Kegg Pathway: Biosynthesis of vancomycin group antibiotics

Acta Paediatr Taiwan. 2007 Nov-Dec; 48(6): 309-16
Jeng MJ, Lee YS, Soong WJ

BACKGROUND: Acute lung injury, such as meconium aspiration syndrome in neonates, may present with exacerbated ventilation and perfusion abnormalities. This can impair the efficacy of intravenous antibiotic therapy in treating pulmonary infection. Intrapulmonary administration via perfluorochemical as a vehicle may adequately deliver drugs, such as the poorly pulmonary-penetrative antibiotic vancomycin, to affect lung regions while maintaining gas exchange and non-toxic serum level. METHODS: Twelve newborn piglets were injured with intra-tracheally installed human meconium, and randomly grouped into intravenous group (intravenous injection with vancomycin 15 mg/kg, followed by conventional gas ventilation) or intrapulmonary group (intrapulmonary instilled with vancomycin 15 mg/kg and perfluorochemical emulsion, followed by partial liquid ventilation). Blood samples were obtained to check vancomycin serum concentrations (0-240 mins). Lung tissues were tested for vancomycin contents. RESULTS: Intrapulmonary group animals had significantly lower vancomycin serum levels than the intravenous group, but vancomycin contents (198.9 +/- 72.5 microg/g dry tissue) in lung tissues was significantly higher than in the intravenous group (134.9 +/- 39.1 microg/g dry tissue) (p < 0.05). Gas exchange and lung compliance in the intrapulmonary group were also significantly better than in the intravenous group. CONCLUSIONS: Perfluorochemical is a good vehicle to deliver vancomycin and maintains gas exchange in severe meconium-injured lungs.

J Biol Chem. 2008 May 2; 283(18): 12354-64
Belcheva A, Golemi-Kotra D

Staphylococcus aureus remains a clinical scourge. Recent studies have revealed that S. aureus is capable of mounting a response to antibiotics that target cell wall peptidoglycan Biosynthesis, such as beta-lactams and vancomycin. A phosphotransfer-mediated signaling pathway composed of a histidine protein kinase, VraS, and a response regulator protein, VraR, has been linked to the coordination of this response. Herein, we report for the first time on the signal transduction mechanism of the VraSR system. We found that VraS is capable of undergoing autophosphorylation in vitro and its phosphoryl group is rapidly transferred to VraR. In addition, phosphorylated VraR undergoes rapid dephosphorylation by VraS. Evidence is presented that VraR has adopted a novel strategy in regulating the output response of the VraSR-mediated signaling pathway. The VraR effector domain inhibits formation of inactive VraR dimers and, in doing so, it holds the regulatory domain into an intermediate active state. We show that only phosphorylation induces formation of the biological active VraR-dimer species. Furthermore, we propose that damage inflicted to cell wall peptidoglycan could be the main source of the stimuli that VraR responds to due to the tight control that VraS has on the phosphorylation state of VraR. Our findings provide for the first time insights into the molecular basis for the proposed role of VraSR as a "sentinel" system capable of rapidly sensing cell wall peptidoglycan damage and coordinating a response that enhances the resistance phenotype in S. aureus.

Pediatr Infect Dis J. 2008 Apr; 27(4): 314-8
Le J, Nguyen T, Okamoto M, McKamy S, Lieberman JM

BACKGROUND: The neonatal intensive care unit at Miller Children's Hospital changed from empiric use of cefotaxime and vancomycin (CEF) to tobramycin and vancomycin (TOB) for hospital-acquired infections in November 1999 because of an increase in infections caused by extended-spectrum beta-lactamase (ESBL)-producing bacteria. The objectives of this study were to evaluate the incidence and impact of this change on the development of ESBL infections. METHODS: We retrospectively reviewed medical records of infants who received CEF or TOB between January 1998 and December 2002. A standardized form was used to collect demographic data, information on antibiotic use, and culture results. RESULTS: The mean gestational age and birth weight of the 250 infants were 28.8 +/- 4.0 weeks and 1213.1 +/- 662 g, respectively. There were no differences between infants who received CEF (N = 130) or TOB (N = 120) in terms of gestational age, birth weight, device use, invasive procedures, or prior antibiotic use. There were 11 ESBL infections. Infants in the CEF group were more likely than those in the TOB group to develop ESBL infection (7.8% versus 0.8%, P = 0.008). There were 11 deaths, with none attributed to ESBL infection. In a multivariate analysis, duration of prior ampicillin and gentamicin use and exposure to CEF were associated with ESBL infection [odds ratio (OR): 3.1, 95% confidence interval (CI): 1.28-7.49, P = 0.012; and OR: 33.7; 95% CI: 1.02-1136, P = 0.05, respectively]. CONCLUSIONS: The change from empiric use of CEF to TOB was associated with a significant decrease in the incidence of ESBL infections.

J Antimicrob Chemother. 2008 May; 61(5): 1099-102
Rose WE, Kaatz GW, Sakoulas G, Rybak MJ

OBJECTIVES: The accessory gene regulator (agr) has been identified as playing a role in the expression of reduced glycopeptide susceptibility in Staphylococcus aureus. Previous studies indicate that strains with agr dysfunctional group II polymorphism have a higher propensity for reduced vancomycin activity. We investigated this relationship in agr groups I-IV using another glycopeptide, teicoplanin, in an in vitro pharmacodynamic model. METHODS: Teicoplanin doses ranging from 1.88 to 30 mg/kg daily (fAUC/MIC 26.1-380.7) were simulated and evaluated for activity and the development of reduced susceptibility over 72 h. RESULTS: A dose-response relationship in activity was noted as doses escalated up to 30 mg/kg daily, but regrowth was identified with all doses. Teicoplanin doses of 3.75 and 1.88 mg/kg daily resulted in isolates with intermediate teicoplanin susceptibility (MIC = 16 mg/L) in agr groups II, IV (MIC = 16 mg/L) and III (MIC = 24 mg/L), regardless of function of the agr operon. Resistance to teicoplanin (> or = 32 mg/L) occurred in agr group I functional and dysfunctional isolates. Minimal changes in MIC were noted with 7.5 mg/kg daily doses in agr groups II-IV. However, this dose resulted in variable susceptibility (4-24 mg/L) in agr group I(+/-) isolates. Higher doses of 15 and 30 mg/kg daily did not produce changes in MIC in any isolate tested. CONCLUSIONS: Agr function did not determine teicoplanin resistance proclivity and is consistent with the previously described higher mutation rate in S. aureus to teicoplanin. Further investigation of agr group and function is warranted for all glycopeptides and compounds with a similar mechanism of action.

Biopolymers. 2008; 90(3): 421-32
Yao N, Wu CY, Xiao W, Lam KS

vancomycin, an important antibiotic against medically relevant gram-positive bacteria such as methicillin-resistant Staphylococcus aureus, exerts its antibacterial effects by binding with moderate affinity to the C-terminal Lys-D-Ala-D-Ala motif (Kaa) of the bacterial cell wall peptide precursor. Essential for Kaa binding to vancomcyin is the free-carboxyl group on the terminal D-Ala in Kaa. In efforts to identify other Kaa-based peptides which bind vancomycin with higher affinity, we utilized our one-bead-one-compound (OBOC) combinatorial library approach, a method which has been widely used to discover highly specific ligands against various receptors. In standard OBOC peptide libraries, the C-terminal end of the synthesized peptide is tethered to a solid-support/resin, however, this study reports development of a synthetic strategy for generating OBOC peptide libraries with a free D-Ala-D-Ala carboxyl end. We screened these "OBOC inverted" peptide libraries against vancomycin, and discovered a series of peptide ligands with strong consensus, which bind vancomycin. To further optimize these ligands, two highly focused Kaa-containing OBOC combinatorial peptidomimetic libraries were designed, synthesized, and screened against vancomycin under more stringent conditions. Peptidomimetic ligands which bind vancomycin with higher affinity than Kaa were identified. The dissociation constant of one of these ligands, Lys(Ac)-HOCit-Glu-Cha-Lys(3,5-dihydroxybenzoyl)-D-Ala-D-Ala (9), as determined by surface plasmon resonance, was 1.03 microM, roughly a 50-fold improvement in affinity compared to Kaa (K(D) = 50 microM).

Appl Environ Microbiol. 2008 Apr; 74(7): 1997-2003
Millette M, Cornut G, Dupont C, Shareck F, Archambault D, Lacroix M

This study demonstrated the capacity of bacteriocin-producing lactic acid bacteria (LAB) to reduce intestinal colonization by vancomycin-resistant enterococci (VRE) in a mouse model. Lactococcus lactis MM19 and Pediococcus acidilactici MM33 are bacteriocin producers isolated from human feces. The bacteriocin secreted by P. acidilactici is identical to pediocin PA-1/AcH, while PCR analysis demonstrated that L. lactis harbors the nisin Z gene. LAB were acid and bile tolerant when assayed under simulated gastrointestinal conditions. A well diffusion assay using supernatants from LAB demonstrated strong activity against a clinical isolate of VRE. A first in vivo study was done using C57BL/6 mice that received daily intragastric doses of L. lactis MM19, P. acidilactici MM33, P. acidilactici MM33A (a pediocin mutant that had lost its ability to produce pediocin), or phosphate-buffered saline (PBS) for 18 days. This study showed that L. lactis and P. acidilactici MM33A increased the concentrations of total LAB and anaerobes while P. acidilactici MM33 decreased the Enterobacteriaceae populations. A second in vivo study was done using VRE-colonized mice that received the same inocula as those in the previous study for 16 days. In L. lactis-fed mice, fecal VRE levels 1.73 and 2.50 log(10) CFU/g lower than those in the PBS group were observed at 1 and 3 days postinfection. In the P. acidilactici MM33-fed mice, no reduction was observed at 1 day postinfection but a reduction of 1.85 log(10) CFU/g was measured at 3 days postinfection. Levels of VRE in both groups of mice treated with bacteriocin-producing LAB were undetectable at 6 days postinfection. No significant difference in mice fed the pediocin-negative strain compared to the control group was observed. This is the first demonstration that human L. lactis and P. acidilactici nisin- and pediocin-producing strains can reduce VRE intestinal colonization.

Ther Drug Monit. 2008 Feb; 30(1): 103-7
Nakayama H, Echizen H, Tanaka M, Sato M, Orii T

Creatinine clearance-based nomograms are used routinely during the early phase of vancomycin therapy for individualizing doses. The authors studied whether such nomograms are also valid for patients receiving the drug for an extended period of longer than 4 weeks. A retrospective analysis was conducted on the therapeutic drug monitoring data obtained from 85 patients who received an intermittent intravenous infusion of vancomycin. The patients were allocated to one of five groups according to the length of drug exposure: group 1 (4-7 days; n = 31), group 2 (8-14 days; n = 22), group 3 (15-21 days; n = 13), group 4 (22-28 days; n = 8), and group 5 (longer than 29 days; n = 11). Systemic clearance of vancomycin and estimated creatinine clearance calculated by Cockcroft & Gault's formula obtained from groups 2 through 5 were compared with those from group 1. Patients who had received vancomycin for longer than 4 weeks (group 5) showed a significant (P < 0.05) reduction in systemic clearance of vancomycin by 50% compared with group 1, whereas creatinine clearance remained unchanged. This study demonstrated that prolonged administration of vancomycin for over 4 weeks may result in a more pronounced reduction in systematic clearance of vancomycin than creatinine clearance. Our data suggest that creatinine clearance-based nomograms for individualizing vancomycin doses should be used with caution in patients who require substantially prolonged drug exposure such as those with infective endocarditis.

Thorac Cardiovasc Surg. 2008 Feb; 56(1): 28-31
Basaran M, Kafali E, Ugurlucan M, Kalko Y, Selimoglu O, Us MH, Ogus TN

BACKGROUND: Sternal infection is a serious complication of cardiac surgery requiring resternotomy and radical debridement. In this experimental study, we aimed to test our hypothesis that the use of cyanoacrylate gluing (application of an acrylic resin, a monomer of cyanoacrylate molecules, which rapidly polymerizes in the presence of water, forming long, strong chains and joining the bonded surfaces together) together with systemic antimicrobial therapy will provide synergy for the treatment of sternal infection caused by methicillin-resistant Staphylococcus aureus (MRSA). METHODS: Forty Wistar albino rats were randomly divided into four groups: group I, uncontaminated sham group; group II, untreated contaminated control group; group III, contaminated group receiving only systemic vancomycin therapy; group IV, contaminated group treated with a combination of cyanoacrylate gluing and systemic vancomycin. Cyanoacrylate gluing was applied on the 3rd postoperative day and all rats alive at the end of 8th week were sacrificed. The degree of sternal infection was assessed histologically and also by quantitative culture analysis. RESULTS: Histological evaluation revealed that cyanoacrylate was degraded and replaced by connective tissue at the end of the 8th week. Culture analysis revealed that the average growth of microorganisms was significantly reduced in groups III and IV. In group IV, the reduction in the amount of growing microorganisms was found to be more pronounced and significantly lower than in groups II and III. CONCLUSION: Our experimental model suggests that cyanoacrylate gluing provides significant synergy for systemic antimicrobial therapy. However, further clinical trials are required in order to use this treatment modality safely in patients, even though our study demonstrated successful results in the treatment of mediastinitis and sternal osteomyelitis in rats.

Int J Antimicrob Agents. 2008 Apr; 31(4): 316-20
Brazier J, Chmelar D, Dubreuil L, Feierl G, Hedberg M, Kalenic S, Könönen E, Lundgren B, Malamou-Ladas H, Nagy E, Sullivan A, Nord CE,

Gram-positive anaerobic cocci (GPAC) are a heterogeneous group of microorganisms frequently isolated from local and systemic infections. In this study, the antimicrobial susceptibilities of clinical strains isolated in 10 European countries were investigated. After identification of 299 GPAC to species level, the minimum inhibitory concentrations of penicillin, imipenem, clindamycin, metronidazole, vancomycin and linezolid were determined by the agar dilution method according to the Clinical and Laboratory Standards Institute. The majority of isolates were identified as Finegoldia magna and Parvimonas micra (formerly Peptostreptococcus micros), isolated from skin and soft tissue infections. All isolates were susceptible to imipenem, metronidazole, vancomycin and linezolid. Twenty-one isolates (7%) were resistant to penicillin (n=13) and/or to clindamycin (n=12). Four isolates were resistant to both agents. The majority of resistant isolates were identified as F. magna and originated from blood, abscesses and soft tissue infections.

Antimicrob Agents Chemother. 2008 Mar; 52(3): 980-90
Muthaiyan A, Silverman JA, Jayaswal RK, Wilkinson BJ

Daptomycin is a lipopeptide antibiotic that has recently been approved for treatment of gram-positive bacterial infections. The mode of action of daptomycin is not yet entirely clear. To further understand the mechanism transcriptomic analysis of changes in gene expression in daptomycin-treated Staphylococcus aureus was carried out. The expression profile indicated that cell wall stress stimulon member genes (B. J. Wilkinson, A. Muthaiyan, and R. K. Jayaswal, Curr. Med. Chem. Anti-Infect. Agents 4:259-276, 2005) were significantly induced by daptomycin and by the cell wall-active antibiotics vancomycin and oxacillin. Comparison of the daptomycin response of a two-component cell wall stress stimulon regulator VraSR mutant, S. aureus KVR, to its parent N315 showed diminished expression of the cell wall stress stimulon in the mutant. Daptomycin has been proposed to cause membrane depolarization, and the transcriptional responses to carbonyl cyanide m-chlorophenylhydrazone (CCCP) and nisin were determined. Transcriptional profiles of the responses to these antimicrobial agents showed significantly different patterns compared to those of the cell wall-active antibiotics, including little or no induction of the cell wall stress stimulon. However, there were a significant number of genes induced by both CCCP and daptomycin that were not induced by oxacillin or vancomycin, so the daptomycin transcriptome probably reflected a membrane depolarizing activity of this antimicrobial also. The results indicate that inhibition of peptidoglycan Biosynthesis, either directly or indirectly, and membrane depolarization are parts of the mode of action of daptomycin.

Int J Clin Pharmacol Ther. 2007 Nov; 45(11): 592-7
Tanaka A, Suemaru K, Otsuka T, Ido K, Nishimiya T, Sakai I, Hasegawa H, Yasukawa M, Inoue T, Murase M, Araki H

OBJECTIVE: Some formulas using the serum cystatin C level to estimate the GFR have recently been reported. However, there has been no report of a serum cystatin C-based formula for adjusting the dosage of the drugs cleared by the kidney. In this study, we compared the predictive performance of the serum vancomycin trough concentration predicted using serum cystatin C-based formulas. METHOD: The data were collected from 158 hospitalized patients. Five formulas have been published to predict the GFR using serum cystatin C. The cystatin C-based formulas were divided into two groups, formulas with or without anthropometric data. We predicted the serum vancomycin trough concentrations using VCM-TDM S_edition ver. 1.00 software. RESULTS: In formulas with anthropometric data, the mean absolute error (MAE) using Hoek's formula was 2.38, the MAE using Grubb's 1 formula was 4.13, the MAE using Sjöström's formula was 2.90, and the MAE using Cockcroft and Gault formula based on creatinine was 4.42. On the other hand, in formulas without an anthropometric data group, the MAE using Larsson's formula was 3.07, and the MAE using Grubb's 2 formula was 3.63. CONCLUSION: These results suggested that Hoek's formula is the most useful formula for determining the initial dosage settings for vancomycin.

Antimicrob Agents Chemother. 2008 Feb; 52(2): 446-51
Garey KW, Lai D, Dao-Tran TK, Gentry LO, Hwang LY, Davis BR

The increased incidence of methicillin-resistant Staphylococcus aureus (MRSA), the emergence of community-acquired MRSA, and the continued high incidence of methicillin-resistant Staphylococcus epidermidis have required that certain institutions choose vancomycin for surgical prophylaxis. However, the data supporting the use of vancomycin for surgical prophylaxis are controversial. The purpose of this project was to assess the effect of the change from cefuroxime to vancomycin for surgical site infection (SSI) rates in patients undergoing coronary artery bypass graft (CABG) surgery. The monthly rates of SSIs from 2001 to 2005 were analyzed before and after a change from cefuroxime to vancomycin antibiotic prophylaxis in patients undergoing CABG by using an interrupted time series analysis. Patients who underwent cardiac valve replacement surgery and who had received vancomycin during the entire study period were used as a comparator group. A total of 6,465 patients underwent CABG surgery (n = 4,239) or valve replacement surgery (n = 2,226) during the study period. On average, the monthly SSI incidence rate in patients undergoing CABG surgery decreased by 2.1 cases per 100 surgeries after the switch from cefuroxime to vancomycin (P = 0.042) when patients undergoing valve replacement were used as a comparator group. The change in SSI rates was associated with a decrease in the incidence of infections caused by coagulase-negative Staphylococcus and MRSA isolates, with little change in the incidence of SSIs due to other gram-positive organisms or gram-negative organisms. In institutions with a high incidence of methicillin-resistant Staphylococcus species, this study provides evidence for the clinical efficacy of vancomycin prophylaxis for the prevention of postoperative SSIs in patients undergoing CABG surgery.

Pediatr Neurosurg. 2007; 43(6): 449-55
Jorgenson L, Reiter PD, Freeman JE, Winston KR, Fish D, McBride LA, Handler MH

OBJECTIVE/AIMS: To determine the cerebrospinal fluid concentrations and percent CNS penetration of intravenous vancomycin in patients with cerebrospinal devices at a pediatric institution. METHODS: We performed a prospective evaluation of intravenous (IV) vancomycin in patients who received a single prophylactic dose of vancomycin (15-20 mg/, maximum dose 1 g) prior to insertion of a CNS shunt (group I) or a therapeutic regimen (a dose of 10-20 mg/kg every 6-12 h) for a documented/suspected shunt infection (group II). Ventricular cerebrospinal fluid (VCSF) samples were taken during the procedure in group I and multiple serum and VCSF samples were collected in group II. Pharmacokinetic parameters were calculated using a one-compartment model, and percent CNS penetration was estimated using area-under-the-curve methodology. RESULTS: group I: 21 VCSF samples were analyzed from 19 patients (mean age 7.2 +/- 6.4 years). Over 40% of samples failed to have detectable vancomycin concentrations (range 0-2 microg/ml). group II: 6 patients (mean age 11 +/- 8.7 years) had VCSF concentrations ranging from nondetectable to 6.59 microg/ml (mean 2.48 +/- 0.52 microg/ml). Percent penetration ranged from 0.77 to 18%. CONCLUSIONS: Single-dose, pre-operative vancomycin results in low VCSF vancomycin concentrations and repeated dosing in patients with documented/presumed device infections yields variable CNS penetration.

J Korean Med Sci. 2007 Oct; 22(5): 791-4
Uh Y, Hwang GY, Jang IH, Kwon O, Kim HY, Yoon KJ

The aim of this study was to investigate antimicrobial susceptibilities and macrolide resistance mechanisms of beta-hemolytic viridans group streptococci (VGS) in a tertiary Korean hospital. Minimum inhibitory concentrations (MICs) of seven antimicrobials were determined for 103 beta-hemolytic VGS isolated from various specimens. The macrolide resistance mechanisms of erythromycin-resistant isolates were studied by the double disk test and polymerase chain reaction (PCR). The overall resistance rates of beta-hemolytic VGS were found to be 47.5% to tetracycline, 3.9% to chloramphenicol, 9.7% to erythromycin, and 6.8% to clindamycin, whereas all isolates were susceptible to penicillin G, ceftriaxone, and vancomycin. Among ten erythromycin-resistant isolates, six isolates expressed a constitutive MLS(B) (cMLS(B)) phenotype, and each of the two isolates expressed the M phenotype, and the inducible MLS(B) (iMLS(B)) phenotype. The resistance rates to erythromycin and clindamycin of beta-hemolytic VGS seemed to be lower than those of non-beta-hemolytic VGS in our hospital, although cMLSB phenotype carrying erm(B) was dominant in beta-hemolytic VGS.

Surg Neurol. 2008 Feb; 69(2): 126-9; discussion 129
Wang Q, Shi Z, Wang J, Shi G, Wang S, Zhou J

BACKGROUND: The purpose of this study was to investigate whether vancomycin CSF concentration can reach therapeutic level when administered intravenously after neurosurgical operation. METHODS: After patients were admitted to the ICU, vancomycin (1.0 g) was injected intravenously, and CSF was collected from either ventricular drainage (VD group, n = 9) or LPD (LPD group, n = 10). The CSF concentration of vancomycin was measured using HPLC. RESULTS: Peak concentration occurred at 15 to 30 minutes after venoclysis (6.24 +/- 3.46 mg/L in the VD group and 4.49 +/- 3.14 mg/L in the LPD group, respectively) and reached or even exceeded the MIC(90) for MRSA (2 mg/L) and MRCoNS (2 mg/L). Twelve hours later, CSF vancomycin concentration in the VD and LPD groups was 2.55 +/- 1.13 and 2.43 +/- 0.41 mg/L, respectively. CONCLUSIONS: Neurosurgical operation may disrupt the integrality of BBB so that vancomycin can penetrate through the BBB easily and reach therapeutic concentration of CSF when administered intravenously after operation. This finding suggests that vancomycin can be administered intravenously when used to treat intracranial infection after neurosugical operation.

J Microbiol Methods. 2007 Dec; 71(3): 305-11
Brady AJ, Kearney P, Tunney MM

A new generation of water soluble tetrazolium salts have recently become available and in this study we compared a colorimetric assay developed using one of these salts, 2-(2-methoxy-4-nitrophenyl)-3-(4-nitrophenyl)-5-(2, 4-disulfophenyl)-2H-tetrazolium, monosodium salt (WST-8), with a previously developed 2,3-bis [2-methyloxy-4-nitro-5-sulfophenyl]-2H-tetrazolium-5-carboxanilide (XTT) colorimetric assay to determine which agent is most suitable for use as a colorimetric indicator in susceptibility testing. The MICs of 6 antibiotics were determined for 33 staphylococci using both colorimetric assays and compared with those obtained using the British Society for Antimicrobial Chemotherapy reference broth microdilution method. Absolute categorical agreement between the reference and test methods ranged from 79% (cefuroxime) to 100% (vancomycin) for both assays. No minor or major errors occurred using either assay with very major errors ranging from zero (vancomycin) to seven (cefuroxime). Analysis of the distribution of differences in the log(2) dilution MIC results revealed overall agreement, within the accuracy limits of the standard test (+/-1 log(2) dilution), using the XTT and WST-8 assays of 98% and 88%, respectively. Further studies on 31 ESBL-producing isolates were performed using the XTT method with absolute categorical agreement ranging from 87% (nitrofurantoin) to 100% (ofloxacin and meropenem). No errors were noted for either ofloxacin or meropenem with overall agreement of 91%. The data suggests that XTT is more reliable and accurate than WST-8 for use in a rapid antimicrobial susceptibility test.

Clin Exp Pharmacol Physiol. 2007 Nov; 34(11): 1181-5
Cetin H, Olgar S, Oktem F, Ciris M, Uz E, Aslan C, Ozguner F

1. The aim of the present study was to investigate the role of oxidative stress in renal injury and to determine whether erythropoietin (EPO) acts as an anti-oxidant in vancomycin (VCM)-induced renal impairment. 2. Twenty-four rats were divided into three groups as follows: (i) control (group 1); (ii) VCM treated (group 2); and (iii) VCM + EPO treated (group 3). vancomycin (200 mg/kg, i.p.) was administered to groups 2 and 3 for 7 days. Erythropoietin (150 IU/kg, i.p.) treatment was started 24 h before VCM and lasted for 7 days. On Day 8, renal tissues were excised and blood samples were collected. Serum creatinine and blood urea nitrogen were measured, along with renal malondialdehyde (MDA) levels, superoxide dismutase (SOD) and catalase (CAT) activity and tissue VCM levels. The kidneys were examined for any histopathological changes. 3. Renal MDA levels were found to be increased, whereas SOD and CAT activity was decreased, in the VCM-treated group compared with the control group. There was a marked decrease in MDA levels and an increase in SOD activity, but not CAT activity, after VCM + EPO treatment. Marked histopathological alterations, including interstitial oedema, tubular dilatation, tubular epithelial cell desquamation and vacuolization, were observed in VCM-treated rats. Histopathological changes were significantly improved after EPO administration. 4. In conclusion, the present data suggest that oxidative stress plays an important role in VCM-induced nephrotoxicity. Erythropoietin seems to act as an anti-oxidant, diminishing the toxic oxidative effects of VCM on renal tissues.

Clinics. 2007 Aug; 62(4): 405-10
Machado JK, Feferbaum R, Kobayashi CE, Sanches C, Santos SR

OBJETIVE: The objective of the present study was to evaluate the kinetic disposition of vancomycin in preterm infants with emphasis on the apparent volume of distribution, biological half-life, and total body clearance as well as whether their variations cause significant modification of the trough plasma concentration of the drug, depending on the postconceptional age (PCA) and the postnatal age (PNA). MATERIAL AND METHOD: Twenty-five selected patients were distributed into 2 groups which differed significantly in terms of mean PCA (31.2-32.3 weeks in group 1, n = 13; 33.5-34.1 weeks in group 2, n = 12: CI95%, P < .001) and PNA (group 1, 12.0-18.5 days; group 2, 18.0-34.0 days, CI95%, P < .05). The parents were informed and signed a written consent for participation of the infants in the protocol that had been previously approved by the Ethics Committee of the hospital. RESULTS: Apparent volume of distribution was significantly increased in group 1 compared with patients of group 2 (0.85 vs. 0.56 L/kg, respectively; P = .01,). Additionally multiple linear regression revealed a good linear correlation (r = 0.85) of trough plasma concentration of vancomycin with the apparent volume of distribution and also with the biological half-life in patients of group 1, while a good correlation (r = 0.91) was obtained for the trough plasma concentration with total body clearance in infants of group 2. The influence of these kinetic parameters on the trough concentration of vancomycin in preterm infants seems to vary according to PCA and PNA. CONCLUSION: In conclusion, the trough plasma concentration of vancomycin depends on the pharmacokinetics, and multiple linear correlation indicates that it varies according to the postconceptional and postnatal age of preterm infants.

Antimicrob Agents Chemother. 2007 Sep; 51(9): 3199-204
Cai XZ, Yan SG, Wu HB, He RX, Dai XS, Chen HX, Yan RJ, Zhao XH

This study sought to investigate the effect of delayed pulsed-wave ultrasound with low frequency on drug release from and the antimicrobial efficacy of vancomycin-loaded acrylic bone cement in vivo and the possible mechanism of this effect. After the implantation of cement and the inoculation of Staphylococcus aureus into the bilateral hips of rabbits, ultrasound (average intensity, 300 mW/cm(2); frequency, 46.5 kHz; on/off ratio, 20 min/10 min) was applied to animals in the normal ultrasound group (UG(0-12)) from 0 through 12 h after surgery and to those in the delayed-ultrasound group (UG(12-24)) from 12 through 24 h after surgery. The control group (CG) was not exposed to ultrasound. Based on vancomycin concentrations in left hip cavities at projected time intervals, the amount of time during which the local drug concentration exceeded the MIC (T(>MIC)) in UG(12-24) was significantly prolonged compared with that in either CG or UG(0-12), and the ratios between the areas under the concentration-time curves over 24 h and the MIC for UG(0-12) and UG(12-24) were both increased compared with that for CG. The greatest reductions in bacterial densities in both right hip aspirates and right femoral tissues at 48 h were achieved with UG(12-24). Local hemorrhage in rabbits of UG(0-12) during the 12-h insonation was more severe than that in rabbits of UG(12-24). Of four variables, the T(>MIC) and the bioacoustic effect were both identified as parameters predictive of the enhancement of the antimicrobial efficacy of cement by ultrasound. Sustained concentrations above the MIC replaced early high maximum concentrations and long-term subtherapeutic release of the drug, provided that ultrasound was not applied until local hemorrhage was relieved. The enhancement of the antimicrobial efficacy of cement by ultrasound may be attributed to the prolonged T(>MIC) and the bioacoustic effect caused by ultrasound.

BMC Infect Dis. 2007; 7: 69
Kulwichit W, Nilgate S, Chatsuwan T, Krajiw S, Unhasuta C, Chongthaleong A

BACKGROUND: Commercial diagnostics are commonly used to identify gram-positive bacteria. Errors have been reported mostly at the species level. We have found certain phenotypic criteria used in API systems which significantly misidentify Leuconostoc, an emerging human pathogen, at the genus level. We also attempt to find practical, conventional phenotypic assays for accurate identification of this group of bacteria. METHODS: Clinical isolates of catalase-negative, gram-positive coccoid or coccobacillary bacteria with non-beta hemolysis in our institute during 1997-2004 were subject to an identification aid by API 20 STREP, following the instruction manual, as an aid to conventional phenotypic tests. Those identified as Leuconostoc by API 20 STREP were re-examined by the same kit and also by API 50 CHL according to the instruction manuals, by our Leuconostoc conventional phenotypic assays, by Leuconostoc- and Lactobacillus-specific PCR's, and, where possible, by 16S rDNA sequence analysis. In addition, catalase-negative gram-positive isolates during 2005-2006 which were resistant to vancomycin at high levels were also evaluated by the same phenotypic and genotypic assays. RESULTS: Out of several thousands of clinical gram-positive isolates, 26 catalase negative gram-positive isolates initially identified as Leuconostoc by API 20 STREP and 7 vancomycin-resistant gram-positive catalase-negative bacteria entered the study. 11 out of the 26 isolates and all the 7 isolates were identified as Leuconostoc by API 20 STREP. Only 5 isolates, however, were confirmed by both genotypic and all defined conventional phenotypic criteria. API 50 CHL also failed to reliably provide accurate identification of Leuconostoc. We have identified key problem tests in API 20 STREP leading to misidentification of the bacteria. A simple, conventional set of phenotypic tests for Leuconostoc identification is proposed. CONCLUSION: The current API systems cannot accurately identify Leuconostoc. Identification of vancomycin-resistant, catalase-negative gram-positive bacteria should be performed by a few practical phenotypic assays, with assistance of genotypic assays where available.