ANTIMICROBIALS FOR BACTERIA

Table of contents :

Antibacterials interfering with ... 

Novel strategies in antibacterial drug developmentref :

Lancet or phenol coefficient : a measure of the bactericidal activity of a chemical compound in relation to phenol. The test is standardized (Rideal-Walker method, U. S. Department of Agriculture method). The coefficient is calculated by dividing the concentration of the test compound at which it kills the test organism in 10 minutes, but not in 5 minutes, by the concentration of phenol that kills the organism under the same conditions. It can be determined in the absence of organic matter, or in the presence of a standard amount of added organic matter.

Woods-Fildes theory : the theory that the antibacterial activity of at least some chemotherapeutic drugs (especially the sulfonamides) is a consequence of a competitive inhibition of essential metabolic reactions of the microorganism.

Adverse events : Leading parenteral antibiotic products in the global hospital market for prophylaxis and therapy in USA and 5 European countries

Current status of antibacterial resistance in the ICU (NNIS, 2002 vs 1997-2001)ref :

The quantity of antimicrobials used in food animals in Denmark has declined 54% from peak use between 1994 and 2001. Before the programme began, most pigs and broiler chickens in Denmark were given antimicrobials, such as avilamycin, avoparcin, tylosin, streptogramins and virginiamycin, for most of their lives. After withdrawal, average use declined to 0.4 days in broiler chickens (with life span of around 42 days) and 7.9 days in pigs (with life span of around 170 days). Pork production
in Denmark has continued to increase, and effects on poultry production were small. Ending the use of the above antimicrobials has greatly reduced the reservoir of resistant Enterococcus faecium in the food animal reservoir, thus reducing the reservoir of resistance genes. For example, resistance to avilamycin, avoparcin, and streptogramins in Enterococcus faecium isolates from broiler chickens declined from 60-80% before withdrawal of antimicrobials to only 5-35% after.

The carboxylic ionophoresref are open-chained oxygenated heterocyclic rings with a single terminal carboxyl group of moderate molecular weight (200-2000). It is a drug for use in animals only, and there is no comparable drug or drug category for humans. Ionophores form lipid-soluble complexes with polar cations (K+, Na+, Ca2+ and Mg2+), have a diverse antibacterial spectra and are produced by fungi, predominantly Streptomyces sp. These compounds are used as anticoccidial and growth promotant feed additives. Clinical pathology of ionophore-induced toxicityref1, ref2, ref3, ref4, ref5 includes elevated enzyme levels of muscle origin such as aspartate transaminase (AST) and creatine phosphokinase (CPK). Other serum enzymes that may be elevated are lactic dehydrogenase (LDH) and alkaline phosphatase. Additonally, there may be elevations in blood urea nitrogen and bilirubin. Serum calcium and potassium levels may fall to life-threatening levels in horses. Hemoconcentration may also occur. The ionophores are generally safe at prescribed levels in intended species. Certain management situations increase the possibility of toxicoses including overdose, mixing errors, premix consumption, and misuse in non-target species such as horses, adult turkeys, and dogs. Concurrent administration of other drugs, including chloramphenicol, erythromycin, sulfonamides and cardiac glycosides, can potentate ionophore toxicosis.

Spray for poultry processing companies to apply to contaminated surface of raw poultry : Scientists of the Kosan Bioscience have overcome an important hurdle in the race to develop new antibiotics: they have made bacteria efficiently churn out chemicals that could prove to be useful drugs. Over the past few decades, bacteria have evolved to resist our antibiotics. As a result, hospitals have seen a dramatic rise in drug-resistant infections, many of which are fatal. To come up with new antibiotics, scientists often work with the natural chemical defences of fungi and bacteria, altering these natural antibiotics to make new ones. Researchers have also attempted to genetically engineer bacteria to pump out new chemicals directly. Although chemicals produced this way have not yet been used to fight human disease, the approach has produced some promising compounds, including  : But scientists have stumbled in trying to get bacteria to spit out chemicals belonging to a class known as polyketides. Polyketides are molecules that contain large rings of carbon and oxygen atoms, and include the well-known antibiotic erythromycin. DNA sequences that produce bits of the proteins that make polyketides were taken from several different bacteria, mixed and matched nside Escherichia coli bacteria. This much has been done before, but the hard part was getting the resulting bits of protein to combine into a functioning polyketide-making machine. Polyketide proteins are very large, so it is particularly difficult to get the components to attach together. To achieve this, special sequences were added to the ends of their genetic fragments that in turn made the protein fragments 'sticky'. This meant the protein bits joined up "like Lego building blocks", resulting in new proteins conformations and new polyketidesref. The team has yet to test whether these polyketides have antibiotic powers. But they anticipate that at least some will be useful. A few natural polyketides attack cancer cells, so some of the bioengineered ones might have anti-cancer properties too.
In Africa's ongoing struggle against tuberculosis, a group of scientists and industry representatives are now exploring a plan to introduce copper pipes, doorknobs and work surfaces to the country's waterways and clinics. The metal's known antibiotic activity could provide a simple way to help fight the deadly infection. Past research has shown that copper has strong anti-bacterial properties against worrisome pathogens such as the superbug MRSA. Whereas all cells need a bit of copper to grow, an excess can overwhelm a cell's mechanism to bind to the metal, effectively killing it from over-exertion. MRSA was unable to survive on copper alloy surfaces for > 90 minutes (Noyce J. O., Michels H.& Keevil C. W. . J. Hosp. Infect., 63. 289 - 297 (2006)). Recent research from a team in South Africa shows that copper also wipes out the bacterium responsible for tuberculosis (TB) — one of Africa's biggest killers. Laboratory tests showed that after 48 hours of exposure, pure copper and 5 of its alloys could inhibit growth in TB bacteria, including strains resistant to usual drugs, with no signs of regrowth over the study period of 15 days. TB is an extremely resilient bug. It often grows back on, say, a stainless-steel surface that has been cleaned with disinfectant, after just a couple of days. So the copper results are promising. Such results have spurred ideas to make hospital surfaces from copper alloys, to help keep background levels of infectious bacteria down. The simple change has resulted in a consistent and significant reduction in surface contamination by Staphylococcus aureus, Escherichia coli and Pseudomonas aeruginosa. Whether it is the best way to keep bugs in check, however, is still up for debate. It can take up to 6 hours for copper to kill bacteria, so there remains a window of opportunity when infection can occur. And TB is transmitted by the inhalation of airborne bugs, so self-sanitizing surfaces might not have as big an impact as hoped with that disease. But reducing the chance of infection in a country such as South Africa, where an estimated 5.3 million people live with HIV and are particularly vulnerable to opportunistic infections, may be of great benefit. Full water treatment systems are obviously better than copper alone, as they are designed to address a number of potential problems with the water supply. But it's good to have a back-up system. Rural water-treatment systems are not always correctly monitored. Here copper would be a good additional barrier. Representatives from the International Copper Development Association, along with African industry participants, engineers and faculty from the Stellenbosch University, gathered at a workshop in Johannesburg immediately after the IFIC conference to plan how best to use copper to fight disease in Africa. They are still at the planning stage, but at least one trial will begin before the end of 2006 at the Kayamandi township clinic outside Stellenbosch. Copper is not the answer for everything, but what we are looking at here is copper's role in making a significant contribution.
In-vitro antibiotic-induced endotoxin release may depend on antibiotic class, presence of serum, type of organism, site of antibiotic action and Gram-stain. Endotoxin release may be different in late or early lysis, proportional to the number of killed pathogens. Morphology of bacteria may have an impact on endotoxin release and phagocytosis. Antibiotic-treated animals may show higher endotoxin levels with a higher survival rate than untreated animals. Plasma endotoxin may increase despite decreasing bacteremia. There may be a similar killing rate by different antibiotics but a difference in endotoxin release. Intestinal endotoxin does not necessarily correlate to the level of gram-negative bacteria. However, the alteration of the gut content by pretreatment may be associated with reduced endotoxemia and increased survival. Antibiotic-induced endotoxin release may be different depending on the type of infection, the location of infection, the virulence of strains, Gram-stain, mode of application and dosage of antibiotic. Different antibiotics may induce the release of different forms of endotoxin which may be lethal for sensitized animals. The combination of antibiotics with inhibitors of endotoxin or the pro-inflammatory response may be responsible for increased survival by decrease of endotoxin release. The clinical significance of antibiotic-induced endotoxin release is documented only in a few clinical disorders, e.g., meningitis, urosepsis. The difference in endotoxin release by PBP 2-specific antibiotics, e.g., imipenem, and PBP 3-specific antibiotics, e.g., ceftazidime, may not be visible in each study. Patients with increased MOF scores may profit from treatment with antibiotics known to decrease endotoxin. In conclusion, the clinical significance of antibiotic-induced endotoxin release remains to be clarified. Type of pathogen and its virulence may be more important than recently suggested. gram-positive pathogens were just recently recognized as an important factor for the development of the host response. In case of FUO in ICU patients either failure of treatment, e.g., failure of source control in IAI, or a side effect of antibiotic treatment, e.g., endotoxin release, should be considered as a cause of the feverref.

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