Efficacy of dicloxacillin-coated polyurethane catheters in preventing subcutaneous Staphylococcus aureus infection in mice.

In a mouse model, dicloxacillin-coated polyurethane catheters or control (uncoated) catheters were placed subcutaneously and then Staphylococcus aureus was inoculated at the time of insertion, 24 or 48 h later. The in vivo half-life of the antibiotic was 11 to 16 h. When 10(5) CFU of S. aureus were inoculated at the time of catheter insertion, dicloxacillin-coated catheters kept the number of S. aureus removed from catheters by sonication below 10(2) CFU at 12, 24, 48, and 96 h after inoculation compared with titers greater than 10(3.5) CFU for control catheters (P less than 0.05). When S. aureus was inoculated 24 h after catheter insertion, control catheters averaged greater than 10(2) CFU of S. aureus removed compared with less than 10(1.5) CFU for the dicloxacillin-coated catheters (P less than 0.05). No difference was found between coated and control catheters when S. aureus was inoculated 48 h after catheter insertion, but S. aureus titers averaged less than 10(2) CFU for all experimental groups. Our data suggest that in mice, regional prophylaxis of S. aureus subcutaneous space infection is feasible with catheters coated with dicloxacillin and that the presence of antibiotic is only necessary for the first 24 to 48 h.     

RNAIII-inhibiting peptide enhances healing of wounds infected with methicillin-resistant Staphylococcus aureus

Quorum sensing is a mechanism through which a bacterial population receives input from neighboring cells and elicits an appropriate response to enable survival within the host. Inhibiting quorum sensing by RNAIII-inhibiting peptide (RIP) has been demonstrated as a very effective mode of prevention and therapy for device-associated staphylococcal infections and was tested here for healing of wounds that are otherwise resistant to conventional antibiotics. Wounds, established through the panniculus carnosus of BALB/c mice, were inoculated with 5 x 10(7) CFU of methicillin-resistant Staphylococcus aureus. Mice were treated with Allevyn, RIP-soaked Allevyn (containing 20 microg RIP), daily intraperitoneal teicoplanin (7 mg/kg of body weight), Allevyn and teicoplanin, and RIP-soaked Allevyn and daily intraperitoneal teicoplanin. The main outcome measures were quantitative bacterial culture and histological examination with assessment of microvessel density and of vascular endothelial growth factor (VEGF) expression in tissue sections. Treatment with RIP-soaked Allevyn together with teicoplanin injection greatly reduced the bacterial load to 13 CFU/g (control untreated animals had 10(8) CFU/g bacteria). All other treatments were also significantly effective but only reduced the bacterial load to about 10(3) CFU/ml. Histological examination indicated that only treatment with RIP-soaked Allevyn with teicoplanin injection restored epithelial, granulation, and collagen scores, as well as microvessel density and VEGF expression, to the levels found with uninfected mice. In conclusion, we observed that RIP may be useful for the management of infected wounds and that it could represent an exciting and future alternative to the conventional antibiotics, at present considered the gold-standard treatments for methicillin-resistant S. aureus infections.     

Pharmacodynamics of daptomycin in a murine thigh model of Staphylococcus aureus infection

Daptomycin is a lipopeptide antibiotic with activity against gram-positive bacteria, including Staphylococcus aureus. We defined the pharmacodynamic parameters that determine the activity of daptomycin for S. aureus using in vitro methods and the Craig (W. A. Craig, J. Redington, and S. C. Ebert, J. Antimicrob. Chemother. 27[Suppl. C]:29--40, 1991) neutropenic mouse thigh infection model. In Mueller-Hinton broth, the MICs for three S. aureus isolates were 0.1 to 0.2 microg/ml. In mouse serum, the MICs were 1.0 microg/ml. The protein binding of daptomycin was 90 to 92.5% in mouse serum. Single-dose intraperitoneal (i.p.) pharmacokinetic studies with infected mice showed a linear relationship between dose versus the maximum concentration of drug in serum and dose versus the area under the concentration-time curve (AUC). The serum half-life of daptomycin in infected mice was approximately 1.8 h. In single-dose, dose-ranging studies using mice, daptomycin showed a dose-response effect described by an inhibitory sigmoid E(max) (maximum effect) curve (r = 0.974; P < 0.001). The density of S. aureus in untreated controls was 8.26 log(10) CFU/g, and the E(max) was 3.97 log(10) CFU/g. The 50% effective dose (ED(50)) was 3.7 mg/kg of body weight i.p. and the stasis dose was 7.1 mg/kg. Dose fractionation studies at schedules of Q6h, Q12h, and Q24h, for total 24-h ED(30), ED(60), and ED(80) doses of 2.5, 5.6, and 15 mg/kg i.p., showed no difference in effect at each total 24-h dose level by schedule, indicating that the AUC/MIC ratio is the dynamically linked variable.     

Efficacy of human simulated exposures of ceftaroline administered at 600 milligrams every 12 hours against phenotypically diverse Staphylococcus aureus isolates

Ceftaroline exhibits bactericidal activity against Gram-positive pathogens, including methicillin-susceptible (MSSA) and methicillin-resistant (MRSA) Staphylococcus aureus, as well as common Gram-negative pathogens. This study evaluated the efficacy of human simulated exposures of ceftaroline against S. aureus in both the neutropenic and immunocompetent mouse thigh infection models. Twenty-six S. aureus isolates (4 MSSA, 22 MRSA) with ceftaroline MICs ranging from 0.125 to 4 μg/ml were collected. All isolates were tested in the neutropenic model and a subset of 13 MRSA isolates were tested in the immunocompetent model. Two hours after inoculation, a ceftaroline regimen that simulated the percentage of the dosing interval that free-drug concentrations remained above the MIC of the infecting organism (fT>MIC) of humans administered ceftaroline at 600 mg every 12 h (q12h) infused over 1 h was given. The change in log(10) CFU/ml after 24 h of treatment was analyzed relative to the 0- and 24-h controls for neutropenic and immunocompetent mice, respectively. The human simulated regimen resulted in efficacy against all isolates tested in both infection models. In the neutropenic model, a 0.95 to 3.28 log(10) CFU/ml reduction was observed when compared with the 0-h control, whereas for the immunocompetent model, all isolates obtained a >1 log(10) CFU/ml reduction (log(10) CFU/ml reduction range: 1.06 to 2.43) in bacterial density. Irrespective of immune competency, a reduction in bacterial density was observed at the highest MIC of 4 μg/ml (fT>MIC of 27.5%). Human simulated exposures of ceftaroline 600 mg q12h provided predictable efficacy against all tested S. aureus isolates in the mouse thigh model independent of immune status. These data support the clinical utility of ceftaroline against S. aureus, including MRSA, with MICs of ≤4 μg/ml.     

Chemotherapy of systemic murine infection due to beta-lactam antibiotic 'tolerant' and non-'tolerant' Staphylococcus aureus

Two in vitro beta-lactam antibiotic (oxacillin, cefotaxime) 'tolerant' (MBC:MIC ratios = greater than 32) strains of Staphylococcus aureus served to intraperitoneally infect cyclophosphamide-pretreated (leukopenic) NMRI mice. With larger bacterial inocula (approximately 5 X 10(8) CFU) neither oxacillin nor gentamicin or netilmicin yielded optimal chemotherapeutic results. Only combination chemotherapy, in particular oxacillin combined with netilmicin, consistently reduced mouse mortality significantly (p less than 0.001). In contrast, moderate 'tolerant' staphylococcal inocula (approximately 2 X 10(8) CFU) were amenable to chemotherapy with either oxacillin or netilmicin, but not with cefotaxime or gentamicin. Oxacillin combined with either gentamicin or netilmicin resulted in significantly lowered murine mortality rates (p less than 0.001). Cefotaxime combined with either aminoglycoside antibiotic gave less satisfactory results. Systemic murine infections due to three non-'tolerant' strains of S. aureus were amenable to chemotherapy with oxacillin, cefotaxime or netilmicin alone and to combination chemotherapy. It is recommended that cases of life-threatening S. aureus infection, not complicated by acute endocarditis, initially be treated with oxacillin plus netilmicin until availability of laboratory results (antibiogram, documentation of 'tolerance').     

Lysostaphin as a treatment for systemic Staphylococcus aureus infection in a mouse model

OBJECTIVES: With the isolation of clinical strains of Staphylococcus aureus carrying the gene that confers vancomycin resistance, the need for novel antistaphylococcals has become more urgent. Lysostaphin, an example of such a novel therapeutic, is an endopeptidase that rapidly lyses S. aureus through proteolysis of the staphylococcal cell wall. We evaluated its efficacy as a therapeutic agent for treatment of systemic S. aureus infection in a mouse model. METHODS: Mice (5-10 per group) challenged with methicillin-susceptible S. aureus developed bacteraemia and organ infections while mice challenged with methicillin-resistant S. aureus (MRSA) developed organ infections. The challenged mice received various intravenous doses of recombinant lysostaphin, administered once a day for 1-3 days when compared with treatment with oxacillin or vancomycin. Some mice also received treatment of lysostaphin combined with oxacillin or vancomycin. Following treatment, bacteraemia was determined, and mice were sacrificed and organ infection was determined. RESULTS AND CONCLUSIONS: Lysostaphin administered at 5 mg/kg once a day for 3 days consistently cleared S. aureus from the blood and the organs of infected mice. Furthermore, the combination of lysostaphin and oxacillin or vancomycin demonstrated increased efficacy against MRSA over lysostaphin alone allowing the therapeutic dose of lysostaphin to be reduced to 1 mg/kg. These results demonstrate that lysostaphin is an effective treatment for eradicating S. aureus from the blood and from the organs of infected mice.     

In vivo efficacies of levofloxacin and ciprofloxacin in acute murine hematogenous pyelonephritis induced by methicillin-susceptible and-resistant Staphylococcus aureus strains.

Levofloxacin, the active L-isomer of ofloxacin, has demonstrated strong activity against Staphylococcus aureus both in vitro and in vivo. In a murine model of hematogenous pyelonephritis, the in vivo efficacies of levofloxacin and ciprofloxacin were evaluated against two methicillin-susceptible and two methicillin-resistant S. aureus strains. All four isolates had virtually identical susceptibilities to levofloxacin and ciprofloxacin. Pyelonephritis was induced in carrageenan-primed mice by an intravenous injection of 0.5 ml of 10(7) CFU of methicillin-susceptible S. aureus isolates per ml or 10(8) CFU of methicillin-resistant S. aureus isolates per ml. At 1 h postinfection, the mice were treated orally with levofloxacin or ciprofloxacin once a day or twice a day (total daily dose of 20 to 160 mg/kg of body weight) for 4 days. Mice were euthanized 24 h after the final treatment, and the kidneys were excised and weighed. The kidneys were prepared for histological examination or were homogenized to determine the numbers of CFU per gram of tissue quantitatively. The reduction in the mean log10 number of CFU per gram as a function of total daily dose was recorded. A dose-response analysis showed that levofloxacin was superior to ciprofloxacin for all four isolates at any dose or regimen tested, independent of the methicillin susceptibility of the isolates. By using an inverse prediction technique, the equivalent effective doses of levofloxacin (once a day) were less than those of ciprofloxacin (twice a day) by 5.2 and 3.2 times, respectively, for methicillin-susceptible S. aureus 9039 and 3087. For methicillin-resistant S. aureus 667 and 2878, the equivalent effective doses of levofloxacin (once a day) were less than those of ciprofloxacin (twice a day) by 4.1 and 6.4 times, respectively. In a separate study, histological examination of all infected, untreated mice showed moderate to marked hematogenous pyelonephritis. Levofloxacin-treated mice (40 mg/kg once a day) showed no evidence of pyelonephritis in the kidneys, whereas the kidneys of mice treated with the same dose of ciprofloxacin showed only a reduction in the severity of the lesions. Treatment with ciprofloxacin (80 mg/kg twice a day) demonstrated a histology comparable to that of treatment with levofloxacin (40 mg/kg once a day). Levofloxacin (40 mg/kg once a day) reduced the log10 numbers of CFU per gram by 5 log10; however, ciprofloxacin (80 mg/kg twice a day) reduced the numbers of CFU per gram by only 3 log10. In the present murine model of pyelonephritis, levofloxacin was superior to ciprofloxacin in preventing pyelonephritis and eradicating S. aureus.     

Activity of ampicillin-sulbactam and oxacillin in experimental endocarditis caused by beta-lactamase-hyperproducing Staphylococcus aureus.

Using a rat model of aortic valve infective endocarditis, we previously found that oxacillin was equally effective against an oxacillin-susceptible strain of Staphylococcus aureus and a beta-lactamase-hyperproducing borderline oxacillin-susceptible strain of S. aureus; also, ampicillin-sulbactam was less effective than oxacillin against both isolates and at low doses was less effective against the borderline-susceptible strain than against the fully oxacillin-susceptible strain (C. Thauvin-Eliopoulos, L. B. Rice, G. M. Eliopoulos, and R. C. Moellering, Jr., Antimicrob. Agents Chemother. 34:728-732, 1990). In the present study, we extended this work, using alternative treatment schedules and additional bacterial strains. Extending treatment with low doses of ampicillin-sulbactam (500 and 250 mg/kg of body weight per day, respectively) to 6.5 days resulted in equalization of effectiveness against the previously studied strains BOSSA-1 and OSSA-1 (3.75 +/- 1.61 log10 and 4.71 +/- 1.79 log10 CFU of residual viable bacteria per g, respectively). Against the borderline oxacillin-susceptible strain BOSSA-1, increasing the sulbactam dosage from 500 to 2,000 mg/kg/day while maintaining a fixed dose of ampicillin (1,000 mg/kg/day) by continuous infusion resulted in lower bacterial counts (4.93 +/- 1.84 log10 versus 3.65 +/- 1.26 log10 CFU of residual viable bacteria per g, respectively), but this difference was of only borderline significance; differences in efficacy between the low-dose and high-dose sulbactam regimens were exaggerated when intermittent intravenous administration was used (6.19 +/- 1.90 log10 versus 3.37 +/- 1.41 log10 CFU/g, respectively; P < 0.001). However, for any individual sulbactam dosage, the model of administration (continuous versus intermittent infusion) did not affect the activity of the regimen. When additional strains were used in the model, oxacillin and ampicillin-sulbactam (1,000 plus 2,000 mg/kg/day) were equally effective against both oxacillin-susceptible and borderline oxacillin-resistant strains of S. aureus. These results support the predictions that oxacillin would be clinically effective in the treatment of infections caused by borderline oxacillin-susceptible strains of S. aureus and that, except at very low doses, ampicillin-sulbactam would also be as effective against borderline-susceptible strains as against fully oxacillin-susceptible strains of S. aureus.     

Experimental bacteriophage protection against Staphylococcus aureus abscesses in a rabbit model

In a rabbit model of wound infection caused by Staphylococcus aureus, 2 x 10(9) PFU of staphylococcal phage prevented abscess formation in rabbits when it was injected simultaneously with S. aureus (8 x 10(7) CFU) into the same subcutaneous site. Phage multiplied in the tissues. Phages might be a valuable prophylaxis against staphylococcal infection.     

In Vitro Characterization of PlySK1249, a Novel Phage Lysin,and Assessment of Its Antibacterial Activity in a Mouse Model of Streptococcus agalactiae Bacteremia

Beta-hemolytic Streptococcus agalactiae is the leading cause of bacteremia and invasive infections. These diseases are treated with β-lactams or macrolides, but the emergence of less susceptible and even fully resistant strains is a cause for concern. New bacteriophage lysins could be promising alternatives against such organisms. They hydrolyze the bacterial peptidoglycan at the end of the phage cycle, in order to release the phage progeny. By using a bioinformatic approach to screen several beta-hemolytic streptococci, a gene coding for a lysin was identified on a prophage carried by Streptococcus dysgalactiae subsp. equisimilis SK1249. The gene product, named PlySK1249, harbored an original three-domain structure with a central cell wall-binding domain surrounded by an N-terminal amidase and a C-terminal CHAP domain. Purified PlySK1249 was highly lytic and bactericidal for S. dysgalactiae (2-log₁₀ CFU/ml decrease within 15 min). Moreover, it also efficiently killed S. agalactiae (1.5-log₁₀ CFU/ml decrease within 15 min) but not several streptococcal commensal species. We further investigated the activity of PlySK1249 in a mouse model of S. agalactiae bacteremia. Eighty percent of the animals (n = 10) challenged intraperitoneally with 10⁶ CFU of S. agalactiae died within 72 h, whereas repeated injections of PlySK1249 (45 mg/kg 3 times within 24 h) significantly protected the mice (P < 0.01). Thus, PlySK1249, which was isolated from S. dysgalactiae, demonstrated high cross-lytic activity against S. agalactiae both in vitro and in vivo. These encouraging results indicated that PlySK1249 might represent a good candidate to be developed as a new enzybiotic for the treatment of systemic S. agalactiae infections.     

Successful single-dose prophylaxis of Staphylococcus aureus foreign body infections in guinea pigs by fleroxacin.

Single-dose administration of fleroxacin was evaluated as a means of preventing foreign body infection due to staphylococci. Tissue cages were implanted into guinea pigs and subsequently infected (100% rate) with 10(2) or more CFU of Staphylococcus aureus Wood 46. When a single dose of 30 mg of fleroxacin or vancomycin per kg of body weight was administered intraperitoneally, bactericidal levels of the antimicrobial agent were found in the tissue cage fluid after 3 h (when guinea pigs were inoculated with S. aureus) and during the next 24 h. Either fleroxacin or vancomycin successfully prevented experimental infection in all tissue cages challenged by 10(2) CFU of S. aureus Wood 46. When tissue cages were challenged with 10(4) CFU of S. aureus Wood 46, however, fleroxacin was more effective than vancomycin (P less than 0.05) in reducing colony counts below the detection limit of 10 CFU/ml in the inflammatory fluid of all tissue cages during the initial 48 h. In contrast to their initially different actions, the effects of the antibiotics were similar after 7 days, mostly because bacterial regrowth occurred more frequently in the fleroxacin-treated than in the vancomycin-treated tissue cages. These data show that experimental infections of subcutaneous tissue cages are a useful model for studying the prophylaxis of foreign body infections with antimicrobial agents.     

Evaluation of ceftaroline activity versus daptomycin (DAP) against DAP-nonsusceptible methicillin-resistant Staphylococcus aureus strains in an in vitro pharmacokinetic/pharmacodynamic model

The objective of this study was to investigate the potential role of ceftaroline, a new broad-spectrum cephalosporin, as a therapeutic option for the treatment of daptomycin-nonsusceptible (DNS) methicillin-resistant Staphylococcus aureus (MRSA) infections. Four clinical DNS MRSA strains, R5717, R5563, R5996 (heteroresistant vancomycin-intermediate S. aureus) and R5995 (vancomycin-intermediate S. aureus) were evaluated in a two-compartment hollow-fiber in vitro pharmacokinetic/pharmacodynamic model at a starting inoculum of 10(7) CFU/ml for 96 h. Simulated regimens were ceftaroline at 600 mg every 12 h (q12h) (maximum free-drug concentration [fC(max)], 15.2 μg/ml; serum half-life [t(1/2)], 2.3 h), daptomycin at 6 mg/kg q24h (fC(max), 7.9 μg/ml; t(1/2), 8 h), and daptomycin at 10 mg/kg q24h (fC(max), 15.2 μg/ml; t(1/2), 8 h). Differences in CFU/ml between 24 and 96 h were evaluated by analysis of variance with Tukey's post-hoc test. Bactericidal activity was defined as a ≥3-log(10) CFU/ml decrease in the colony count from the initial inoculum. The ceftaroline MIC values were 0.25, 0.5, 0.5, and 0.5 μg/ml, and the daptomycin MIC values were 2, 2, 4, and 4 μg/ml for R5717, R5563, R5996, and R5995, respectively. Ceftaroline displayed sustained bactericidal activity against 3 of the 4 strains at 96 h (R5717, -3.1 log(10) CFU/ml; R5563, -2.5 log(10) CFU/ml; R5996, -5.77 log(10) CFU/ml; R5995, -6.38 log(10) CFU/ml). Regrowth occurred during the daptomycin at 6-mg/kg q24h regimen (4 strains) and the daptomycin at 10-mg/kg q24h regimen (3 strains). At 96 h, ceftaroline was significantly more active, resulting in CFU/ml counts lower than those obtained with daptomycin at 6 mg/kg q24h (4 strains, P ≤ 0.008) and daptomycin at 10 mg/kg q24 h (3 strains, P ≤ 0.001). Isolates with increased MIC values for daptomycin (all 4 strains) but not for ceftaroline were recovered. Ceftaroline was effective against the 4 isolates tested and may provide a clinical option for the treatment of DNS MRSA infections.     

In vitro and in vivo antibacterial activities of heteroaryl isothiazolones against resistant gram-positive pathogens

The activities of several tricyclic heteroaryl isothiazolones (HITZs) against an assortment of gram-positive and gram-negative clinical isolates were assessed. These compounds target bacterial DNA replication and were found to possess broad-spectrum activities especially against gram-positive strains, including antibiotic-resistant staphylococci and streptococci. These included methicillin-resistant Staphylococcus aureus (MRSA), vancomycin-nonsusceptible staphylococci, and quinolone-resistant strains. The HITZs were more active than the comparator antimicrobials in most cases. For gram-negative bacteria, the tested compounds were less active against members of the family Enterobacteriaceae but showed exceptional potencies against Haemophilus influenzae, Moraxella catarrhalis, and Neisseria spp. Good activity against several anaerobes, as well as Legionella pneumophila and Mycoplasma pneumoniae, was also observed. Excellent bactericidal activity against staphylococci was observed in time-kill assays, with an approximately 3-log drop in the numbers of CFU/ml occurring after 4 h of exposure to compound. Postantibiotic effects (PAEs) of 2.0 and 1.7 h for methicillin-susceptible S. aureus and MRSA strains, respectively, were observed, and these were similar to those seen with moxifloxacin at 10x MIC. In vivo efficacy was demonstrated in murine infections by using sepsis and thigh infection models. The 50% protective doses were 相似文献   

Impact of Enterococcus faecalis on the bactericidal activities of arbekacin, daptomycin, linezolid, and tigecycline against methicillin-resistant Staphylococcus aureus in a mixed-pathogen pharmacodynamic model

We inoculated an in vitro pharmacodynamic model simultaneously with clinical isolates of methicillin-resistant Staphylococcus aureus and an enterocin-producing enterococcus (vancomycin-resistant Enterococcus faecalis, ampicillin susceptible) at 7 log10 CFU/ml to examine enterocin effects and antimicrobial activity on staphylococci. The investigated antimicrobial regimens were 100 mg arbekacin every 12 h (q12h), 6 mg daptomycin per kg of body weight/day, 600 mg linezolid q12h, and 100 mg tigecycline q24h alone and in combination (daptomycin, linezolid, and tigecycline) with arbekacin. Simulations were performed in triplicate; bacterial quantification occurred over 48 h, and development of resistance was evaluated throughout. When we evaluated the impact of antimicrobial activity against S. aureus alone, daptomycin demonstrated bactericidal activity (>or=3 log10 CFU/ml kill), whereas arbekacin, linezolid, and tigecycline displayed bacteriostatic activities (<3 log10 CFU/ml kill). In the mixed-pathogen model, early and distinctive stunting of S. aureus growth was noted (1.5 log CFU/ml difference) in the presence of enterocin-producing E. faecalis compared to growth controls run individually (P=0.02). Most noteworthy was that in the presence of enterocin-producing E. faecalis, bactericidal activity was observed with arbekacin and tigecycline and with the addition of arbekacin to linezolid. Antagonism was noted for the combination of tigecycline and arbekacin against S. aureus in the presence of enterocin-producing E. faecalis. Our research demonstrates that the inhibitory effect of E. faecalis contributed significantly to its overall antimicrobial impact on S. aureus. This contribution was enhanced or improved compared to the activity of each antimicrobial alone. Further research is warranted to determine the impact of polymicrobial infections on antimicrobial activity.     

UVC light prophylaxis for cutaneous wound infections in mice

UVC light has long been known to be highly germicidal but has not been much developed as a therapy for infections. This study investigated the potential of UVC light for the prophylaxis of infections developing in highly contaminated superficial cutaneous wounds. In vitro studies demonstrated that the pathogenic bacteria Pseudomonas aeruginosa and Staphylococcus aureus were inactivated at UVC light exposures much lower than those needed for a similar effect on mammalian keratinocytes. Mouse models of partial-thickness skin abrasions infected with bioluminescent P. aeruginosa and S. aureus were developed. Approximately 10(7) bacterial cells were inoculated onto wounds measuring 1.2 by 1.2 cm on the dorsal surfaces of mice. UVC light was delivered at 30 min after bacterial inoculation. It was found that for both bacterial infections, UVC light at a single radiant exposure of 2.59 J/cm(2) reduced the bacterial burden in the infected mouse wounds by approximately 10-fold in comparison to those in untreated mouse wounds (P < 0.00001). Furthermore, UVC light increased the survival rate of mice infected with P. aeruginosa by 58.3% (P = 0.0023) and increased the wound healing rate in mice infected with S. aureus by 31.2% (P < 0.00001). DNA lesions were observed in the UVC light-treated mouse wounds; however, the lesions were extensively repaired by 48 h after UVC light exposure. These results suggested that UVC light may be used for the prophylaxis of cutaneous wound infections.     

Daptomycin and tigecycline have broader effective dose ranges than vancomycin as prophylaxis against a Staphylococcus aureus surgical implant infection in mice

Vancomycin is widely used for intravenous prophylaxis against surgical implant infections. However, it is unclear whether alternative antibiotics used to treat methicillin-resistant Staphylococcus aureus (MRSA) infections are effective as prophylactic agents. The aim of this study was to compare the efficacies of vancomycin, daptomycin, and tigecycline as prophylactic therapy against a methicillin-sensitive S. aureus (MSSA) or MRSA surgical implant infection in mice. MSSA or MRSA was inoculated into the knee joints of mice in the presence of a surgically placed medical-grade metallic implant. The efficacies of low- versus high-dose vancomycin (10 versus 110 mg/kg), daptomycin (1 versus 10 mg/kg), and tigecycline (1 versus 10 mg/kg) intravenous prophylaxis were compared using in vivo bioluminescence imaging, ex vivo bacterial counts, and biofilm formation. High-dose vancomycin, daptomycin, and tigecycline resulted in similar reductions in bacterial burden and biofilm formation. In contrast, low-dose daptomycin and tigecycline were more effective than low-dose vancomycin against the implant infection. In this mouse model of surgical implant MSSA or MRSA infection, daptomycin and tigecycline prophylaxis were effective over a broader dosage range than vancomycin. Future studies in humans will be required to determine whether these broader effective dose ranges for daptomycin and tigecycline in mice translate to improved efficacy in preventing surgical implant infections in clinical practice.     

Efficacy of quinupristin-dalfopristin against methicillin-resistant Staphylococcus aureus and vancomycin-insensitive S. aureus in a model of hematogenous pulmonary infection

BACKGROUND: Quinupristin-dalfopristin (Q-D) is a mixture of quinupristin and dalfopristin, which are semisynthetic antibiotics of streptogramin groups B and A, respectively. METHODS: We compared the effect of Q-D to that of vancomycin (VCM) in murine models of hematogenous pulmonary infections caused by methicillin-resistant Staphylococcus aureus (MRSA) and VCM-insensitive S. aureus (VISA). RESULTS: Treatment with Q-D resulted in a significant decrease in the number of viable bacteria in the lungs of mice in an MRSA infection model [Q-D 100 mg/kg, Q-D 10 mg/kg, VCM and control (mean +/- SEM): 2.99 +/- 0.44, 6.38 +/- 0.32, 5.75 +/- 0.43 and 8.40 +/- 0.14 log10 CFU/lung, respectively]. Compared with VCM, high-dose Q-D significantly reduced the number of bacteria detected in the VISA hematogenous infection model [Q-D 100 mg/kg, Q-D 10 mg/kg, VCM and control (mean +/- SEM): 5.17 +/- 0.52, 7.03 +/- 0.11, 7.10 +/- 0.49 and 7.18 +/- 0.36 log10 CFU/lung, respectively]. Histopathological examination confirmed the effect of Q-D. CONCLUSION: Our results suggest that Q-D is potent and effective in the treatment of MRSA and VISA hematogenous pulmonary infections.     

Pretreatment with recombinant murine tumor necrosis factor alpha/cachectin and murine interleukin 1 alpha protects mice from lethal bacterial infection

Tumor necrosis factor/cachectin (TNF/C) is the principal mediator of bacterial endotoxin-induced shock and death. We found that the C3H/HeJ mouse, which is less able to produce TNF/C in response to endotoxin, has a 1,000-fold greater susceptibility to lethal infection with Escherichia coli than the TNF-responsive congenic mouse, C3H/HeN. This surprising finding suggested that this lethal peptide may also be involved in host protection. To test this hypothesis we pretreated the C3H/HeJ mouse with a combination of recombinant murine TNF/C-alpha and IL-1 alpha. This combination protected these mice against an intraperitoneal bacterial challenge of greater than 20 LD50S (nearly 2 x 10(2) CFU) that grew to a level of greater than 10(7) CFU/ml of blood and per gram of liver in untreated mice. This suggests a significant role for these cytokines in host defenses against invasive infections that require bacterial replication within the host. These protective mechanisms may not be important for less virulent organisms. These findings may have important implications for the proposed use of anti-TNF/C agents in the treatment of septic shock.     

Inhibition of biofilm formation by esomeprazole in Pseudomonas aeruginosa and Staphylococcus aureus

Staphylococcus aureus and Pseudomonas aeruginosa are common nosocomial pathogens responsible for biofilm-associated infections. Proton pump inhibitors (PPI), such as esomeprazole, may have novel antimicrobial properties. The objective of this study was to assess whether esomeprazole prevents sessile bacterial growth and biofilm formation and whether it may have synergistic killing effects with standard antibiotics. The antibiofilm activity of esomeprazole at 0.25 mM was tested against two strains each of S. aureus and P. aeruginosa. Bacterial biofilms were prepared using a commercially available 96-peg-plate Calgary biofilm device. Sessile bacterial CFU counts and biomass were assessed during 72 hours of esomeprazole exposure. The killing activities after an additional 24 hours of vancomycin (against S. aureus) and meropenem (against P. aeruginosa) treatment with or without preexposure to esomeprazole were also assessed by CFU and biomass analyses. P. aeruginosa and S. aureus strains exposed to esomeprazole displayed decreased sessile bacterial growth and biomass (P < 0.001, each parameter). After 72 h of exposure, there was a 1-log(10) decrease in the CFU/ml of esomeprazole-exposed P. aeruginosa and S. aureus strains compared to controls (P < 0.001). After 72 h of exposure, measured absorbance was 100% greater in P. aeruginosa control strains than in esomeprazole-exposed strains (P < 0.001). Increased killing and decreased biomass were observed for esomeprazole-treated bacteria compared to untreated controls exposed to conventional antibiotics (P < 0.001, each parameter). Reduced biofilm growth after 24 h was visibly apparent by light micrographs for P. aeruginosa and S. aureus isolates exposed to esomeprazole compared to untreated controls. In conclusion, esomeprazole demonstrated an antibiofilm effect against biofilm-producing S. aureus and P. aeruginosa.     

Efficacy of oxacillin and ampicillin-sulbactam combination in experimental endocarditis caused by beta-lactamase-hyperproducing Staphylococcus aureus.

Optimal therapy of infections caused by borderline oxacillin-susceptible, beta-lactamase-hyperproducing Staphylococcus aureus has not been established. We used a rat model of aortic valve endocarditis to examine efficacies of antibiotic regimens against a borderline oxacillin-susceptible strain as compared with a fully susceptible S. aureus strain. Animals were treated with oxacillin alone or in combination with sulbactam or with ampicillin-sulbactam combinations at two dose levels. Infections caused by the borderline susceptible and fully susceptible strains responded equally well to oxacillin alone, with residual bacterial titers in vegetations falling to 4.8 +/- 1.6 and 4.4 +/- 1.7 (mean +/- standard deviation) log10 CFU/g, respectively. Addition of sulbactam to oxacillin (1:2) did not enhance the efficacy of oxacillin against either strain in the animal model. A high-dose regimen of ampicillin-sulbactam (2:1) yielding mean (+/- standard deviation) levels in serum of 16.8 +/- 7.4 and 9.5 +/- 1.1 micrograms/ml, respectively, proved equally effective against both strains (bacterial titers, 6.6 log10 CFU/g). However, at lower doses (8.3 +/- 2.6 and 5.9 +/- 2.4 micrograms/ml, the combination showed greater efficacy against the fully susceptible strain, with residual titers of 7.1 +/- 2.0 versus 9.0 +/- 1.6 log10 CFU/g (P less than 0.05). In vitro studies revealed that the beta-lactamase inhibitor sulbactam was also a potent inducer of staphylococcal beta-lactamase at clinically relevant concentrations. Based on this short-term in vivo therapy study, oxacillin would be predicted to be clinically effective in the therapy of infections caused by borderline oxacillin-susceptible strains of S. aureus, while the combination of ampicillin with sulbactam appears to be inferior to oxacillin alone against such infections.