Antimicrobial xenobiotics

ANTIMICROBIAL XENOBIOTICS

They use comparative biochemical differences between mammalian machineries at one side and Archaea, Bacteria, lower Eukarya or viral machineries at the other side. Antimicrobials may have a cidal (killing) effect or a static (inhibitory) effect (useful to induce active immunization against recurrent infections, but dangerous in immunocompromised patients) on a range of microbes (antibiosis) : sometimes a static compound may become a cidal compound just by increasing its dose. The range of Bacteria or other microorganisms that is affected by a certain antibiotic is expressed as its activity spectrum / range of activity.

broad spectrum : kill or inhibit a wide range of Gram-positive and Gram-negative Bacteria
narrow spectrum : effective mainly against Gram-positive or Gram-negative Bacteria
limited spectrum : effective against a single organism or disease

Please note sometimes antimicrobial chemotherapy can be started before knowing the identity of the infecting microorganism, using likelihood considerations (age, sex, endemic infections, immunological status, localization of infection, ...).
Parameters that influence antimicrobial choice are :

effectiveness as determined by antibiogram
pharmacokinetics as determined by experimental in vivo studies
side effects (organ toxicity must be evaluated if individual already has organ failure(s))

Antimicrobial therapy usually lasts > 5 days (> 5 months in prostatis) to avoid cronicization of infection.
Antimicrobial associations are rare (obviously only sinergy and indifference are useful !) and increase just the number of side effects : so associations are used only if microbe undergoes rapid gene drift (e.g.

Antimicrobials can be classified according to source as follows :

antibiotics : low-molecular weight substances that are produced as secondary metabolites by certain groups of microorganisms, especially Streptomyces spp., Bacillus spp., and a few molds (Penicillium and Cephalosporium) that are inhabitants of soils : they are produced at the same time that the cells begin sporulation . Antibiotics may require as many as 30 separate enzymatic steps to synthesize : the maintenance of a substantial component of the bacterial genome leads to the conclusion that the process (or molecule) is important, if not essential, to the survival of these organisms in their natural habitat. Most of the microorganisms that produce antibiotics are resistant to the action of their own antibiotic, although the organisms are affected by other antibiotics, and their antibiotic may be effective against closely-related strains [e.g. : penicillin G ].
semisynthetic antibiotic : an antimicrobial produced by the microbe subsequently modified by the chemist to achieve desired properties.
chemotherapeutic agents : completely chemically-synthesized antimicrobials [e.g. : sulfonamides ]

synthetic antibiotics : antimicrobial compounds, originally discovered as products of microorganisms, that can be synthesized entirely by chemical means [e.g. penicillin G ]

Antimicrobial susceptibility testing (AST) => antibiograms

disk diffusion test : Petri dishes containing semisolid medium are homogeneously inoculated with a standardized suspension of a microorganism. Antimicrobial-soaked disks are applied to the agar surface (Kirby-Bauer, Barry, Ericsson, Stokes and comparative methods). Following overnight incubation, the diameters of the zones of inhibition or clearing surrounding the disks are measured. Zone diameters are related to the minimal cydal concentration and interpreted as sensitive (susceptible), indeterminate (or intermediate), or resistant.
scalar microdilution tests : in liquid or semisolid media. MIC₉₀ and MIC / LC / IC₅₀ (minimum inhibitory concentration (mg/mL)) < MBC₅₀ (minimum bactericidal concentration)

mutant prevention concentration (MPC)

Microorganisms may have ...

phenotypical resistance to an antibiotic

innate or intrinsic resistance if ... :

persister : in bacteriology, a microorganism that resists a generally toxic level of a drug but is not genetically resistant. They tolerate but do not become resistant to antibiotics (neither grow nor die in the presence of microbicidal antibiotics), preexist in a population and their random switching between normal and slow-growing persister states enables them to escape antibiotic killing^ref. Persisters are largely responsible for the complete tolerance of biofilms to killing by antibiotics : the number of persisters does not change in lag or early exponential phase, and increases dramatically in mid-exponential phase^ref.
lack or possess a modified version of the target of the antibiotic (e.g. : cell wall-building enzymes in cell wall-less Bacteria; PBP in MRSA)
certain antibiotics trigger the SOS response in bacteria, resulting in shutdown of DNA replication and transient dormancy, enabling survival of the antibiotic sensitive bacteria. The SOS response prevents damaged DNA from being copied at cell division : it's common throughout the whole plant, animal, bacterial world^ref
possess an alternative pathway to create such metabolites
intracellular-acting antibiotic can't reach high intracellular concentrations due to ..

production of an enzyme that inactivates the antibiotic (e.g. : b-lactamase, inducible exoenzymes in Gram +ve, while constitutive or inducible endoenzymes in the periplasmic space of Gram -ve Bacteria : Richmond classification is based on substrate specificity, while Sykes-Matthew one is based on genetic allocation; acetyltransferase, phosphotransferase, adenylyltransferase)

extended-spectrum beta lactamases (ESBLs) are enzymes elaborated by bacteria, most often Klebsiella spp., but other Enterobacteriaceae (e.g. Escherichia coli ) as well. These enzymes cleave, and, thereby, inactivate most penicillins and cephalosporins. These have become common nosocomial pathogens in many regions, and nosocomial outbreaks may occur. Treatment can be difficult, but most isolates remain susceptible to the carbapenem antibiotics, such as imipenem . In New York, where hospital-acquired infections with ESBL-producing bacilli are fairly commonplace, an increasing number of these isolates are carbapenem-resistant and many are amikacin-resistant. Polymyxin B has retained activity, however, against most strains. Monitoring the number of cases of ESBL coliform infection is important but is only one step in their overall control, which must include control of overuse of antimicrobial drugs, aggressive, well-supported infection control programs and the development of both rapid diagnostic and new therapeutic methodologies.

production of a binding protein that inhibits normal uptake
lack of an effective transport system for the antibiotic (e.g. : porin modification in Pseudomonas aeruginosa)
enhanced efflux mechanisms to pump the antibiotic out of the cell

acquired or extrinsic resistance is driven by 2 genetic processes that create one of the conditions listed above :

vertical evolution : mutation (the mutation rate for most bacterial genes is approximately 10^-8/-9) and natural selection
horizontal evolution : horizontal or lateral gene transfer (LGT) between strains and species through conjugation (since Bacteria usually develop their genes for drug resistance as transposons, these can integrate themselves on R plasmids : so often resistance to more than one antimicrobial is acquired), transduction or transformation . Not only is there a problem in finding new antibiotics to fight old diseases (because resistant strains of Bacteria have emerged), there is a parallel problem to find new antibiotics to fight new diseases.

tolerance to an antibiotic, a temporary condition due to environmental conditions or growth phase, causing higher MBC₅₀ but same MIC₅₀.
Hata phenomenon : increase in severity of an infectious disease when a small dose of a chemotherapeutical remedy is given.

microbicide : an agent that destroys microbes. The ideal vaginal microbicide must have in vivo activity against HIV-1 and other STD pathogens as well as a differential effect on the viability of human cells and tissues encountered during use as a topical agent. On the one hand, the ideal agent should be effective against incoming cells infected by STD pathogens. Specifically, microbicides that effectively reduce or eliminate the risk of HIV-1 transmission must kill HIV-1-infected immune cells (T cells, monocytes, and macrophages) as well as inactivate cell-free virions. On the other hand, topical microbicides must have minimal or no impact on the viability, function, and structural integrity of the vaginal and cervical epithelium. Although preclinical, in vitro assays of immune and epithelial cell sensitivity to candidate microbicides are necessary steps in the development of a potential microbicide, in vitro assays may fail to predict a compound's in vivo activity^ref1,
ref2. One approach previously thought to be a necessary prerequisite for defining the fidelity of in vitro assays was the use of tissues or cells of primary human origin to test candidate microbicides^ref1,
ref2. However, compared to available human immune and epithelial cell lines, primary tissues and cells are more difficult to acquire and isolate, less convenient and more expensive to maintain, potentially contaminated with unwanted cell populations, and prone to donor-specific variation^ref.

nonoxynol-9 (N-9) (also a spermicide) : intravaginal N-9 is found in the uterus shortly after its insertion. Exposure of the female upper reproductive tract to N-9 may alter epithelial integrity, thereby increasing HIV-1 transmission risk. It is thought to attack and weaken vaginal cell walls, as well as the target virus^ref. N-9 has in vitro activity against several STD pathogens, including HIV-1^ref1,
ref, but cannot be classified as broadly effective, since it has no activity against nonenveloped viruses such as HPV^ref. In vivo effectiveness of N-9 as a microbicide is unclear. Clinical studies have provided conflicting indications of N-9 effectiveness against transmission of HIV-1 and other STD pathogens^{ref1,
ref2,
ref3,
ref4,
ref5,
ref6}. Results from human and animal studies also indicate a narrow margin between N-9 effectiveness and safety^ref, as well as associations between N-9 use and vaginal irritation, inflammation, tissue infiltration by host immune cells, and changes in vaginal flora^{ref1,
ref2,
ref3,
ref4,
ref5}. These adverse effects may increase the risk for HIV-1 transmission during sexual intercourse. N-9 is 10-fold more toxic than C31G or SDS in long-term experiments using primary vaginal keratinocytes. This observation may be particularly relevant to considerations of long-term toxicity during N-9 use. A clinical study of N-9 retention following vaginal insertion of a contraceptive film containing N-9 demonstrated that levels of N-9 recovered by vaginal lavage remained constant for up to 2 h after product insertion and decreased to under 50% after 4 h^ref. A similar report described levels of retention between 19 and 7% after 2 h, detectable levels of N-9 as long as 24 h after insertion, and levels of retention dependent on the contraceptive formulation^ref.
C31G is an equimolar mixture of 2 amphoteric, surface-active molecules: a C14 alkyl amine oxide and a C16 alkyl betaine. C31G is a broad-spectrum antimicrobial and spermicidal agent^{ref1,
ref2,
ref3,
ref4}. However, like N-9, C31G has no activity against HPV^ref, a sexually transmitted virus that has a direct causative role in the development of human cervical cancer. It has broad-spectrum antibacterial and antiviral properties^{ref1,
ref2,
ref3,
ref4}, including HIV infection : glyminox (Savvy™; source : Biosyn, Inc.) is a 1.2% vaginal gel formulation of C31G as a potential contraceptive and for the potential prevention of transmission of sexually transmitted diseases. In March 2002, glyminox was in phase II/III trials for Chlamydia treatment and as a contraceptive, and in phase II trials for HSV shedding^ref.
sodium dodecyl sulfate (SDS) / sodium lauryl sulfate : has in vitro activity against STD pathogens, including HIV-1 and HSV-2^{ref1,
ref2,
ref3,
ref4}. It is an attractive candidate microbicide due to its lower cytotoxicity^{ref1,
ref2,
ref3} and ability to inactivate HPVs^ref. SDS, an alkyl sulfate commonly used in research applications and in commercially available personal hygiene products, is significantly less cytotoxic than either N-9 or C31G and is effective against HIV-1, HSV-2, and, importantly, papillomaviruses from several species, including humans^ref1,
ref2

Web resources

Antimicrobial resistance at FDA

Alliance for Prudent Use of Antibiotics (APUA)
Antimicrobial resistance : an ecological perspective, by American Society for Microbiology
British Society for Antimicrobial Therapy (BSAC)
Canadian Committee on Antibiotic Resistance (CCAR)
Drugs for Neglected Diseases Initiative (DNDi)
European Antimicrobial Resistance Surveillance System (EARSS)
International Partnership for Microbicides (IPM)
Reunions Interdisciplinaires de Chimiotherapie anti-infectieuse (RICAI)
CDC

Antimicrobial Resistance and Antibiotic Resistance

Antibiotic resistance

Get Smart : know when antibiotic work

Antimicrobial susceptibility testing educational resources
M.A.S.T.E.R. (antimicrobial susceptibility testing educational resources)

Sanford Guide for Antimicrobial therapy 2005, PDA edition (source : USBMIS )
Journals

Antimicrobial Agents and Chemotherapy

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