16. R. Villano “Superbugs & Superdrugs”, You plot historical notes on the concept of antibiosis, on research, discovery and production of antibiotics and their global role not only therapeutic but also strategic since World War II. Then, you look at national and international issues related consumption, misuse and overuse of antibiotics in humans, in animal husbandry, agriculture, and thus in the food chain and the environment; policies to combat the phenomenon of excessive prescription and citizens in the degree of information and awareness of the risks; guidelines of good practice behavior of the patient; the main documents of struggle in this emergency. We make also an analytical overview and a discussion of some super diseases (tuberculosis, gonorrhea, meningitis, etc.) And bacterial resistance to major antibiotics. We realize, finally, a survey on current technologies and addresses of applied research and a survey on major recent new therapies. Closes work a technical appendix containing an apparatus essential regulations and ministerial directives Italian and European Community on the theme. (Chiron dpt Praxys, Roma, June 2015, pp. 176);

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2. Raimondo Villano
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3. Superbugs & Superdrugs
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Contents index
Sommario 13
Abstract 15
Résumé 17
Abstrakt 19
Abstracto 21
1. A brief history of antibiotics 25
2. Issues and contrast of antibiotic 33
3. Major resistance to antibiotics 49
4. Look back at some super diseases 55
5. Technologies and research directions 65
6. New therapeutic compounds 77
7. Appendix 85
8. Author profile 169

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“Life is short, art is long,
the favorable opportunity,
attempting misleading,
the difficult decision”
Hippocrates

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Parole chiave
antibiotici, resistenza, batteri.
Keywords
antibiotics, resistance, bacteria.
Classification LCC
RM 265 - 267.
Title
Antibiotic resistance.

7. Raimondo Villano
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Sommario
Si tracciano cenni storici sul concetto di antibiosi, su ricerche, scoperta e
produzione degli antibiotici e sul loro ruolo mondiale non solo terapeutico
ma anche strategico dal secondo dopoguerra. Poi, si esaminano a livello
nazionale ed internazionale: le problematiche inerenti consumo, uso
improprio e abuso di antibiotici nell’uomo, in zootecnia, agricoltura e,
quindi, nel ciclo alimentare e nell’ambiente; le politiche di contrasto al
fenomeno dell’iperprescrizione e nei cittadini il grado di informazione e
consapevolezza dei rischi; le linee guida di buona prassi comportamentale
del malato; i documenti principali di lotta a tale emergenza. Si effettuano,
inoltre, una rassegna analitica e un approfondimento su alcune super
patologie (tubercolosi, gonorrea, meningite, ecc.) e sulle resistenze
batteriche ai principali antibiotici. Si realizzano, infine, una ricognizione
sull’attualità delle tecnologie e degli indirizzi di ricerca applicata e una
rassegna sulle principali recenti nuove terapie. Chiude il lavoro
un’appendice tecnica contenente un apparato essenziale di normative e
direttive ministeriali italiane e comunitarie europee sul tema.

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Abstract
You plot historical notes on the concept of antibiosis, on research,
discovery and production of antibiotics and their global role not only
therapeutic but also strategic since World War II. Then, you look at
national and international issues related consumption, misuse and overuse
of antibiotics in humans, in animal husbandry, agriculture, and thus in the
food chain and the environment; policies to combat the phenomenon of
excessive prescription and citizens in the degree of information and
awareness of the risks; guidelines of good practice behavior of the patient;
the main documents of struggle in this emergency. We make also an
analytical overview and a discussion of some super diseases (tuberculosis,
gonorrhea, meningitis, etc.) And bacterial resistance to major antibiotics.
We realize, finally, a survey on current technologies and addresses of
applied research and a survey on major recent new therapies. Closes work
a technical appendix containing an apparatus essential regulations and
ministerial directives Italian and European Community on the theme.

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Résumé
Vous tracez notes historiques sur le concept de antibiose, sur la recherche,
la découverte et la production d’antibiotiques et de leur rôle dans le monde
non seulement thérapeutique, mais aussi stratégique depuis la Seconde
Guerre mondiale. Ensuite, vous regardez les questions nationales et
internationales liées à la consommation, utilisation abusive et excessive
d’antibiotiques chez l’homme, dans l'élevage, l'agriculture et, donc, dans la
chaîne alimentaire et l’environnement; politiques de lutte contre le
phénomène de la prescription excessive et les citoyens dans le degré
d’information et de sensibilisation des risques; lignes directrices de bonne
conduite de la pratique du patient; les principaux documents de lutte dans
cette situation d’urgence. Nous faisons également un aperçu analytique et
une discussion de certaines super maladies (tuberculose, la gonorrhée, la
méningite, etc.) et de la résistance bactérienne aux antibiotiques majeurs.
Nous nous rendons compte, enfin, une enquête sur les technologies et les
adresses de la recherche appliquée en cours et une enquête sur les
principales nouvelles thérapies récentes. Ferme fonctionne une annexe
technique contenant les règlements essentiels de l’appareil et les directives
ministérielles italiennes et de la Communauté européenne sur le thème.

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Abstrakt
Sie plotten historische Anmerkungen über das Konzept der Antibiose, auf
Forschung, Entdeckung und Herstellung von Antibiotika und ihre Rolle in
der Welt nicht nur therapeutisch, sondern auch strategische dem Zweiten
Weltkrieg. Dann schauen Sie auf nationalen und internationalen Fragen im
Zusammenhang mit Konsum, Missbrauch und übermäßige Einsatz von
Antibiotika bei Menschen, in der Tierhaltung, Landwirtschaft, und damit in
die Nahrungskette und die Umwelt; Politik zur Bekämpfung des
Phänomens die übermäßige Verschreibung und Bürger in den Grad der
Information und Sensibilisierung der Risiken; Leitlinien für die gute Praxis
Verhalten des Patienten; die wichtigsten Dokumente des Kampfes in
diesem Notfall. Wir machen auch einen analytischen Überblick und eine
Diskussion einiger Super Krankheiten (Tuberkulose, Gonorrhö, Meningitis,
etc.) und bakterieller Resistenz gegen wichtige Antibiotika. Wir wissen,
schließlich eine Umfrage zu aktuellen Technologien und Adressen von
angewandter Forschung und eine Umfrage zu den wichtigsten aktuellen
neuen Therapien. Schließt Arbeit eine technische Anlage, die eine
Vorrichtung wesentliche Vorschriften und Ministerialrichtlinien
italienischen und europäischen Gemeinschaft über das Thema.

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Abstracto
Trazar notas históricas sobre el concepto de antibiosis, en la investigación,
el descubrimiento y la producción de antibióticos y su papel global no sólo
terapéutico, sino también estratégico desde la Segunda Guerra Mundial. A
continuación, nos fijamos en los asuntos nacionales e internacionales
relacionados con el consumo, el mal uso y abuso de los antibióticos en los
seres humanos, en la ganadería, la agricultura, y por lo tanto en la cadena
alimentaria y el medio ambiente; políticas de lucha contra el fenómeno de
la prescriptión excesiva y los ciudadanos en el grado de información y
conocimiento de los riesgos; pautas de comportamiento de buenas
prácticas de la paciente; los principales documentos de lucha en esta
emergencia. Hacemos también un resumen analítico y una discusión de
algunas enfermedades súper (tuberculosis, gonorrea, meningitis, etc.) y la
resistencia bacteriana a los principales antibióticos. Nos damos cuenta,
por último, un estudio sobre las tecnologías y las direcciones de la
investigación aplicada en curso y una encuesta sobre las principales
nuevas terapias recientes. Cierra funciona un anexo técnico que contiene
un aparato regulaciones esenciales y directivas ministeriales italianas y de
la Comunidad Europea sobre el tema.

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S U P E R B U G S & S U P E R D R U G S

13. Raimondo Villano
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3. Major resistance to antibiotics

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15. Raimondo Villano
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There are few drugs to replace those that have become ineffective, the last
new class of antibacterial drugs was discovered 27 years ago, according to
the Report of the Organization for the United Nations.
As global usage of drugs of last resort grows, the resistance to these drugs
accelerates aggravating the crisis.
The superbug, which is resistant bacteria to antibiotics, continue to spread
and are no longer found only in hospitals. Overuse of antibiotics becomes
an even bigger threat if combined with globalization: trade, travel,
migration and medical tourism spread the multidrug-resistant pathogens in
every corner of the world in a few days.
"More than 70% of the bacteria that cause infections are resistant to at least
one of the antibiotics used to treat them. In the basic medicine it is quite
common that doctors meet streptococcal infections resistant to
azithromycin(37)
. "
And the Italian situation is alarming for the increase of resistance in Gram-
negative bacteria: the frequency of antibiotic-resistance in strains of
Pseudomonas aeruginosa is still high (21%). In Escherichia coli strains, in
particular, resistance to antibiotics fluoroquinolones increased from 25% in
2003 to 41% in 2011, and with the same trend also increases the resistance
to third generation cephalosporins, increased from 6% to 20%( 38)
.
The given sull'antibiotico-resistance, deteriorates especially for bacteria
such as Escherichia coli, Staphylococcus aureus and Klebsiella
pneumoniae, with peaks of 40% of ineffectiveness of drugs.
The Escherichia coli, apparently 'super-resistant', in 2011 is responsible for
the deaths of 51 people in Europe, especially in Germany(39)
.
At the European level continues to increase the 'no answer' to
fluoroquinolones and third generation cephalosporins for the germ(40)
.
______________
(37) Tarayn A. Fairlie, epidemiologist at the Centers for disease control and prevention,
in: Morbidity and mortality weekly report September 2, 2011/60 (34); 1153-1156.
(38) European center for disease prevention and control (ECDC), Document on
antibiotic resistance of the main 7 invasive pathogens (Streptococcus pneumoniae,
Staphylococcus aureus, Escherichia coli, Enterococcus faecalis, Enterococcus faecium,
Klebsiella pneumoniae and Pseudomonas aeruginosa) in 29 European countries , 2011.
(39) 51 th Congress ICAAC - Interscience conference on antimicrobial agents and
chemotherapy, Chicago, USA, 2011.
(40) Report of the European Center for Diseases Control (ECDC), published on the
occasion of the seventh day of antibiotics, Stockholm, November 18, 2014.

16. Superbugs & Superdrugs
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The latest WHO report, for example, focuses on Klebsiella pneumoniae,
intestinal bacterium among the most common causes of hospital-acquired
infections such as pneumonia, neonatal or intensive care patients with fatal
outcomes especially in newborns and those in intensive: in some countries,
because of the resistance developed by the germ, more than half of patients
do not respond to carbapenems, antibiotics "last line" that is already used
when others have failed. In Italy it is an emergency for the strains of
Klebsiella pneumoniae producing carbapenemases, enzymes that inactivate
carbapenems, antibiotics of last resort to treat infections with multi-
resistant bacteria: have gone from 1.6% in 2009 to 15% in 2010, to 27% in
2011(41)
, to 29% in 2013. The disturbing result is that our country is
"second only to Greece(42)
."
At European level there is an increase in resistance to cephalosporins of the
third generation and carbapenems for Klebsiella pneumoniae(43)
. "To
understand the extent and rate of spread of the phenomenon of resistance to
carbapenems in Italy just think that in 2008 less than 1% of Klebsielle was
resistant. The percentage became 15% in 2010, 29% in 2012 and 35% in
2013. The carbapenem antibiotics are of last resort, real lifesaver for
infections already resistant to most antibiotics available. The resistance to
carbapenems is due to an excess mortality of at least 30%, even value that
rises in an even more significant in patients particularly fragile(44)
.
Rampant, then, is also the resistance to fluoroquinolones, used in urinary
infections from Escherichia coli: the time of their introduction in the 80s,
resistance to them was virtually zero, while today there are countries in
many areas of the world where They are ineffective in more than one
patient on 2. In our country the resistance of Escherichia coli to
fluoroquinolones was 40%, while cephalosporins exceed 25%(45)
.
Another major problem for Italy is the multi-resistant Acinetobacter (ie
resistant to fluoroquinolones, aminoglycosides and carbapenems) that in
Italy represents more than 50% of the Acinetobacter isolates(46)
.
______________
(41) European center for disease prevention and control (ECDC), Ibid.
(42) Farmacista33, WHO Report: Antibiotic resistance is a real threat, May 7, 2014.
(43) Report of the European Center for Diseases Control (ECDC), Ibid.
(44) National Institute of Health.
(45) Farmacista33, WHO Report, Ibid.
(46) Report of the European Center for Diseases Control (ECDC), Ibid.

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As for gonorrhea, infecting the planet 1 million people a day, cases of 'flop'
of third-generation cephalosporins have been confirmed in Austria,
Australia, Canada, France, Japan, Norway, South Africa, Slovenia, Sweden
and the UK. Gonorrhea, a time well treated with antibiotics, it is once again
a serious threat to public health because of the emergence of new resistant
strains. Drugs that were once a resort treatment for the sexually transmitted
disease that can lead to infertility, blindness and increased likelihood of
HIV transmission if untreated, are now the first-line treatment and
sometimes ineffective among patients in countries such as the United
Kingdom, Canada, Australia, France, Japan, Norway, South Africa,
Slovenia and Sweden(47)
.
Methicillin-resistant Staphylococcus aureus (MRSA), one of the most
feared bacteria in hospitals, until two decades ago found mostly in hospitals
and in agriculture, 'it is good' even in homes, at least in the United States of
America. The study says that those who are infected in hospitals or nursing
homes then carries the bacillus at home(48)
.
"The majority of strains of MRSA were found endemic in homes(49)
" for
which "probably do reservoir for colonization, diversification and the
transmission of these bacteria(50)
."
The new study found that even the homes of 161 residents in the city of
New York were infected with MRSA superbug strain of large tanks (called
USA300, which is among the leading causes of infection in the United
States) that, starting from homes these people, it is further spread.
According to the study, therefore, is not enough to cure the infection in the
hospital, but we must try to 'clean up' also the home of patients.
The bacteria are spread through virtually everything you touch, from the
sheets to household appliances, and while it was not yet well understood
the way the superbug is transferred from one surface to another, it is well
known that any object may be contaminated sterilized by washing with hot
water and bleach.
A good idea, then, is to wash your hands often(51)
.
______________
(47) Dina Fine Maron, Ibid.
(48) Study of the Department of Medicine, Division of Infectious diseases at Columbia
University Medical Center in New York, published in the journal PNAS in 2014, based
on analysis of 139 infected patients between 2009 and 2011, which have been tested
home and closest relatives to verify the presence of the bacterium.
(49) Anne-Catrin Uhlemann, lead author of the study.
(50) Anne-Catrin Uhlemann, Ibid.
(51) Anne-Catrin Uhlemann, Ibid.

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In Italy the frequency of methicillin-resistant Staphylococcus aureus
(MRSA) is at 38% in 2011, against the EU average of less than 20%(52)
;
percentage of resistance in 2014 in Italy remains critical (about 35%) while
most European countries have managed to bring it back to lower levels.
In conclusion, the increasing trend of antibiotic resistance in our country
can only be reversed by a combination of effective interventions whose
main points are the promotion of prudent use of antibiotics in the territory
and effective control strategies for stopping the spread of multi-resistant
bacteria in care facilities(53)
.
Efforts to limit the spread of multidrug-resistant tuberculosis, malaria and
HIV are all under threat due to increasing bacterial resistance. Although the
development of resistance is predictable over time, the abuse of drugs has
accelerated the process by providing additional selective pressure, noted
the report that was written by a large team of researchers with the World
Health Organization(54)
. For example, "for respiratory diseases in Uganda, it
collides with a multi-resistant pneumococcal disease by as much as 90% to
treatment with drugs", and alternative medications in that context were not
readily available(55)
.
Streptococcus pneumoniae is also kept in check because it is becoming
resistant to antibiotics of last generation. Among other things, it is the only
streptococcus to which there is also a vaccination indicated for subjects
suffering from chronic bronchitis and immunosuppressed(56)
.
Finally, there are various other superbugs such as, for example, IFN-1 New
Delhi metallo-lattasio, in India since 2010 and defined 'persistent threat(57)
'.
______________
(52) European center for disease prevention and control (ECDC), Document on
antibiotic resistance of major sects invasive pathogens (Streptococcus pneumoniae,
Staphylococcus aureus, Escherichia coli, Enterococcus faecalis, Enterococcus faecium,
Klebsiella pneumoniae and Pseudomonas aeruginosa) in 29 European countries , 2011.
(53) Report of the European Center for Diseases Control (ECDC), Ibid.
(54) Dina Fine Maron, Ibid.
(55) Stuart Levy, a collaborator of WHO Report and Director of the Center for
Adaptation Genetics and Drug Resistance at Tufts University School of Medicine. Abs.
by: Dina Fine Maron, Antibiotic resistance is now rife throughout the whole world,
Scientific American April 30.
(56) Farmaday, Grew streptococcal infections: strike at any age, from the throat to the
hip, Science and Health, Year III, No. 445, p. 4.
(57) 51st Congress ICAAC - Interscience conference on antimicrobial agents and
chemotherapy, Chicago, USA, 2011.

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8. Author profile

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Born in 1960. He lives in Rome and Torre Annunziata. Role:
General Manager Villano International Business Team (from
2012); Chiron CEO Publisher, Honorary Member (2013) and
Associate Professor in History of Health Pharmaceutical
Administration Department of Ruggero II University (Miami,
2014), Trader (since 1976), Trader operating financial
independent of bags and forex (since 1983), Knight SMO Malta
(since 2002), President of Chiron Humanitarian Foundation (since 1985).
Academies: History Art Health-Ministry BC, former papal Tiberina, Melitensi
Studies, Medical Tradition Smithsonian Institution-USA, International Society
History Pharmacy, Acc. History Italian Pharmacy, Soc. Napoletana National
History in. h. Noble College Chemical Pharmaceutical. Over 100 conferences
and chairman in dozens of conferences. He collaborates with important
national and international magazines. You Advisory Board Member for the US
Publisher DPC, which publishes in more than 150 nations. Studies: Classical;
degree and abil .: Pharmacy (1985); courses certificates: Medicinal herbs,
Cosmetic Techniques, Corporate Security, HACCP, History, Social Doctrine of
the Church, theology. Degrees h.c.: Human and Social Sciences (2009); History
and Philosophy (2010); Communication Sciences (2013). Master h.c.: Science
Medical Ethics (2010). He was author, organizer and chairman Safety Course for
managers, obtaining the High Patronage of the Head of State and the UN (2000),
Secretary International Committee Biothecnologies Wabt-Unesco 2008-13,
Diplomatic Adviser AEREC dpt ENVA (from 2011), member of World
Academy Biomedical Technology (Unesco 2007-12), 11 years in the Scientific
Committee of the Health Security IBD (company responsible for the security of
the Courts Naples Appeal Court), Board Beaumont Foundation Onlus research
on cancer with the Prefect of Naples (2011-12), member of European Academy
for Economic and Cultural Relations (2004-15). 32 years partner and owner of
the pharmacy. Partner since 1990, Secretary to 29 years 1990-95 and 2000
Rotary Club President Pompeii-Vesuvius; Comm.ni in Rotary District 2100-
Italy: Professional Ethics, Global Action, Computer; among the many
international roles: archeology Pompeii-Carthage; Committee Prize Magna
Grecia. Napoli president, national Coordinator and founder Federation Young
Chemists; Representative National Trade Union Federative. Assistant
Microbiology Fac. F.cia Na (1985-90, Chair Prof. Lembo-Inst. Sup. Health).
International awards: Diploma of Honor for exceptional services individually
in 5 Vie Action by President Rotary International (Evanston 2001: only 100 /

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year / 1.5 million members); Merit Anti-Crime Task Force-Rotary Italy, Albania,
former Yugoslavia, San Marino (Zurich 2001); Sapientia Mundi-Ethics (Rm
2008); Union Legion of Gold-Work (Rm 2010); Veritas in Charitate-Religion
(2011); Bonifaciano-Culture and Society (2011); Norman-Publishing Gold
Medal (Rm 2014); Norman-Health Galen of Pergamum (Rm 2014). National
Awards: Aesculapius-Health Patronage Ministers Council (Rm 1987); LXVIII
Piccinini-Search (Rm 2006); LXV Stramezzi-Health (Rm 2007); Capitolino-
humanitarian activities (Rm 2010); Tiberino-Culture (Rm 2012); LXXIV
Serono-History (Rm 2012), AEREC-Culture (Rm 2013); Merit Public Health
(DPR 2013), Tiberino-Science (Rm 2014). Author of over 730 publications
health, professional, scientific, historical, religious; more than 50 books (many
translated into English, French, some German, Spanish) with prestigious
publishers as Zanichelli and sponsorship by the Ministry of Cultural Heritage,
Unesco, Rotary, University, etc., present in Italian libraries (including:
Quirinale, National Academy Science, Ministries) and more than 40 countries
(including: National Health Institute-USA, Nationale de France, Congress UK),
in cultural institutes, Universities, Museums; a book made its debut at the
Frankfurt Fair. Catalogues: 2000 Outstanding Intellectuals IBC-Cambridge from
2010; OPAC SBN with over 160 works; from 2010 Sheet Authority Ministry
BAC. Various books are appreciated by authorities, including several times the
Head of State and the Holy Father.
Some books: Global Information Society, 1996; Rotary for Man, 2001;
Managing security in Pharmacy (pres. Dr. Renzulli, already the UN Security
Consultant, 2004); Art and history Pharmacy (pres. Professor Ledermann, Presid.
Em. International Pharmacy History Society, 2 ed., 2006); History and activities
of the SMOM (4th ed., 2007); Pharmaceutical meridians between secular ethics
and Catholic moral (pres. Professor Tarro, Comm. Naz.le Bioethics, 3 ed., 2008);
Thesaurus Pharmacologicus (pres. Presid. Pharmacists Italian Dr. Mandelli
2009); Time sculpted silent eternity. Reflections on diachronic investigation for
memory homo faber (pres. Eminent historian Fra 'von Lobstein and critic Prof.
Carosella, 2 ed., 6 repr., 2010); Pharmaceutical business United Naples (Pres .:
Presid. It Accemia. History Pharmacy Dr. Ravens, 2010); Logos and Theophany
in the digital time (pres. Mons. Trafny, President Dpt Science-Faith Pontifical
Cons. Culture, 2012); Religious aspects and ecclesial dimension SMOM (2013).
Among the more than 40 multimedia: Outline art and history pharmacy (patr.
AISF, 2002); Influenza A / H1N1 (patr. Unesco, 2009).

24. Raimondo Villano
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“There are remedies worse than the disease”
Publilius Syrus, Sentences

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