MICRO-ORGANISMS IN PHARMACEUTICAL AND COSMETIC PREPARATIONS 417 follow I he intravenous injection of fluids in which organisms have multiplied before injection and the organisms are nearly always Gram-negative bacilli, including members of the pseudomonas, ldebsiella, enterobacter and serratia groups. The same serious clinical consequences--bacteraemic shock and generalized septic infection--occur in all classes of patient and with most of the Gram-negative bacilli, but Flavobacterium meningosepticum, which causes severe and usually fatal infection in newborn infants when applied to the body surface, causes only a short episode of fever when given intravenously to adults in enormous doses (1). The resistance of the meninges to small numbers of organisms is believed to be significantly lower than that of the bloodstream, but in practice meningitis following the intraspinal injection of contaminated fluids--now fortunately uncommon--is usually also attributable to Gram- negative bacteria that can multiply in the fluids. On the other hand, sepsis following subcutaneous or intramuscular injection may be due to a much wider variety of organisms, including Staphylococcus aureus, haemolytic streptococci and the clostridia. With the possible exception of the haemolytic streptococci, the minimum infective dose of these organisms on injection into absolutely healthy tissues is generally high, but if the contaminated medicament has a necrotic or vaso- constrictive action only a minute dose of organisms is necessary for infection. Infections following subcutaneous or intramuscular injection are nowadays rarely caused by organisms present in the preparation, and more often by contamination with organisms from the injector or the skin of the patient. Solutions that contain Gram-negative bacteria in large numbers usually cause only local inflammation on subcutaneous injection unless the recipient has a greatly lowered general resistance to infection. Implantation into wounds and normally sterile areas o.f the body surface Again, most of the infections attributable to medicaments are due to Gram-negative bacilli. Infection of wounds and secondary infection of pre-existing skin lesions with organisms present in creams and lotions have been described by Noble and Savin (2), and by Bassett, Stokes and Thomas (3), but it was sometimes difficult to assess the ill effect on the patients. Contaminated fluids used for irrigation of the bladder have caused out- breaks of urinary-tract infection (4, 5). Respiratory infection with Gram- negative bacteria more often results from the contamination of apparatus than of medicaments, but Mertz, Scharer and McClement (6) described an

418 JOURNAL OF THE SOCIETY OF COSMETIC CHEMISTS outbreak due to nebulization of fluid from a contaminated stock bottle, and Phillips (7) attributed infection to contaminated lignocaine jelly used to lubricate endotracheal tubes. Serious infections of the eye due to contaminated irrigation fluids, eye drops and ointments fall into a class of their own, because they are numerous, are nearly always due to Pseudomonas aeruginosa, and almost invariably result in loss of the eye (8-10). Relatively trivial injuries to the eye (11), even minute abrasions due to the improper use of contact lenses (12), can act as the portal of entry for the organisms. According to Crompton, Anderson and Kennare (13), the intraocular injection of as few as 60 cells of Ps. aeruginosa in the rabbit invariably causes panophthalmitis, but how many are needed to establish infection in a corneal wound in man is not known. Deposition on the normal skin In infants during the first few days of life, the application of certain Gram-negative bacilli to the skin results in colonization, and a proportion of the colonized infants develop serious and often fatal generalized infec- tions including meningitis. In carrier-epidemics of Ps. aeruginosa in nurseries for the newborn, the organism can be isolated not only from the faeces but also from the skin particularly of the umbilical region (14). Spread of the organism in some nurseries is attributable to contaminated resuscitation apparatus and is probably by the respiratory route. In others, however, this possibility can be excluded, and as long ago as 1901 Wasser- mann (15) observed spread of the organism along the umbilical artery in fatal Ps. aeruginosa infections in infants. It is likely that multiplication of the organism in the umbilical wotmd is a frequent preliminary to invasion. Cooke, Shooter, O'Farrell and Martin (16) observed colonization of infants with the strain of Ps. aeruginosa present in a detergent solution used to clean the napkin area, Victorin (17) traced an epidemic of neonatal otitis media to a similar solution, and we are aware of several other unrecorded outbreaks in British hospitals in which the causative strain was found in 'antiseptic' skin-care lotions applied to babies. McCormack and Kunin (18) attributed an outbreak of umbilical sepsis to Serratia in the saline solution used to moisten the cord stump. In several outbreaks of neonatal meningitis due to Fl. meningosepticum the organism was isolated from ward tap water or other moist situations, but it was not clear how the infants were infected in one instance, Plotkin and McKitrick (19) found the organism in con- tainers of saline used to cleanse the babies' eyes.