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RAQUEL REGINA BONELLI , . HANS-GEORG SAHL , in Handbook of Biologically Active Peptides , 2006
Lanthionine-containing antibiotic peptides (lantibiotics) have been known for more than 60 years and the prototype peptide nisin has been used safely in food preservation for half a century. Lantibiotics derive from ribosomally synthesized prepeptides through unique posttranslational modifications involving serine, threonine, and cysteine residues. Approximately 50 lantibiotics are known to date, and almost 20 gene clusters, containing the determinants for prepeptides, modification, processing, export, and producer self-protection have been sequenced. Recent progress in in vitro synthesis and insights into multiple antibiotic mechanisms combined in a single molecule make lantibiotics attractive model compounds for design of novel antiinfective drugs.
Bacteriophage therapy: an overview and the position of Italian Society of Infectious and Tropical Diseases
In recent years, the increase of antibiotic resistance and the lack in the pipeline of novel antimicrobial molecules make bacterial infections difficult to treat. Among European countries, Italy is the one region with a higher number of deaths caused by antibiotic-resistant bacteria. Moreover, a major concern is represented by biofilm-related infections. The ability of bacteria to form biofilm in presence of implanted-medical devices represents a further challenge for the treatment of bacterial infections. Thus, the development of alternative strategies to fight multi-drug resistant bacteria embedded in biofilms is an urgent need. Nowadays, bacteriophage therapy represents one of the potential and promising treatment options to overcome antibiotic resistance phenomenon. Bacteriophages are viruses capable to infect and replicate within bacterial cell. They are widespread in soil and water and play a role in microbial physiology. Since their discovery at the beginning of the twentieth century bacteriophages were used with therapeutic purposes against bacterial infections. However, the advent of the antibiotic era spurred medical doctors to abandon phage therapy in return for the most promising antibiotic therapy. For historical reasons, only few countries in the world, including Georgia, Russia and Poland have carried on the use of phages for therapeutic purposes and have developed specialised research and treatment centres, where phage therapy is permitted and applied to cure infectious disease. Although the efficacy of bacteriophages for treatment of infections is widely documented, the introduction of phage therapy in common management of bacterial infections in European hospital is hindered by the lack of an appropriate legal and regulatory framework. Different strategies have been used to overcome this problem, like the "Magistral Phage" preparation in Belgium. Here, we provide a review of the fundamental concept on bacteriophage therapy and propose this treatment as a possible alternative choice when antibiotics and surgery are not enough to eradicate a bacterial infection. We believe that the introduction of phage therapy in Italy might improve the quality of life of patients suffering of chronic bacterial infections and fight antibiotic resistances problem. To reach this goal the support and the promotion of Italian government and the scientific authorities is essential. SIMIT, the Italian Society of Infectious and Tropical Diseases, proposes to support the creation of an Italian Task Force to improve knowledge on bacteriophage therapy, collect stronger evidence about their efficacy and develop appropriate protocols for phage administration.
About Antibiotic Resistance
Antibiotic resistance happens when germs like bacteria and fungi develop the ability to defeat the drugs designed to kill them. That means the germs are not killed and continue to grow.
Infections caused by antibiotic-resistant germs are difficult, and sometimes impossible, to treat. In most cases, antibiotic-resistant infections require extended hospital stays, additional follow-up doctor visits, and costly and toxic alternatives.
Antibiotic resistance does not mean the body is becoming resistant to antibiotics it is that bacteria have become resistant to the antibiotics designed to kill them.
Antibiotic Resistance Threatens Everyone
On CDC&rsquos website, antibiotic resistance is also referred to as antimicrobial resistance or drug resistance.
Antibiotic resistance has the potential to affect people at any stage of life, as well as the healthcare, veterinary, and agriculture industries, making it one of the world&rsquos most urgent public health problems.
Each year in the U.S., at least 2.8 million people are infected with antibiotic-resistant bacteria or fungi, and more than 35,000 people die as a result.
No one can completely avoid the risk of resistant infections, but some people are at greater risk than others (for example, people with chronic illnesses). If antibiotics lose their effectiveness, then we lose the ability to treat infections and control public health threats.
Many medical advances are dependent on the ability to fight infections using antibiotics, including joint replacements, organ transplants, cancer therapy, and treatment of chronic diseases like diabetes, asthma, and rheumatoid arthritis.
Brief History of Resistance and Antibiotics
Learn how CDC is leading efforts to combat antibiotic resistance through the Antibiotic Resistance Solutions Initiative.
Penicillin, the first commercialized antibiotic, was discovered in 1928 by Alexander Fleming. Ever since, there has been discovery and acknowledgement of resistance alongside the discovery of new antibiotics. In fact, germs will always look for ways to survive and resist new drugs. More and more, germs are sharing their resistance with one another, making it harder for us to keep up.
Select Germs Showing Resistance Over Time
Penicillin-resistant Staphylococcus aureus
Penicillin-resistant Streptococcus pneumoniae
Penicillinase-producing Neisseria gonorrhoeae
Vancomycin-resistant Staphylococcus aureus
Find more information on the development of antibiotic resistance in the latest AR Threats Report.
1.4.1 Effect of Molecular Weight
Molecular weight has an important role in determining antimicrobial activity. 7 Chen et al. synthesized polypropylenimine dendrimers functionalized with quaternary ammonium groups and found that the antimicrobial properties have parabolic dependence on molecular weight. 79 In the case of polyacrylates and polymethylacrylates with biguanide groups, the optimal range of molecular weight was reported to be from 5吆 4 to 1.2吆 5 Da, with variance above and below this range significantly reducing efficacy. 181 Similarly, poly(tributyl 4-vinylbenzyl phosphonium chloride) also showed optimal antimicrobial action within a range of 1.6吆 4 to 9.4吆 4 Da. 182 However, the bacteriostatic action of fractioned quaternary ammonium salts against Escherichia coli, Pseudomonas aeruginosa and Staphylococcus aureus had little dependence on molecular weight. 7,183
1.4.2 Effect of Counter Ions
Counter ion effect on antimicrobial properties is not clearly known, except where they change or alter the solubility of host polymers. Kanazawa et al. investigated the counter anion dependence of poly[tributyl (4-vinylbezyl) phosphonium] salts where the antimicrobial activity is in the order hexafluorophosphate<perchlorate<tetrafuoride<chloride, which can be correlated with the solubility products of those polymers. 182 Chlorides and bromides exhibit the highest antimicrobial activity in the case of quaternary ammonium compounds. Counter ions with strong binding affinity towards quaternary compounds show lower antibacterial action because of slow and reduced release of free ions in the medium. 79
1.4.3 Charge Density
Usually, a positive charge density can impart better polymeric electrostatic interaction with negatively charged bacterial cell walls. For chitosan, with increasing degrees of deacetylation, the charge density increase enhances the electrostatic interaction of the polymer and thus antimicrobial property. Higher charge density groups were incorporated in chitosan to form guanidinylated chitosan and asparagine N-conjugated chitosan oligosaccharide, which resulted in high antimicrobial action, whereas N-carboxyethyl chitosan did not show any antimicrobial action due to a lack of free amino groups. 206–208
1.4.4 Effect of Spacer Length and Alkyl Chain Length
Spacer length affects the interaction of antimicrobial agents with the bacterial cytoplasmic membrane due to changes in charge density and conformation of the polymer. 184 The antimicrobial activity of quaternary ammonium chlorides depends on the hydrophilic–lipophilic balance. Poly(trialkyl vinyl benzyl ammonium chloride) with the longest carbon chain (C12) showed higher antimicrobial activity. 7
1.4.5 pH Effect
The pH effect can be seen mostly in amphoteric polymers and chitosan. At acidic pH, chitosan exhibits maximum antimicrobial activity because of polycation formation and better solubility. However, at basic pH, there are no reports of its antimicrobial effect. 185
Hydrophilic nature is considered an important prerequisite for any antimicrobial agent to show activity. Tailoring of hydrophobic group content and molecular weight in amphiphilic polymethacrylate derivatives showed improvements in antimicrobial activity. 186 In the same manner, compared to the original form, the water-soluble chitosan derivatives synthesized by alkylation, metallization, quaternization and saccharization displayed greater antimicrobial action. 187,188
Antimicrobial resistance in E. coli has increased worldwide and its susceptibility patterns show substantial geographic variation as well as differences in population and environment 17 . The isolation rate of E. coli in the present study was 14.2% and it was commonly isolated from urine samples (45.5%). These findings are in conformity with reports by other researchers 13 , 18 , 19 .
In this study, the overall resistance of E. coli to antimicrobials was high. The result is consistent with the findings of previous studies 20 . The resistance rates recorded in this study are higher than the results of Khan et al. 6 and lower than the results of Iqbal and Patel 21 and Okonko et al. 22 . High level of resistance in E. coli was reported to tetracycline from a study conducted in Ethiopia 23 and to erythromycin from a study done in Slovenia 24 .
In all clinical samples, E. coli showed high resistance rates of > 80% to erythromycin and amoxicillin and > 60% to tetracycline. The results of this study are in line with the findings of other studies conducted in different parts of the world 25 , 26 . However, the antimicrobial resistance rates obtained in this study were higher compared to susceptibility patterns reported from previous studies 27 , 28 , 29 .
E. coli isolates were sensitive to gentamicin, nitrofurantoin, ciprofloxacin and chloramphenicol. Similar studies conducted in Ethiopia 30 and Nigeria 31 have reported comparable susceptibility rates. High sensitivity to ciprofloxacin and gentamicin and norfloxacin have been recorded from previous studies conducted in Nigeria and India 31 , 32 . In this study, norfloxacin, ciprofloxacin, gentamicin and chloramphenicol were found to be the most effective antimicrobials against E. coli isolates.
Furthermore n this study, a high rate of multiple antimicrobial resistance was recorded, which is consistent with the reports of studies done elsewhere 21 , 33 . The chi-square test for trend demonstrated increased resistance rates to all antimicrobials except ciprofloxacin. Increases in rates of resistance to different antimicrobials have been reported from previous studies conducted in different parts of the world 20 , 33 , 34 .
Clinical approaches to P. aeruginosa bacteremia
P. aeruginosa bloodstream infection (BSI) is a serious disease that requires prompt attention and pertinent clinical decisions in order to achieve a satisfactory outcome. Currently, Pseudomonas spp. represent a leading cause of hospital-acquired bacteremia, accounting for 4% of all cases and being the third leading cause of gram-negative BSI . Several studies indicate an increased risk of death among patients with P. aeruginosa BSI, as compared with the risk for similar patients with other gram-negative or  S. aureus BSI [73,74]. Therefore, the adequate management of P. aeruginosa should be considered as a significant challenge for clinicians.
Once P. aeruginosa is isolated from blood, efforts should be made to establish the source of the infection and to choose an appropriate empirical antibiotic therapy as soon as possible. As for the source of the infection, most patients have an identifiable focus of infection at the time of initial evaluation, but the source remains unknown in up to 40% of the cases [73,75]. The most common sources of P. aeuruginosa BSI are in respiratory (25%) and urinary tract (19%) followed by central venous catheter and skin and soft tissues . Identification of the source is essential because its adequate control represents a critical issue in the correct management of P. aeruginosa infection (i.e. early CVC removal or surgical drainage of abscess). Accordingly, a careful patient history and a physical examination, as well as radiological and microbiological work-up are important.
Empirical antibiotic therapy should include two agents from different classes with in vitro activity against P. aeruginosa for all serious infections known or suspected to be caused by P. aeruginosa. The rationale of the so-called 𠆍ouble coverage effect’ is to increase the likelihood that antibiotic treatment will be active against P. aeruginosa, especially in the setting of a high-risk of antimicrobial resistance. Once results of susceptibility are available, definitive therapy should be tailored accordingly, using a single in vitro active agent with the highest antimicrobial activity and the lowest propensity to select resistance. Indeed, at the time of the present review, no convincing data exist demonstrating a mortality benefit to combination therapy ( Figure 1 ) .