Factors Affecting Choice of Antimicrobial Agent

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Chapter: Pharmaceutical Microbiology : Chemical Disinfectants, Antiseptics And Preservatives

Choice of the most appropriate antimicrobial compound for a particular purpose depends on many factors and the key parameters are described.



Choice of the most appropriate antimicrobial compound for a particular purpose depends on many factors and the key parameters are described.


a)    Properties Of The Chemical Agent


The process of killing or inhibiting the growth of microorganisms using an antimicrobial agent is basically that of a chemical reaction and the rate and extent of this reaction will be influenced by concentration of agent, temperature, pH and formulation. Tissue toxicity influences whether a chemical can be used as an antiseptic or preservative, and this limits the range of agents for these applications or necessitates the use of lower concentrations of the agent.


b)   Microbiological Challenge


The types of microorganism present and the levels of microbial contamination (the bioburden) both have a significant effect on the outcome of treatment. If the bioburden is high, long exposure times and/or higher concentrations of antimicrobial may be required. Microorganisms vary in their sensitivity to the action of chemical agents. Some organisms merit attention either because of their resistance to disinfection or because of their significance in cross-infection or nosocomial (hospital-acquired) infections. Of particular concern is the significant increase in resistance to disinfectants resulting from microbial growth in biofilm form rather than free suspension. Microbial biofilms form readily on available surfaces, posing a serious problem for hospital infection control committees in advising suitable disinfectants for use in such situations.


The efficacy of an antimicrobial agent must be investigated by appropriate capacity, challenge and in-use tests to ensure that a standard is obtained which is appropriate to the intended use. In practice, it is not usually possible to know which organisms are present on the articles being treated. Thus, it is necessary to categorize agents according to their antimicrobial activity and for the user to be aware of the level of antimicrobial action required in a particular situation.


          i)   Vegetative bacteria


At in-use concentrations, chemicals used for disinfection should be capable of killing bacteria and other organisms expected in that environment within a defined contact period. This includes ‘problem’ organisms such as methicillin-resistant Staphylococcus aureus (MRSA), vancomycin-resistant enterococci (VRE) and species of ListeriaCampylobacter and Legionella. Antiseptics and preservatives are also expected to have a broad spectrum of antimicrobial activity but at their in-use concentrations, after exerting an initial biocidal (killing) effect, their main function may be biostatic (inhibitory). Gram-negative bacilli, which are a major causes of nosocomial infections, are often more resistant than Gram-positive species. Pseudomonas aeruginosa, an opportunistic pathogen has gained a reputation as the most resistant of the Gram-negative organisms. However, problems mainly arise when a number of additional factors such as heavily soiled articles or diluted or degraded disinfectant solutions are employed.


ii)                 Mycobacterium tuberculosis


M. tuberculosis (the tubercle bacillus) and other mycobacteria are resistant to many bactericides. Resistance is either (1) intrinsic, mainly due to reduced cellular permeability or (2) acquired, due to mutation or the acquisition of plasmids . Tuberculosis remains an important public health hazard, and indeed the annual number of tuberculosis cases is rising in many countries. The greatest risk of acquiring infection is from the undiagnosed patient. Equipment used for respiratory investigations can become contaminated with mycobacteria if the patient is a carrier of this organism. It is important to be able to disinfect the equipment to a safe level to prevent transmission of infection to other patients (Table 19.2).

iii)              Bacterial spores


Bacterial spores can exhibit significant resistance to even the most active chemical disinfectant treatment. The majority of disinfectants have no useful sporicidal action in a pharmaceutical context, which relates to disinfection of materials, instruments and environments that are likely to be contaminated by the spore-forming genera Bacillus and Clostridium. However, certain aldehydes, halogens and per-oxygen compounds display very good activity under controlled conditions and are sometimes used as an alternative to physical methods for sterilization of heat-sensitive equipment. In these circumstances, correct usage of the agent is of paramount importance, as safety margins are lower in comparison with physical methods of sterilization .


Clostridium difficile is a particularly problematic contaminant in hospital environments, resulting in high levels of morbidity and mortality. In addition to stringent hand-washing, meticulous environmental disinfection procedures must be in place, e.g. using solutions of 5.25–6.15% sodium hypochlorite for routine disinfection. When high-level disinfection of Cl. difficile is required, 2% glutaraldehyde, 0.55% o-phthalaldehyde and 0.35% peracetic acid are effective.


The antibacterial activity of some disinfectants and antiseptics is summarized in Table 19.2.


iv)               Fungi


The vegetative fungal form is often as sensitive as vegetative bacteria to chemical antimicrobial agents. Fungal spores (conidia and chlamydospores) may be more resistant, but this resistance is of much lesser magnitude than that exhibited by bacterial spores. The ability to rapidly destroy pathogenic fungi such as the important nosocomial pathogen Candida albicans, filamentous fungi such as Trichophyton mentagrophytes, and spores of common spoilage moulds such as Aspergillus niger is put to advantage in many applications of use. Many disinfectants have good activity against these fungi (Table 19.3). In addition, ethanol (70%) is rapid and reliable against Candida species.


v)                 Viruses


Susceptibility of viruses to antimicrobial agents can depend on whether the viruses possess a lipid envelope. Non-lipid viruses are frequently more resistant to disinfectants and it is also likely that such viruses cannot be readily categorized with respect to their sensitivities to antimicrobial agents. These viruses are responsible for many nosocomial infections, e.g. rotaviruses, picornaviruses and adenoviruses and it may be necessary to select an antiseptic or disinfectant to suit specific circumstances. Certain viruses, such as Ebola and Marburg, which cause haemorrhagic fevers, are highly infectious and their safe destruction by disinfectants is of paramount importance. Hepatitis A is an enterovirus considered to be one of the most resistant viruses to disinfection.


There is much concern for the safety of personnel handling articles contaminated with pathogenic viruses such as hepatitis B virus (HBV) and HIV. Disinfectants must be able to treat rapidly and reliably accidental spills of blood, body fluids or secretions from HIV-infected patients. Such spills may contain levels of HIV as high as 104 infectious units/ml. Fortunately, HIV is inactivated by most chemicals at in-use concentrations. However, the recommendation is to use high-level disinfectants (see Table 19.2) for decontamination of HIV-or HBV-infected reusable medical equipment. For patient care areas, cleaning and disinfection with intermediate-level disinfectants is satisfactory. Flooding with a liquid germicide is required only when large spills of cultured or concentrated infectious agents have to be dealt with.


The World Health Organization (WHO) and epidemiologists in many countries track outbreaks of influenza, especially in relation to potential epidemic and pandemic situations arising. The H1N1 outbreak in 2009 generated considerable concern. As an influenza A virus, however, it is susceptible to a large number of disinfectant products when they are used on hard, non-porous surfaces that may be contaminated. Although no research has been conducted on the susceptibility of 2009 H1N1 influenza virus to chlorine and other disinfectants in swimming pools and spas, studies have demonstrated that free chlorine levels of 1–3 mg/L (1–3 ppm) are adequate to disinfect avian H5N1 influenza virus.


vi)              Protozoa


Acanthamoeba spp. can cause acanthamoeba keratitis with associated corneal scarring and loss of vision in wearers of soft contact lenses. The cysts of this protozoan present a particular problem in respect of lens disinfection. The chlorine-generating systems in use are generally inadequate. Polyaminopropyl biguanide with or without chlorhexidine (0.003%) and polyhexamethylene biguanide (0.0005%) both show ability as an acanthamoebicide in combating 103levels of cysts. Hydrogen peroxide-based disinfection is considered completely reliable and consistent in producing an acanthamoebicidal effect.


vii)             Prions


Prions are generally considered to be the infectious agents most resistant to chemical disinfectants and sterilization processes; strictly speaking, however, they are not microorganisms because they have no cellular structure nor do they contain nucleic acids. As small proteinaceous infectious particles they are a unique class of infectious agent causing spongiform encephalopathies such as bovine spongiform encephalopathy (BSE) in cattle and Creutzfeldt–Jakob disease (CJD) in humans. There is considerable concern about the transmission of these agents from infected animals or patients. Risk of infectivity is highest in brain, spinal cord and eye tissues. Prions are considered resistant to most disinfectant procedures. For heat-resistant medical instruments that come into contact with high infectivity tissues or high-risk contacts, immersion in sodium hydroxide (1 M) or sodium hypochlorite (20 000 ppm available chlorine) for 1 hour is advised in WHO guidelines and this must be followed by further treatment including autoclaving, cleaning and routine sterilization. Recently, a formulation of 0.2% sodium docecyl sulphate, 0.3% NaOH in 20% n-propanol, has achieved potent decontamination of steel carriers contaminated with PrPTSE, the biochemical marker for prion infectivity, from 263K scrapie hamsters (5.5 log10 units reduction) or patients with sporadic or variant Creutzfeldt–Jacob disease. No low-temperature sterilization technology is effective.


c)    Intended Application


The intended application of the antimicrobial agent, whether for preservation, antisepsis or disinfection, will influence its selection and also affect its performance. For example, in medicinal preparations the ingredients in the formulation may antagonize preservative activity. The risk to the patient will depend on whether the antimicrobial is in close contact with a break in the skin or mucous membranes or is introduced into a sterile area of the body.


In disinfection of instruments, the chemicals used must not adversely affect the instruments, e.g. cause corrosion of metals, affect clarity or integrity of lenses, or change the texture of synthetic polymers. Many materials such as fabrics, rubber and plastics are capable of adsorbing certain disinfectants, e.g. quaternary ammonium compounds (QACs) are adsorbed by fabrics, while phenolics are adsorbed by rubber, the consequence of this being a reduction in the concentration of active compound. A disinfectant can only exert its effect if it is in contact with the item being treated. Therefore, access to all parts of an instrument or piece of equipment is essential. For small items, total immersion in the disinfectant must also be ensured.


d) Environmental Factors


Organic matter can have a drastic effect on antimicrobial capacity either by adsorption or chemical inactivation, thus reducing the concentration of active agent in solution or by acting as a barrier to the penetration of the disinfectant. Blood, body fluids, pus, milk, food residues or colloidal proteins, even when present in small amounts, all reduce the effectiveness of antimicrobial agents to varying degrees, and some are seriously affected. In their normal habitats, microorganisms have a tendency to adhere to surfaces and are thus less accessible to the chemical agent. Some organisms are specific to certain environments and their destruction will be of paramount importance in the selection of a suitable agent, e.g. Legionella in cooling towers and non-potable water supply systems, Listeria in the dairy and food industry and HBV in blood-contaminated articles.


Dried organic deposits may inhibit penetration of the chemical agent. Where possible, objects to be disinfected should be thoroughly cleaned. The presence of ions in water can also affect activity of antimicrobial agents, thus water for testing biocidal activity can be made artificially ‘hard’ by addition of ions.


These factors can have very significant effects on activity and are summarized in Table 19.4.


e)    Toxicity Of The Agent


In choosing an antimicrobial agent for a particular application some consideration must be given to its toxicity. Increasing concern for health and safety is reflected in the Control of Substances Hazardous to Health (COSHH) Regulations that specify the precautions required in handling toxic or potentially toxic agents. In respect of disinfectants these regulations affect, particularly, the use of phenolics, formaldehyde and glutaraldehyde. Toxic volatile substances, in general, should be kept in covered containers to reduce the level of exposure to irritant vapour and they should be used with an extractor facility. Limits governing the exposure of individuals to such substances are now listed, e.g. 0.7 mg/m3 (0.2 ppm) glutaraldehyde for both short-and long-term exposure. Many disinfectants including the aldehydes, glutaraldehyde less so than formaldehyde, may affect the eyes, skin (causing contact dermatitis) and induce respiratory distress. Face protection and impermeable nitrile rubber gloves should be worn when using these agents. Table 19.4 lists the toxicity of many of the disinfectants in use and other concerns of toxicity are described below for individual agents.


The COSHH Regulations specify certain disinfectants that contain active substances not supported under the BPD that had to be phased out by 2006. Specified disinfection procedures applied to laboratories in relation to spills and routine use state that certain phenolic agents (including 2,4,6-trichlorophenol and xylenol) can no longer be employed in disinfectant products.


Because of the historically high number of occupational asthma cases caused by glutaraldehyde (an alkylating agent) products in chemical disinfection of endoscopes, an HSE report (2007) sought alternatives to this agent. The report recommended the preferential use of an oxidizing agent such as a chlorine-based or peroxygen-based product rather than a product containing an alkylating agent. However, it was recognized that consideration must be given to incompatibility of disinfectants with endoscope construction materials in some cases (Table 19.5).


In all situations where the atmosphere of a workplace is likely to be contaminated by disinfectant, sampling and analysis of the atmosphere may need to be carried out on a periodic basis with a frequency determined by conditions.


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