Virginia R. Coleman

Treatment resistance to idoxuridine in herpetic keratitis.

Whenever a new antimicrobial drug has been used on a large scale in medical treatment, the selection pressure exerted by that drug has favored the emergence of drugresistant microbial variants. Failure of clinical treatment has often been the first indication of the emergence of drug resistance. Idoxuridine (5-iodo-2-deoxyuridine, IUDR) was the first drug employed on a significant scale in the United States for the treatment of a human viral infection, herpes simplex keratitis 1 . During the past 4 years ophthalmologists, observing patients with herpetic keratitis who failed to respond to IUDR treatment, have speculated as to the nature of this “resistance” and its possible increasing frequency. Buthala 2 , Smith 3 and others 4 , 5 , 6 have studied the emergence of IUDR-resistant herpes simplex viruses (HSV) in cell culture. Repeated passage of HSV in medium containing IUDR promptly yielded strains that could replicate in the presence of IUDR up to 500 μg/ml. About 1 in 1000 or 1 in 10,000 particles appeared to be highly IUDR-resistant, and this resistance was stable on passage. On the other hand it has been reported 7 that some HSV strains are fully susceptible to IUDR in vitro yet are treatment-resistant in vivo, because they escape the action of the drug by rapidly progressing into the depths of the infected cornea. Therefore, it was of interest to determine whether HSV strains of increased resistance to IUDR could be isolated from patients whose herpetic keratitis had failed to respond to IUDR treatment. As a corollary we determined the influence of IUDR treatment on the frequency of HSV isolation from herpetic keratitis in patients, and made observations on IUDR resistance induced in HSV isolates in vitro and in herpetic keratitis of rabbits.

Inactivation of Herpes Simplex Virus by Thiosemicarbazones and Certain Cations

We demonstrated that herpes simplex virus types 1 and 2, including a type 2 strain which transforms hamster cells in vitro, and Herpesvirus saimiri are inactivated by exposure to thiosemicarbazones. Because thiosemicarbazones are thought to interact with heavy metals in this inactivation process (9), we tested and found some of these herpesviruses to be susceptible to exposure to certain heavy metals. A virion polymerase was sought because the ribonucleic acid (RNA)-dependent deoxyribonucleic acid (DNA) polymerase of Rous sarcoma virus and the DNA-dependent RNA polymerase of vaccinia virus are inhibited. However, neither DNA nor RNA polymerase activity could be demonstrated in herpes simplex virions. The ability of thiosemicarbazone to ameliorate the course of herpes simplex virus infection in rabbit eyes was observed, but was considered insufficient to be of clinical importance.

Inactivation of Herpesvirus hominis Types 1 and 2 by Silver Nitrate In Vitro and In Vivo

Herpes simplex virus (HSV) types 1 and 2 (two strains each) were inactivated at different rates in vitro by 40 μM AgNO3. The inactivation of HSV type 1 strains was virtually complete in 10 to 15 min, whereas almost half of the infectivity of HSV type 2 strains survived this exposure. One strain of type 1 inoculated into rabbit eyes was almost completely inactivated by 1% AgNO3 solution dropped into the eye 20 min later, so that there was markedly reduced viral replication and less corneal herpetic disease. One strain of HSV type 2 in the rabbit eye was not effectively inactivated by 1% AgNO3. From these results, it seems likely that AgNO3 instillation into the eyes of a newborn who has passed through a birth canal infected with HSV might prevent eye infection with HSV type 1 but not with type 2. The greater resistance of HSV type 2 strains to chemical inactivation in vitro and in vivo may be of medical concern.

The mode of action of antibiotic synergism and antagonism: the effect in vitro on bacteria not actively multiplying.

Summary: The synergistic effect of certain pairs of antibiotics might be due to action on ‘persisters’; i.e. members of a bacterial population which survive exposure to single drugs, perhaps while in a state of reduced metabolic activity, although their offspring do not show enhanced resistance. Hence, antibiotics were tested in vitro under conditions minimizing bacterial multiplication and metabolism. At 37°, neomycin, polymyxin, and streptomycin were more effective in the absence of nutrients than in nutrient broth; oxytetracycline and bacitracin were equally effective in either environment; but penicillin had little effect in the absence of nutrients. At 4°, bactericidal action varied with the test organism so that differences could not be attributed solely to the ‘resting’ state of the bacteria. Conditions not permitting bacterial multiplication prevented synergism and those antagonisms demonstrable in broth. Probably synergism depends upon rapid bactericidal action preventing the emergence of persisters rather than upon destruction of these relatively inactive forms.

THE PARTICIPATION OF POLYMYXIN B IN COMBINED ANTIBIOTIC ACTION

Excerpt The polymyxins are a group of stable basic polypeptides isolated fromBacillus polymyxa.1Depending upon their amino acid composition, they have been designated by letters A, B, C, D and E. P...

Observations on the Mode of Action of Antibiotic Synergism and Antagonism.

SUMMARY: Inactive analogues and degradation products of active antibiotics failed to participate in either synergistic or antagonistic antimicrobial action in combination with active antibiotics. Streptobiosamine hydrochloride contaminated with 2–3% (w/w) streptomycin was synergistic with other antibiotics because of the active streptomycin present. The ratio of the smallest amount of antibiotic participating in synergism to that having independent antimicrobial activity varied with the drug and the micro-organism. Synergism with another antibiotic usually required from 1/20 to 1/3 of the minimal inhibitory concentration of an antibiotic when acting alone. Streptomycin, however, in 1/1000 of the minimal inhibitory concentration was synergistic with penicillin in its action on a strain of Streptococcus faecalis.