An in Vivo Pyelonephritis Assay for Screening Therapeutic Agents

Abstract

Eighty to 100°0 of mice stressed with an intraperitoneal dose of 200-240 mg bromoethylamine hydrobromide (BEA)/kg and infected intraveneously 72 hours later with Proteus mirabilis, Pseudomonas, Escherichia coli or Serratia host large numbers of bacteria in their kidneys 3-4 days post-infection.If death (probably due to uremic poisoning) does not intervene, the infection lasts for weeks. The therapeutic effects of carbenicillin and ampicillin were tested in this pyelonephritis model. Carbenicillin was effective against Pseudomonas; ampicillin had an effect against P. mirabilis, but neither carbenicillin nor ampicillin was effective against Serratia-induced pyelonephritis.While many experimental pyelonephritis models have been proposed1-20) they are for technical reasons either most reproducible in the laboratories sponsoring them or are not suitable for routine assay work. The pyelonephritis model proposed in this paper, although based on the old idea of preliminary kidney damage, has the advantages of being technically simple, of having less than a loo mortality due to preparational causes, of being reproducible in routine evaluations of antibiotics, and can be used in studies for host responses where the kidneys have been damaged by a prior bacterial kidney infection.The model is based on the observations that 2-bromoethylamine hydrobromide (BEA) causes papillary necrosis of the kidney14,21,22,23) FUWA14) found that rats given a subcutaneous injection of BEA developed a localized pathology limited to the inner medulla. MURRAY, et al.22) found that after an intravenous injection of BEA complete necrosis of the rat papilla took place between 4 and 7 days with the dead papilla being sequestered by 21 days. Moreover, HILL, et al.21) also found that the progressive pathology of the papillary region coincided with a defect in the concentrating ability of the kidney, a rise in serum urea nitrogen, and a tubular atrophy that developed secondarily to the papillary damage. KAYE and ROCHE24) and ROLAND, et al.25) demonstrated that kidney infections correlated with decreased urinary concentrating ability. From the above papers it was reasoned that if the mouse kidney was susceptible to BEA damage without a subsequent rise in blood urea nitrogen (BUN) then the kidney might host a bacterial population without depressing the host defenses so that a bacterial invasion of tissues other than the kidney occurs. The data given below show that mice stressed with BEA 3-4 days prior to intravenous infection with different bacterial species results in a strictly localized kidney infection. This infection can persist for many weeks providing a BEA-bacterial induced uremic death does not intervene. It has further been shown that carbenicillin is effective against a Pseudomonas kidney infection, that ampicillin has some therapeutic value against a P. mirabilis pyelonephritis but that neither antibiotic was effective against a Serratia-induced kidney infection.

Crystalluria, Medullary Matrix Crystal Deposits and Bladder Calculi Associated with an Acutely Induced Renal Papillary Necrosis

“…The presence of calculi has generally been regarded as a late complicating factor of the analgesic abuse syndrome and there appears to be no published data on the chemical composition of the urolithiases. In fact, the induction of urinary tract infection in rats is much easier after a BEAinduced RPN (Thiele, 1974) and if analgesics are given concomitantly (Vivaldi, 1968). Similar matrix changes, together with electrolyte wastage, mineralisation and recurrent urinary tract infection in human analgesic abusers may be relevant to the development of urinary calculi in this population.…”

Experimental urinary tract infection with Pseudomonas aeruginosa in mice

“…As a model of hematogenous infection, several workers have used intravenous injections of the organism (5)(6)(7)(8)19), but the closeness of the kidney infection dose to the lethal dose makes this model difficult. To increase the susceptibility of the kidneys to P. aeruginosa, artificial manipulations such as administration of ferric sorbital citrate (2) or 2-bromoethylamine hydrobromide (26), massage of the renal parenchyma, thermocautery injury of the renal medulla, and ureteral ligation (23) have been performed before intravenous inoculation of the organisms. As a model of ascending infection, methods such as surgical implantation of a foreign body with inoculation of P. aeruginosa into the bladder (24), inoculation of the organism into the renal pelvis by transvesical ureteral catheterization (21), and inoculation of the organism into the obstructed ureter (14) have been used.…”

Detection of Fibrinolytic and Elastase Activity Among Clinical Isolates of <i>Serratia Marcescen</i><i>s</i>

“…To date, little work has been done with respect to the host-parasite relationships of this particular microorganism [3,11,13,14,16,20,25,29,30,31,38], It has been known for a long time that S. marcescens strains elaborate pathobiologically powerful endotoxins which are capable of eliciting generalized Shwartzman reactions [1,6]. Very recently, Q uarles et al [24] demonstrated dialyzable toxic products (maximal molecular weight 15,000) produced by a strain of S. marcescens that had been maintained in an ingeniously conceived goat artificial kid ney fermentor system; it was shown that when the population of bacterial cells had exceeded lO'/ml, and when the cells had reached the stationary phase of growth, the experimental animals became toxemic, leukopenic, and developed fever.…”