an on-list e-mail to participate in the study (see Appendix C). Through the invitation, per the guidance of Ayling and Mewes (2009), I instructed interested members to create a free 103 email account using a fictitious name and to respond to my invitation via off-list, individual email with their new email account and fictitious name. I responded to the first 15 volunteers (not including myself) via off-list, individual emails and sent them a Consent Form (see Appendix D) explaining that they were chosen for the study because they are women with a thyroid disease diagnosis. Please note that I used implied, rather than informed, consent to safeguard participant anonymity. I instructed each volunteer to review the consent form and to respond to my email off-list using her new email account and fictitious name to set up a date and time for her individual interview if she was still interested in participating. The consent form informed prospective participants about the procedures and time commitments of the study, potential risks and benefits, limits to confidentiality, their right to withdraw from the study at any time without penalty, and contact information for myself and my advisor. The consent form also explained that by emailing me to establish a date and time for an individual interview, their consent to participate in the study was implied. Upon receiving implied consent via off-list, individual emails from volunteers, I individually emailed each participant to establish a date and time for her individual online interview. Each participant was asked to not respond to my e-mails from her workplace, as employers may have legal access to her e-mail (Keller & Lee, 2003). For additional security, I encouraged participants to engage in the interview in a private, non-public area (Kraut et al. As noted under “Data Management,” I copied and pasted each interview transcript onto a password- 104 protected thumb drive, which I will store in a locked cabinet in my office for a period of five years, after which the drive(s) will be destroyed. As my colleague had access to the data, she was asked to sign a confidentiality agreement (see Appendix E) before any data analysis or interpretation began. My colleague saved the participants’ interview transcripts, electronic journals/diaries, and my interpretations onto a password-protected thumb drive and destroyed all data related to my study after sending me her feedback via ShareFile. Qualitative Trustworthiness Data trustworthiness and quality was verified through use of the following techniques: prolonged engagement, triangulation, member checking, and reflexive journaling. Prolonged Engagement Prolonged engagement involves an understanding of the culture one plans to investigate, as well as building trust with one’s participants (Creswell, 2007; Schensul & LeCompte, 1999). Because I have been a member of The Thyroid Support Group since 2004, trust had been established with the group owner-moderator and potential participants. In addition, as a member, I have a comprehensive understanding of the context and phenomena under study. Triangulation Triangulation includes the use of different sources, theories, and investigators in an attempt to substantiate evidence (Creswell, 2007, 2008; Schensul & LeCompte, 1999). I collected data from an interview guide and had planned to collect personal electronic 105 journals or diaries. Triangulation was achieved by using more than one theoretical position (feminism and social constructionism) to interpret the data (theoretical triangulation; Denzin, 1970). I also used the services (on a voluntary basis) of a colleague for data interpretation (consensual validation; Eisner, 1991). Member Checking Member checking involves seeking and including participants’ feedback in assessing the credibility of the study’s findings (Creswell, 2007; Schensul & LeCompte, 1999). At the end of each interview, participants reviewed their individual interview transcript for accuracy. I also asked the participants to review the findings of the research for accuracy and thoroughness. Reflexive Journaling Reflexive journaling involves acknowledging and keeping a record of one’s personal thoughts and feelings while conducting research in an attempt to eliminate researcher bias (Creswell, 2007; Moustakas, 1994). I maintained a record of personal thoughts and feelings that occurred throughout the research process. Dissemination of Findings I will be the sole researcher involved in the dissemination of the findings. First, results will be shared with participants who indicated an interest in reading the study. Second, I plan to publish a condensed form of the study in a scholarly journal so that healthcare professionals can utilize the information in practice and future research. Third, I will condense the study to 106 the scope of a conference paper with the intention of presenting the study and its results at appropriate conferences. Summary This qualitative, phenomenological study explored the lived experiences of a sample of 16 women diagnosed with thyroid disease in order to answer questions regarding their treatment experiences and the effect of gender on their relationships with their doctors. Using the phenomenological approach of Stevick/Colaizzi/Keen as modified by Moustakas (1994) and enriched by Van Manen (1997), I identified common themes as well as discordant information among the participants. Two approaches to understanding participants’ experiences, social constructionism and feminism, were used in data interpretation. Results of this study may, consistent with Van Manen’s five principles and the university’s mission to effect positive social change, result in improvements in medical practice with female patients with thyroid disease. In Chapter 5, the findings are interpreted and discussed along with implications for social change and recommendations for further research. A phenomenological approach was used in order to examine the meaning of the experience of thyroid disease treatment as described by women who had experienced treatment for thyroid disease. Based upon the theories of social constructivism and feminism, the following research questions were answered: “What are the treatment experiences of women with thyroid disease? I discuss the setting, participant demographics, data collection and management, data analysis, evidence of trustworthiness, and the major themes and subthemes that emerged during data analysis. Setting Data were collected via individual online chat interviews with members of The Thyroid Support Group. Before each interview, participants were informed that they had the right to leave the study at any time for any reason, without explanation. Participants were provided with free, international crisis hotline telephone numbers in case they felt upset as a result of their interviews (see Appendix D, Consent Form). It is not known if any of the participants used the crisis hotline telephone numbers provided. No unexpected events occurred that might have influenced my interpretation of the data. The median age was 54 years, with the youngest participant at 32 years old and the oldest participant at 82 years old. The sample was mostly Caucasian (14 out of 16 participants), with one participant identifying as Hispanic and another participant identifying as Czech Polish. The majority of the participants (15 out of 16) reported having education beyond high school. More specifically, three participants reported having “some college,” two had associate’s degrees, seven had bachelor’s degrees, and three had master’s degrees. Eight of the participants reported having male doctors, six reported having female doctors, and two reported having both male and female doctors. The majority of the participants’ doctors were Caucasian (13 out of 18 total doctors), two were Middle Eastern, one was Asian, one was East Indian, and one was Nigerian (see Table 2).

It is expected that by blocking the free amine group in amoxicillin and cephalexin by a suitable linker the interaction of the antibacterial with bitter taste receptors on the tongue will be blocked cheap pilex 60caps. Carbapenems Carbapenems are broad spectrum β-lactam antibiotics; they are stable to almost all β- lactamases cheap pilex 60caps with visa. They differ from other β-lactam antibiotics in their nuclear structure buy cheap pilex on-line, in which the sulfur is replaced by a carbon group and there is an unsaturated bond between carbon 1 and 3 in the thiazolidine moiety (Figure 20) [17] purchase pilex cheap online. The first carbapenem introduced into clinical practice was imipenem (Figure 21); it has a broad specrum of activity but was susceptible to hydrolysis by human renal dehydrogenase 1. Meropenem is more active against gram negative bacteria than imipenem, while the latter is more active against gram positive bacteria. Other carbapenems are ertapenem, panipenem, biapenem, lenapenem and sanfetrinem [17]. Vancomycin This glycopeptide antibiotic (Figure 23) was developed in 1950, the basic structure of this type of antibiotics is seven amino acids, sugars and amino sugars [18]. Vancomycin inhibits cell wall synthesis by forming a complex with peptidoglycan which inhibits transpeptidase [19]. Vancomycin is used for the treatment of infections caused by gram positive bacteria. Excessive use of vancomycin resulted in amplification of vancomycin resistant enterococci. In addition, it caused an increase in staphylococcus resistance, which is caused by the increase in cell wall thickness and a decrease in permeability [20]. Rapid infusion of vancomycin is associated with "red man" or "red neck" syndrome, a nonimmunological reaction which causes pruritus and hypotension. Intravenous administration is also associated with thrombophlebitis at the site of administration. Vancomycin may cause hypersensitivity reactions which includes skin rash and drug fever. After ototoxicity the drug must be discontinued, this side effect is reversible [22]. Vancomycin has a poor oral bioavailability caused by the polar nature of the drug. Studies have shown that the use of water in oil in water multiple emulsion incorporating unsaturated fatty acids increased the intestinal absorption [23]. Antibiotics 57 Protein Synthesis Inhibitors This group of antibiotics targets bacterial ribosome, which composed of 50S and 70S subunits. Thetracyclines Thetracylines are lipophilic nonionized molecules composed of a linear fused six membered nucleus (Figure 24). The first members of tetracyclines are chlortetracycline and oxytertracycline, both were discovered in 1940 [24]. Both have a serum half life range from 6 to 10 hours, they are absorbed in the stomach duodenum and small intestine [25]. Thetracyclines are bacteriostatic to a wide range of gram positive and gram negative bacteria, they inhibit protein synthesis by inhibiting the 30S ribosome [26]. They penetrate well across sebum which makes tetracycline largely used for acne treatment [24]. Doxycyline and minocycline (Figure 25) are second generation tetracyclines, which have better tissue penetration, longer half life, and large volume of distribution compared to the original tetracylines [26]. Doxycycline has a bioavailability of more than 80%, its half life ranges from 12 to 25 hours. Doxycyline is used for gonorrhea and Chlamydia pelvic infections, Lyme disease, malaria prophylaxis and syphilis. The majority of its dose is absorbed in the duodenum, and it is better taken with food to decrease G. Thetracycline Clinical Uses Thetracyclines generally are used for the treatment of Pasteurella infections, brucellosis, Borrelia recurrentis that cause relapsing fever, early stages of cholera, Mycoplasma pneumoniae infections, rickettsial infections, Shigella dysentery in which a single dose therapy of tetracyclines is effective, Chlyamidia psittaci infections, conjunctivitis, trachoma, L-serotypes of Chlamydia infections, ureteritis caused by Chlamydia or Ureaplasmas, syphilis prophylaxis and chronic bronchitis in which minocycline and doxycycline are preferred [27]. Minocycline is also preferred for long term low dose treatment of mild to moderately severe acne caused by Corynebacterium acnes, due to its ability to penetrate quite well the lipid layers of the dermis and possess minor side effects [27]. Thetracylines Side Effects The most common side effects associated with tetracylines are G. In addition, tetracyclines cause tooth discoloration in adults and children, it can cause this discoloration in developing teeth even during pregnancy [26]. Thetracyclines should not be used for patients less than 8 years old and pregnant women [27]. Resistance to Thetracyclines The extensive use of tetracycline leads to the development of bacterial resistance, this resistance is caused by: Protection of the tetracycline target, ribosome. There are two types of tetracycline efflux pumps tetracycline specific and multidrug resistance efflux pumps. The resistance and its widespread by the mobile tetracycline resistance (tet) genes caused a decrease in the therapeutic effectiveness of tetracyclines [29], and consequently has led to the development of the third generation tetracycline, glycylcylines. Glycylcylines have the same structural features of tetracycline, but they are not substrates for efflux pumps, which makes this generation effective against the resistant organisms [30]. Aminoglycosides A group of molecules that have a nucleus of amino-cyclitol attached to two or more sugars by a glycoside linkage. This positive charge makes glycosides able to bind to the negatively charged lipopolysaccharides on the bacterial cell wall, but also contributes to the side effects of aminoglycosides [33]. Clinical Uses of Aminoglycosides Aminoglycosides have a broad spectrum of activity and rapid bactericidal effect. Aminoglycosides generally are used for the treatment of aerobic gram negative bacilli, staphylococci and certain mycobacteria. Gentamicin, amikacin and netilmicin (Figure 27) are used for pneumonia, sepsis and meningitis. Aminoglycosides are only available for parenteral, intramuscular and intravenous administrations because they are polar compounds [33]. There have been studies to increase aminoglycosides absorption using mixed micellar solutions. It was found that the combinations of bile salts and certain lipids increased the absorption of gentamycin and streptomycin [34]. Another common side effect is ototoxicity that can be acute, reversible, or chronic and irreversible hearing loss which can be caused by cochlear hair cells degeneration [35]. Bacterial Resistance to Aminoglycosides The widespread therapeutic use of aminoglycosides results in the development of resistance. Macrolides Erythromycin (Figure 28) was the first antibiotic discovered in 1952 among this group. After its discovery many semisynthetic compounds were developed such as clarithromycin, azithromycin and roxithromycin that are all derivatives of erythromycin with better microbiological and pharmacokinetic properties. The general structure of macrolides is a 12 to 16 atoms lactone ring that is attached via a glycosidic linkage to one or more sugars. Macrolides are widely used for the treatment of gram positive bacterial infections such as Staphylococcus aureus and Staphylococcus pneumonia. Erythromycin Erythromycin (Figure 28) is a 14-membered lactone ring attached to two sugars. The main side effects of erythromycin are nausea, vomiting, diarrhea, abdominal cramps and phlebitis caused by intravenous administration [38]. Clarithromycin Clarithromycin is a 14-membered lactone ring, a derivative of erythromycin. I of all macrolides with 50% bioavailability, administered twice daily and not available for intravenous administration. It is used for the treatment of upper and lower respiratory tract infections [38]. Clarithromycin is well tolerated in doses less than 2000 mg, but it occasionally causes nausea, diarrhea, abdominal pain, headache and metallic taste. Azithromycin Azithromycin (Figure 29) is the only 15 membered lactone ring antibiotic of this group. It was developed by the addition of amino group to the erythromycin ring and it has a better gram negative bacterial activity than erythromycin [37]. The primary side effects are gastrointestinal including nausea diarrhea and mild abdominal pain [41].

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