Hazard to Health

HAZARD TO HEALTH

Nowadays, it is well recognized that the inadvertent use of a contaminated pharmaceutical product may also present a potential health hazard to the patient. Although isolated outbreaks of medicament-related infections had been reported since the early part of the 20th century, it was only in the 1960s and 1970s that the significance of this contamination to the patient was more fully understood.

Inevitably, the infrequent isolation of true pathogens, such as Salmonella spp. and the reporting of associated infections following the use of products contaminated with these organisms (tablets with pancreatin and thyroid extract), attracted considerable attention. More often, the isolation of common saprophytic and non-fastidious opportunist contaminants with limited pathogenicity to healthy individuals has presented a significant challenge to compromised patients.

Gram-negative contaminants, particularly Pseudomonas spp., which have simple nutritional requirements and can multiply to significant levels in aqueous products, have been held responsible for numerous outbreaks of infection. For example, while the intact cornea is quite resistant to infection, it offers little resistance to pseudomonads and related bacteria when scratched, or damaged by irritant chemicals; loss of sight has frequently occurred following the use of poorly designed ophthalmic solutions which had become contaminated by Ps. aeruginosa and even supported its active growth. Pseudomonads contaminating ‘antiseptic’ solutions have infected the skin of badly burnt patients, resulting in the failure of skin grafts and subsequent death from Gram-negative septicaemia. Infections of eczematous skin and respiratory infections in neonates have been traced to ointments and creams contaminated with Gram-negative bacteria. Oral mixtures and antacid suspensions can support the growth of Gram-negative bacteria and serious consequences have resulted following their inadvertent administration to patients who were immuno-compromised as a result of antineoplastic chemotherapy. Growth of Gram-negative bacteria in bladder washout solutions has been held responsible for painful infections. In more recent times, Pseudomonas contamination of TPN fluids during their aseptic compounding in the hospital pharmacy caused the death of several children in the same hospital.

Fatal viral infections resulting from the use of contaminated human tissue or fluids as components of medicines are well recorded. Examples of this include HIV infection of haemophiliacs by contaminated and inadequately treated factor VIII products made from pooled human blood, and Creutzfeldt–Jakob disease (CJD) from injections of human growth hormone derived from human pituitary glands, some of which were infected.

Pharmaceutical products of widely differing forms are known to be susceptible to contamination with a variety of microorganisms, ranging from true pathogens to a motley collection of opportunist pathogens (see Table 17.1). Disinfectants, antiseptics, powders, tablets and other products providing an inhospitable environment to invading contaminants are known to be at risk, as well as products with more nutritious components, such as creams and lotions with carbohydrates, amino acids, vitamins and often appreciable quantities of water.

The outcome of using a contaminated product may vary from patient to patient, depending on the type and degree of contamination and how the product is to be used. Undoubtedly, the most serious effects have been seen with contaminated injected products where generalized bacteraemic shock and in some cases death of patients have been reported. More likely, a wound or sore in broken skin may become locally infected or colonized by the contaminant; this may in turn result in extended hospital bed occupancy, with ensuing economic consequences. It must be stressed, however, that the majority of cases of medicament-related infections are probably not recognized or reported as such. Recognition of these infections presents its own problems. It is a fortunate hospital physician who can, at an early stage, recognize contamination shown as a cluster of infections of rapid onset, such as that following the use of a contaminated intravenous fluid in a hospital ward. The chances of a general practitioner recognizing a medicament-related infection of insidious onset, perhaps spread over several months, in a diverse group of patients in the community, are much more remote. Once recognized, of course, there is a moral obligation to withdraw the offending product; subsequent investigations of the incident therefore become retrospective.

Microbial Toxins

Gram-negative bacteria contain lipo-polysaccharides (endotoxins) in their outer cell membranes; these can remain in an active condition in products even after cell death and some can survive moist heat sterilization. Although inactive by the oral route, endotoxins can induce a number of physiological effects if they enter the bloodstream via contaminated infusion fluids, even in nanogram quantities, or via diffusion across membranes from contaminated haemodialysis solutions. Such effects may include fever, activation of the cytokine system, endothelial cell damage, all leading to septic and often fatal febrile shock.

The acute bacterial toxins associated with food poisoning episodes are not commonly reported in pharmaceutical products, although aflatoxin-producing aspergilli have been detected in some vegetable and herbal ingredients. However, many of the metabolites of microbial deterioration have quite unpleasant tastes and smell even at low levels, and would deter most patients from using such a medicine.