Combination Of Novobiocin Research Articles

In Vivo Effects of Cefazolin, Daptomycin, and Nafcillin in Experimental Endocarditis with a Methicillin-Susceptible Staphylococcus aureus Strain Showing an Inoculum Effect against Cefazolin

Several reports have implicated the inoculum effect that some strains of type A beta-lactamase (Bla)-producing, methicillin-susceptible Staphylococcus aureus (MSSA) show against cefazolin as the cause for clinical failures in certain serious deep-seated infections. Here, using a previously reported MSSA strain displaying this phenotype (TX0117), we obtained a Bla-cured derivative (TX0117c) with a combination of novobiocin and high temperature. Both isolates were then used in a rat endocarditis model and treated with cefazolin, nafcillin, and daptomycin, given to simulate human dosing. Animals were treated for 3 days and either sacrificed at 24 h after the last antibiotic dose (standard group) or left untreated for an additional 3 days (relapse group). With TX0117 in the standard treatment group, daptomycin and nafcillin were both significantly better than cefazolin in reducing CFU/g of vegetations, achieving mean log10 reductions compared to levels in untreated rats of 7.1, 5.3, and 1.8, respectively (cefazolin versus daptomycin, P < 0.0001; cefazolin versus nafcillin, P = 0.005; daptomycin versus nafcillin, P = 0.053). In addition, cefazolin was significantly more effective in reducing vegetation titers of TX0117c than of TX0117 (mean log10 reduction of 1.4 versus 5.5, respectively; P = 0.0001). Similar results were observed with animals in the relapse group. Thus, these data show that there can be an in vivo consequence of the in vitro inoculum effect that some MSSA strains display against cefazolin and indicate a specific role for Bla production using a Bla-cured derivative strain against which cefazolin regained both in vitro and in vivo activity.

Evaluation of Two Treatment Protocols against Staphylococcus aureus at Drying-off

A lot is known about control strategies to treat and prevent Staphylococcus aureus mastitis in dairy cattle. However, S. aureus continues to be one of the major causes of mastitis in dairy herds worldwide. The efficacy of current lactating cow antimicrobial therapy is clearly limited. Although intra-mammary dry cow therapy improves cure rate, the high proportion of treatment failures prevents this procedure from forming the basis for an effective control program. It has been suggested that extended lactational therapy prior to drying-off might improve cure rate. The goal of this study is to compare the efficacy of two treatment protocols, using either the combination of novobiocin and penicillin as a dry cow therapy (Novodry plus®), or the same treatment preceded by 3 complete treatments with Pirlimycin (Pirsue®), on bacteriological cure and reduction of somatic cell count (SCC) in cows infected with S. aureus.

In vitro activity of novobiocin against multiresistant strains of Enterococcus faecium

Sixty strains of vancomycin- and ampicillin-resistant Enterococcus faecium were evaluated for their susceptibilities to novobiocin in vitro. In Mueller-Hinton broth, novobiocin inhibited all strains when it was used at a concentration of < or = 2 microgram/ml and 40 of 60 strains when it was used at a concentration of < or = 0.5 micrograms/ml. MICs were 8- to 16-fold higher in 50% serum. Novobiocin alone resulted in 2-log-unit killing at 24 h. Combinations of novobiocin and a fluoroquinolone (either ciprofloxacin or ofloxacin) were additive and bactericidal for quinolone-susceptible strains in either broth or 50% serum. Gentamicin did not affect novobiocin activity, and rifampin and doxycycline were antagonistic.

Serum inhibitory and bactericidal activity against methicillin-resistant Staphylococcus aureus in volunteers receiving novobiocin and rifampin alone and in combination

The combination of novobiocin and rifampin is effective in eliminating colonization due to methicillin-resistant Staphylococcus aureus (MRSA) and in treating experimental MRSA soft tissue infections. To evaluate novobiocin, rifampin, and the combination of the two agents for potential oral therapy in patients with MRSA infections, we measured the serum inhibitory and bactericidal activity from four volunteers against 20 MRSA strains obtained from seven different institutions. When Stratton-Reller methods employing 50% human serum were used to perform the assay, rifampin produced peak mean serum inhibitory titers of 1:40, whereas novobiocin alone produced essentially no inhibitory activity. The combination of novobiocin plus rifampin had similar inhibitory activity as rifampin alone. The bactericidal titers produced by the three regimens were significantly less than inhibitory titers. In additional studies, involving serum from five volunteers tested against seven representative strains, peak mean serum inhibitory activity of novobiocin was 1:232 when Mueller-Hinton broth was used as the diluent compared with <1:2 when 50% human serum was used. We conclude that despite the high degree of activity of novobiocin in broth, its activity against MRSA in serum is minimal, probably related to the high degree of protein binding of that antibiotic.

Randomized double-blinded trial of rifampin with either novobiocin or trimethoprim-sulfamethoxazole against methicillin-resistant Staphylococcus aureus colonization: prevention of antimicrobial resistance and effect of host factors on outcome

Methicillin-resistant Staphylococcus aureus (MRSA) is a major pathogen in hospitals. Current antimicrobial regimens for eradicating colonizing strains are not well defined and are often complicated by the emergence of resistance. The combination of novobiocin plus rifampin in vitro and in vivo was found to prevent the emergence of resistant populations of initially susceptible strains of MRSA, particularly resistance to rifampin. We therefore studied, in a randomized, double-blind, multicenter comparative trial, the combination of novobiocin plus rifampin versus trimethoprim-sulfamethoxazole (T/S) plus rifampin in order to determine the efficacy of each regimen in eradicating MRSA colonization and to further characterize the host factors involved in the response to this antimicrobial therapy. Among the 126 individuals enrolled in the study, 94 (80 patients; 14 hospital personnel) were evaluable. Among the 94 evaluable subjects, no significant demographic or medical differences existed between the two treatment groups. Successful clearance of the colonizing MRSA strains was achieved in 30 of 45 (67%) subjects receiving novobiocin plus rifampin, whereas successful clearance was achieved in 26 of 49 (53%) subjects treated with T/S plus rifampin (P = 0.18). The emergence of resistance to rifampin developed more frequently in 14% (7 of 49) of subjects treated with T/S plus rifampin than in 2% (1 of 45) of subjects treated with novobiocin plus rifampin (P = 0.04). Restriction endonuclease studies of large plasmid DNA demonstrated that the same strain was present at pretherapy and posttherapy in most refractory cases (24 of 29 [83%] subjects). Among the 56 successfully treated subjects, clearance of MRSA was age dependent: 29 of 36 (80%) subjects in the 18- to 49-year-old age group, 19 of 35 (54%) subjects in the 50- to 69-year-old age group, and 8 of 23 (35%) in the 70- to 94-year-old age group (P < 0.01). Clearance was also site dependent; culture-positive samples from wounds were related to a successful outcome in only 22 (48%) of 46 subjects, whereas culture-positive samples from sites other than wounds (e.g., nares, rectum, and sputum) were associated with a success rate of 34 of 48 (71%) subjects (P = 0.02). Foreign bodies in wounds did not prevent the eradication of MRSA by either regimen. T/S plus rifampin was less effective in clearing both pressure and other wounds, whereas novobiocin plus rifampin was equally effective in clearing both pressure and other wounds. There were no significant differences in toxicity between the two regimens. Thus, the combination of novobiocin plus rifampin, in comparison with T/S plus rifampin, was more effective in preventing the emergence of resistance to rifampin and demonstrated a trend toward greater activity in clearing the MRSA carrier state. The response to either combination depended on host factors, particularly age and the site of MRSA colonization.

Novobiocin-induced anti-proliferative and differentiating effects in melanoma B16

The antibiotic drug novobiocin was evaluated for its anti-tumour properties in B16 melanoma cells. Novobiocin is shown to inhibit melanoma B16 cell proliferation. The anti-proliferative effect was gradually reversible upon removal of novobiocin from the culture medium. Growth inhibition by novobiocin was accompanied by phenotypic alterations, that included morphological changes, lipid accumulation and marked increases in the activities of NADPH cytochrome c reductase and gamma glutamyl transpeptidase. In vivo administration of repeated i.p. doses of novobiocin, to mice implanted with B16 melanoma cells resulted in growth retardation. The combined treatment of the B16 melanoma cells with novobiocin and other chemical inducers of differentiation was examined in a cell growth assay. Novobiocin and sodium butyrate inhibited cell growth in a near additive manner, while combination of novobiocin with the GTP-depleting agents, tiazofurin or mycophenolic acid resulted in a synergistic decrease in cell growth. Our results support the contention further that novobiocin and other differentiating agents might be of potential value in melanoma therapy.

Ability of four potential topoisomerase II inhibitors to enhance the cytotoxicity ofcis-diamminedichloroplatinum (II) in Chinese hamster ovary cells and in an epipodophyllotoxin-resistant subline

Four drugs known to interact with topoisomerase II were assessed for their ability to enhance the cytotoxicity of cis-diamminedichloroplatinum(II) (CDDP) in Chinese hamster ovary (CHO) cell lines sensitive and resistant to VM-26. The combination treatments were analyzed by isobologram methodology. On 24 h exposure, there was no significant difference in the cytotoxicity of novobiocin or ciprofloxacin toward either cell line. The resistant cells were approximately 9-fold more resistant to 4'-(9-acridinylamino)methanesulfon-m-anisidide (m-AMSA) and approximately 170-fold more resistant to etoposide after a 24-h exposure. The combination of novobiocin and cisplatin produced greater than additive cell kill over the entire dose range of cisplatin tested in both cell lines. m-AMSA and CDDP produced cell kill that fell within the envelope of additivity. Etoposide and CDDP resulted in cytotoxicity that was slightly greater than additive at low CDDP concentrations and additive at the highest concentration of CDDP tested in the parental cell line and was slightly greater than additive in the resistant cell line. Ciprofloxacin and CDDP, like novobiocin, resulted in greater than additive cell kill in both cell lines. The enhancement of CDDP cytotoxicity by novobiocin that was seen in exponentially growing cells was lost in stationary-phase cultures. In these studies, novobiocin and, to a lesser degree, ciprofloxacin produced greater than additive cell kill in combination with CDDP in parental and epipodophyllotoxin-resistant CHO cells.

Activity of fluoroquinolone antibiotics against Plasmodium falciparum in vitro.

The fluoroquinolone antibiotics are structurally related to nalidixic acid. Their primary antibacterial action appears to be mainly due to inhibition of DNA gyrase (DNA topoisomerase II). We determined the activity of several fluoroquinolones in vitro against two strains of Plasmodium falciparum, FCC1 (chloroquine susceptible) and VNS (chloroquine resistant). [3H]hypoxanthine incorporation by malarial parasites was determined at 48 and 96 h. The molarity at which each agent caused a 50% decrease in the incorporation of [3H]hypoxanthine compared with that of drug-free controls was defined as the 50% inhibitory concentration. The fluoroquinolones evaluated were amifloxacin, ciprofloxacin, enoxacin, norfloxacin, ofloxacin, and pefloxacin. Other DNA gyrase inhibitors tested were nalidixic acid, oxolinic acid, novobiocin, and coumermycin A1. Among the fluoroquinolones, ciprofloxacin had the lowest 50% inhibitory concentrations at 48 h against both chloroquine-susceptible and -resistant strains of P. falciparum, (0.26 +/- 0.08) x 10(-4) and (0.38 +/- 0.15) x 10(-4) M, respectively (mean +/- standard deviation). Enoxacin had the lowest 50% inhibitory concentrations against FCC1 and VNS at 96 h, 0.23 x 10(-5) and (0.06 +/- 0.04) x 10(-5) M, respectively. With the VNS strain, fractional inhibitory concentration indexes for the combination of ciprofloxacin and tetracycline were calculated at 48 and 96 h to be 0.93 and 0.79, respectively, indicating modest additive effects. The combination of novobiocin with ciprofloxacin showed indifference in the same system. The antimalarial effects of some fluoroquinolones occur at achievable serum concentrations. Whether inhibition of DNA gyrase contributes to the antimalarial activity of the fluoroquinolones is unknown at present.

Effect of Novobiocin and Its Combination with Tetracycline, Chloramphenicol, Erythromycin, and Lincomycin on the Microbial Generation of Escherichia coli

Inhibition of the steady-state generation of Escherichia coli by the bacteriostatic antibiotic novobiocin is linearly related to drug concentration in the range of 0 to 30 mug/ml. Increased cell sizes result because the drug inhibits cell division. The generation rate dependence on drug concentration depends on the nonionized fraction of novobiocin and is invariant with inoculum size or medium composition. However, the antibacterial activity of novobiocin decreases as the concentration of nutrients and Mg(2+) increases, although the inhibitory action of novobiocin on generation rate remains unchanged for concentrations of Mg(2+) above 8.1 x 10(-4) M. Novobiocin is synergistic in combinations with tetracycline in broth, but not when the Mg(2+) was maintained at 4.05 x 10(-3) M. Combinations of novobiocin with the 50S ribosomal subunit inhibitors chloramphenicol, erythromycin, or lincomycin are antagonistic, and the degree of growth inhibition is determined only by that component of the binary combination that would have the greater potency if it were acting alone.

Antibiotic combinations; antibacterial action of plasma after ingestion of novobiocin or penicillin G or both.

THIS paper reports another in a series of studies designed to throw some light on the combined action of antibiotics in vivo by controlled observations on the antibacterial action of blood after the administration of antibiotics to the same subjects singly and in combinations.§ The present study deals with the combination of novobiocin with penicillin and, like most of the others, was carried out in normal men given the same total amount of each agent separately or of both together in equal parts. The plasma obtained at intervals after each dose was assayed for antibacterial action against 4 different bacterial . . .