Microbial multi-drug resistance (mdr) and oligodynamic silver

MICROBIAL MULTI-DRUG RESISTANCE (MDR) AND
OLIGODYNAMIC SILVER
Newsweek reported in 1992 that 13,000 hospital patients died from drug resistant infections.1 The startling news was that this mortality rate climbed to 70,000 for the very next year. As a result, the CDC in 1994 declared this health crises as America’s number one health issue.2 Today, over 2 million Americans suffer with nosocomial super germ infections.3 In fact, other the industrial countries such as Great Britain are reporting an infection rate for super germs that exceeds 3.5 per 1,000 hospital admissions.4 This translates into a stunning 350 patients per 100,000 patients admitted. Simply stated, those numbers are approaching epidemic levels within many hospitals throughout the industrialized world. As early as 1940 Goetz remarked that, “The minimum lethal concentration of oligodynamically active silver definitely depends upon the nature of the substrate in which the test is made as well as upon the nature and concentration of the test microorganisms.” 5 Right up to the present time, microbial resistance to medicinal silver has not been scientifically established. This point has been made by Lansdown (2002).
J Wound Care 2002 Apr 11:125-30
Silver. I: Its antibacterial properties and mechanism of action.
Lansdown AB
Abstract: Silver products have two key advantages: they are broad-spectrum antibiotics and are not yet
associated with drug resistance. This article, the first in a two-part series, describes the main mechanism of
action of this metallic element.
MeSH: Anti-Infective Agents, Local; History of Medicine, 18th Cent.; History of Medicine, 19th Cent.; History
of Medicine, 20th Cent.; Human; Silver Compounds; Skin Diseases, Bacterial; Support, Non-U.S. Gov't;
Wounds and Injuries

Author Address: Imperial College School of Medicine, London, UK. [email protected]

So-Called Resistant Strains
Over the past two decades, multiple studies with differing designs and speciations of silver- based drugs have indicated that certain bacterial species and strains have physiological mechanisms that circumnavigate silver’s toxicity.6, 7, 8, 9 These mechanisms are essentially either plasmid based or chromosomal based;10 the latter expressing as ATPase translocating mechanisms.11 In neither case did investigators employ nanoscalar oligodynamic silver. Instead, the experimental designs typically utilized silver salt compounds, which deliver poor amounts of bioactive silver. Another most common problem of these experimental designs was the inadvertent culture contamination with various salts, something which will reduce silver efficacy. The colloidal state and dynamics of living tissues is at odds with typical culture techniques and mediums, and brings about the unfortunately situation of requiring readers to compare apples to oranges. Notwithstanding, within these parameters investigators have determined the following select strains of bacteria exhibit various degrees of resistance to the bactericidal effects of silver-based drugs: 1. Acinetobacter baumani BL8812 2. Citrobacter freundii13, 14 3. Entamoeba histolytica cysts15 4. Enterobacter cloacae16, 17, 18, 19 5. Enterobacteriaceae (some strains)20, 21, 22 6. Enterococcus hiraea, 23 7. Escherichia coli (J62, C600, R1 & S1) 8. E. coli (K-12 & 0157:H7)24 9. Helicobacter pylori25 10. Klebsiella pneumoniae26, 27, 28 ,29 11. Mycobacteria30 12. Pseudomonas aeruginosa 10, E. cloacae31,32 13. Ps. stutzeri (AG256, AG259, JM303) 33,34 14. Ps. putida CYM31835 15. Proteus mirabilis36, 37 16. Salmonella typhimurium38, 39 17. Staphylococcus aureus40 18. Thiobacillus ferro-oxidans41 19. Thiobacillus thio-oxidans42 20. Vegetative B. Cereus Spores43 Zhao and Stevens stated that, “With the rise of antibiotic-resistant bacteria, silver is re- emerging as a modern medicine because all pathogenic organisms have failed to develop an immunity to it (silver ion).”44 It is more probable than not that microbes lack sufficient defense mechanisms to circumvent the toxic effects of silver ions if sufficient Ag+ reaches the foci over an appropriate time frame. That’s the critical “if” and “must.” More specifically stated, the “apparent” resistance of microbes to silver-based drugs is typically due to (1) an inadequate protocol or procedure, or (2) neglect of the necessary parameters so carefully reviewed by Goetz, Zhao and a NASA commissioned study. Hamilton-Miller et al., have reported that bacterial strains completely resistant to the salt speciations of silver have proved erroneous when proper study designs were employed.45 J Antimicrob Chemother 1992 Jun 29:661-8
Comparison of the in-vitro activities of the topical antimicrobials azelaic acid, nitrofurazone,
silver sulphadiazine and mupirocin against methicillin-resistant Staphylococcus aureus.
Maple PA, Hamilton-Miller JM, Brumfitt W
Abstract: The in-vitro activities of the topical agents azelaic acid, nitrofurazone, silver sulphadiazine and
mupirocin have been determined against 80 strains of MRSA collected from worldwide sources. MICs were
determined by agar dilution (with an inoculum of approximately 5.0 x 10(5) cfu) in Iso-Sensitest agar, and
MBCs were measured by replica-plating from MIC plates using velvet pads. The agents tested were uniformly
active against MRSA, mupirocin being the most active (MIC50 0.15 mg/L) followed by nitrofurazone (MIC50
19 mg/L), silver sulphadiazine (MIC50 85 mg/L) and azelaic acid (MIC50 850 mg/L). Concentrations of
azelaic acid, nitrofurazone and silver sulphadiazine close to the MIC were bactericidal, but mupirocin was
only bactericidal at concentrations substantially greater than the MIC. In time-kill experiments, azelaic acid
and nitrofurazone were gradually bactericidal, silver sulphadiazine was rapidly bactericidal and mupirocin
was not bactericidal. Silver sulphadiazine killed sulphonamide-sensitive and sulphonamide-resistant strains
equally rapidly. No resistant mutants were found to azelaic acid, nitrofurazone or silver sulphadiazine in an
inoculum of 10(9) cfu, but two strains yielded (frequency: 1.0 x 10(-9)) mutants resistant to mupirocin. Our
in-vitro results suggest azelaic acid, nitrofurazone and silver sulphadiazine could be of use for clearing
staphylococcal carriage.
a By way of Cu(I)/Ag(I)-translocating ATPases.
MeSH: Anti-Infective Agents; Comparative Study; Dermatologic Agents; Dicarboxylic Acids; Drug
Resistance, Microbial; Human; Methicillin Resistance; Microbial Sensitivity Tests; Mupirocin; Nitrofurazone;
Silver Sulfadiazine; Staphylococcus aureus

Author Address: Department of Medical Microbiology, Royal Free Hospital School of Medicine, Hampstead,
London, UK.
Grier stated that, “Some so-called Ag+ resistant microorganisms may result from an apparent neutralization of the metal’s inhibitory action or other assay artifacts. These include the presence of
chelators such as serial amino acids, constituents of hard water, different buffers, light, incubation
temperature, and particularly, soluble components of trypticase soy agar (TSA) and tryptose glucose
extract agar (TGE).”46 Schierholz in 1998 reviewed the majority of the salient issues governing
inactivation of oligodynamic Ag+ in the varieties of media now in common use.
Zentralbl Bakteriol 1998 May 287:411-20

Activity of silver ions in different media.
Schierholz JM, Wachol-Drewek Z, Lucas LJ, Pulverer G
Abstract: A major problem in medicine is the large number of infections associated with implanted and
indwelling devices. Silver coating of medical devices is believed to preserve infection resistance. Several in
vitro and animal studies as well as clinical observations on silver-nylon, silver-intramedullary pins, silver-
oxide-Foley catheters and silver-coated vascular protheses have been interpreted as successful for the
prophylaxis of foreign-body infections. Nevertheless, these products have not been established in clinical
use. In this study we have been able to present physico-chemical and pharmacological data as well as
simple microbiological experiments explaining the reduced anti-microbial activity of silver-ions in some
biological fluids.
MeSH: Bacterial Adhesion; Culture Media; Escherichia coli; Ions; Microbial Sensitivity Tests; Silver Nitrate;
Staphylococcus aureus; Staphylococcus epidermidis

Author Address: B. Braun Melsungen AG, Melsungen, Germany.
J Hyg Epidemiol Microbiol Immunol 1988 32:299-306
Effect of certain chelating agents on the antibacterial action of silver nitrate.
Kaur P, Vadehra DV
Abstract: EDTA and EGTA when used in conjunction with AgNO3 enhanced the antibacterial action of the
latter significantly, so that strains of Klebsiella pneumoniae and Staphylococcus aureus resistant to 70
micrograms/ml of AgNO3 were observed to become sensitive to 10 micrograms/ml of this compound. The
synergistic effect of EDTA appears to be due to a mechanism other than the removal of lipopolysaccharide
from outer membrane, as its effect could be observed in even non-LPS containing gram positive S. aureus
cells. Penicillamine, another potent chelator had an opposite effect so that it decreased the toxicity of silver
ions.
MeSH: Antibiotics; Chelating Agents; Drug Resistance, Microbial; Drug Synergism; Edetic Acid; Egtazic Acid;
Klebsiella pneumoniae; Penicillamine; Silver Nitrate; Staphylococcus aureus
Author Address: R.S.I.C., Panjab University, Chandigarh, India.
Conclusion

The physician’s skill is challenged when using oligodynamic silver hydrosol because of four key factors: (1) where is the foci and what form of administration will best deliver oligodynamic silver; (2) what is the total pathogen load; (3) what specific pathogen strain is involved; and (4) what frequency and concentration of oligodynamic silver is required to bring about a sero-negative conversion (typically from 1 ppm to 10 ppm of bioactive silver is required within a specific therapeutic window). These factors applying to the physician’s skill set mean the difference between therapeutic failure or success. Success against the so-called resistant strains of infection may only be a matter of follow-through when the proper speciation of bioactive silver is employed along with competent and skillful medical management.47 References

1 Newsweek Magazine, March 28, 1994. 2 Garret, L, “Antibiotics Effectiveness Shrinking,” The Idaho Statesman, via Newsday wire service, May 13, 1994; p. 3A. 3 DHLTH – Cable Channel 187, Hollywood, Fl, Tuesday night, Dec. 2002. 4 “Surveillance of Hospital-Acquired Bacteraemia in English Hospitals: 1997 – 2001,” Nosocomial Infection National Surveillance Service, Public Health Laboratory Service, Central Public Health Laboratory, 61 Colindale Avenue, London, NW9 5HT, UK. 5 Goetz, A, “The Oligodynamic Effect of Silver,” Chapter 16, edited by Lawrence Addicks, Silver in Industry, Reinhold Publishing Corp., NY, 1940; p. 415. 6 Hall, RE, Bender, G, Marquis, RE, “Inhibitory and Cidal Antimicrobial Actions of Electrically Generated Silver Ions,” J Oral Maxillofac Surg, 1987; 45:783. 7 McHugh, GL, et al., “Salmonella typhymurium Resistant to Silver Nitrate, Chloramphenicol and Ampicillin,” Lancet, 1975; 1:235. 8 Summers, AO, et al., “Metal Cation and Osyanion Resistances in Plasmids of Gram Negative Bacteria,” In: Schlessinger, edit., Microbiology, Am Soc Microbiol, Washington, DC, 1978. 9 Bridges, K, et al., “Gentamicin and Silver Resistant Pseudomonas in a Burn Unit,” Br Med J, 1979; 1:446. 10 Rensing C, Ghosh M, Rosen BP. Families of Soft-Metal-Ion-Transporting ATPases. J Bacteriology, 1999
Oct;181(19):5891-7.
11 Solioz M, Vulpe C. CPx-type ATPases: a class of P-type ATPases that pump heavy metals. Trends Biochem
Sci 1996; 21:237-241
12 Clement JL, Jarrett, PS, “Antibacterial Silver,” Metal Based Drugs, ed. By Frank Shaw, III, August 17th-20th, 1994; 1(5-6):472. 13 Thurman, RB, Gerba, CP, “The Molecular Mechanisms of Copper and Silver Ion Disinfection of Bacteria and Viruses,” A paper presented in the First International Conference on Gold and Silver in Medicine. The Silver Institute, Washington, 1989; 18(4):301 14 Russell, AD, Hugo, WB, “Antimicrobial Activity and Action of Silver,” Prog Med Chem, 1994; 31:365. 15 Russell, AD, Hugo, WB, “Antimicrobial Activity and Action of Silver,” Prog Med Chem, 1994; 31:354 & 65. 16 Thurman, RB, Gerba, CP, “The Molecular Mechanisms of Copper and Silver Ion Disinfection of Bacteria and Viruses,” A paper presented in the First International Conference on Gold and Silver in Medicine. The Silver Institute, Washington, 1989; 18(4):301 17 Russell, AD, Hugo, WB, “Antimicrobial Activity and Action of Silver,” Prog Med Chem, 1994; 31:364-5 18 Clement JL, Jarrett, PS, “Antibacterial Silver,” Metal Based Drugs, ed. By Frank Shaw, III, August 17th-20th, 1994; 1(5-6):472. 19 Annear DI, Mee BJ, Bailey M. Instability and linkage of silver resistance, lactose fermentation, and colony structure in Enterobacter cloacae from burn wounds. J Clin Path 1976;29:441-443 20 Slawson, RM, Van Dyke, MI, Lee, H, Trevors, JT, “Germanium and Silver Resistance, Accumulation, and Toxicity in Microorganisms,” Plasmid, Academic Press, Inc., San Diego, 1992; 27(1):73-9. 21 Russell, AD, Hugo, WB, “Antimicrobial Activity and Action of Silver,” Prog Med Chem, 1994; 31:365. 22 Clement JL, Jarrett, PS, “Antibacterial Silver,” Metal Based Drugs, ed. By Frank Shaw, III, August 17th-20th, 1994; 1(5-6):472. 23 Rensing C, Ghosh M, Rosen BP. Families of Soft-Metal-Ion-Transporting ATPases. J Bacteriology, 1999
Oct;181(19):5891-7.
24 Gupta A, et al. Diversity of silver resistance genes in IncH incompatibility group plasmids. Microbiology 2001;147:3393-402. 25 Rensing C, Ghosh M, Rosen BP. Families of Soft-Metal-Ion-Transporting ATPases. J Bacteriology, 1999
Oct;181(19):5891-7.
26 Thurman, RB, Gerba, CP, “The Molecular Mechanisms of Copper and Silver Ion Disinfection of Bacteria and Viruses,” A paper presented in the First International Conference on Gold and Silver in Medicine. The Silver Institute, Washington, 1989; 18(4):301 27 Searle, A B, The Use of Colloids in Health and Disease, (Quoting C.E. A. MacLeod in Lancet, Feb. 3, 1912). E. P. Dutton and Company, NY, 1919; p. 83. 28 Russell, AD, Hugo, WB, “Antimicrobial Activity and Action of Silver,” Prog Med Chem, 1994; 31:351-70. 29 Clement JL, Jarrett, PS, “Antibacterial Silver,” Metal Based Drugs, ed. By Frank Shaw, III, August 17th-20th, 1994; 1(5-6):472. 30 Russell, AD, Hugo, WB, “Antimicrobial Activity and Action of Silver,” Prog Med Chem, 1994; 31:351-70. 31 Grier, N, “Silver and Its Compounds.” In: Disinfection, Sterilization and Preservation, S. Block, edit., Lea & Febiger, Philadelphia, PA, 1983; p. 381. 32 Russell, AD, Hugo, WB, “Antimicrobial Activity and Action of Silver,” Prog Med Chem, 1994; 31:351-70. 33 Slawson, RM, Van Dyke, MI, Lee, H, Trevors, JT, “Germanium and Silver Resistance, Accumulation, and Toxicity in Microorganisms,” Plasmid, Academic Press, Inc., San Diego, 1992; 27(1):73-9. 34 Clement JL, Jarrett, PS, “Antibacterial Silver,” Metal Based Drugs, ed. By Frank Shaw, III, August 17th-20th, 1994; 1(5-6):472. 35 Clement JL, Jarrett, PS, “Antibacterial Silver,” Metal Based Drugs, ed. By Frank Shaw, III, August 17th-20th, 1994; 1(5-6):472. 36 Thurman, RB, Gerba, CP, “The Molecular Mechanisms of Copper and Silver Ion Disinfection of Bacteria and Viruses,” A paper presented in the First International Conference on Gold and Silver in Medicine. The Silver Institute, Washington, 1989; 18(4):301 37 Clement JL, Jarrett, PS, “Antibacterial Silver,” Metal Based Drugs, ed. By Frank Shaw, III, August 17th-20th, 1994; 1(5-6):472. 38 Russell, AD, Hugo, WB, “Antimicrobial Activity and Action of Silver,” Prog Med Chem, 1994; 31:364. 39 Clement JL, Jarrett, PS, “Antibacterial Silver,” Metal Based Drugs, ed. By Frank Shaw, III, August 17th-20th, 1994; 1(5-6):472. 40 Russell, AD, Hugo, WB, “Antimicrobial Activity and Action of Silver,” Prog Med Chem, 1994; 31:364. 41 Russell, AD, Hugo, WB, “Antimicrobial Activity and Action of Silver,” Prog Med Chem, 1994; 31:365. 42 Russell, AD, Hugo, WB, “Antimicrobial Activity and Action of Silver,” Prog Med Chem, 1994; 31:365. 43 Thurman, RB, Gerba, CP, “The Molecular Mechanisms of Copper and Silver Ion Disinfection of Bacteria and Viruses,” A paper presented in the First International Conference on Gold and Silver in Medicine. The Silver Institute, Washington, 1989; 18(4):302 44 Zhao, G, Stevens, SE, “Multiple Parameters for the Comprehensive Evaluation of the Susceptibility of Escherichia coli to the Silver Ion,” BioMetals, 1998; 11:28. 45 Hamilton-Miller, JM, Shah, S, Smith, C, “Silver Sulfadiazine: A Comprehensive in vitro Reassessment,” Chemotherapy, 1993; 39:405-9. 46 Grier, N, “Silver and Its Compounds,” p. 385; In: Disinfection, Sterilization and Preservation, S. Block, edit., Lea & Febiger, Philadelphia, PA, 1983. 47 Yin, HQ, Langford, R, Burrell, RE, “Comparative Evaluation of the Antimicrobial Activity of ACTICOAT Antimicrobial Barrier Dressing,” J Burn Care Rehabil, May-Jun 1999; 20(3):195-200.

Source: http://www.imref.org/articles/pdfs/Microbial_Multi-Drug_Resistance_(MDR)_And_Oligodynamic_Silver.pdf