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Pharmacokinetics and administration regimens of vancomycin in neonates, infants and children.

The increased use of vancomycin in neonatal and paediatric patients has prompted numerous pharmacokinetic studies and the development of many empirical administration methods. The majority of dosage guidelines use the relationship between pharmacokinetic parameters and patient variables such as chronological age, bodyweight, and/or measures of renal function. Currently, those dosage guidelines which are based upon postconceptional age and bodyweight seem to provide the best options for empirical administration in neonates and infants. In addition, serum creatinine may prove to be a useful guide to the empirical administration of vancomycin in neonates older than 7 to 14 days. Several investigators have reported the individualisation of dosage regimens based on pharmacokinetic-based administration methods. The most common techniques employed have been Sawchuk-Zaske method and Bayesian forecasting. However, only a limited number of studies have evaluated either empirical administration or individualised administration techniques in patient populations outside those of the original reports; this makes choosing between the methods difficult. Pharmacokinetic data and administration recommendations have gradually become available in special paediatric patient populations. The majority of studies have focused on patients requiring cardiopulmonary bypass surgery or with burns, cancer or central nervous system infections. However, a limited amount of information is available regarding vancomycin disposition in children older than 1 year of age with and without end-stage renal failure. The monitoring of serum vancomycin concentrations may be useful in selected neonatal and paediatric patient populations, especially where large interpatient variability occurs and administration guidelines are not clearly established. Similar to the literature on adults, the lack of conclusive evidence concerning the relationship between serum vancomycin concentrations and therapeutic responses leaves this topic open to debate.

Anti-Bacterial Agents↗

Successful vancomycin desensitization with a combination of rapid and slow infusion methods.

Vancomycin, an antibiotic to which methicillin-resistant Staphylococcus aureus (MRSA) is sensitive, frequently induces hypersensitivity reactions. Lowering the vancomycin infusion rate and/or premedicating with antihistamine effectively reduce hypersensitivity in most cases. However, vancomycin desensitization is sometimes the only way to ensure safe use. Two types of desensitization protocols have been reported, and these utilize different infusion intervals; rapid desensitization and slow desensitization. We herein report a case of vancomycin hypersensitivity with methicillin-resistant Staphylococcus aureus infection. A combination of the two desensitization protocols, rapid desensitization followed by slow desensitization, effectively inhibited the hypersensitivity reaction during vancomycin infusion, and methicillin-resistant Staphylococcus aureus was successfully eradicated.

Adult↗

Multivalent vancomycins and related antibiotics against infectious diseases.

This review discusses the recent development of multivalent antibiotics as potential therapeutic agents against infections caused by antimicrobial drug resistant microbes. The discussion focuses on vancomycin because of its important clinical relevance and well-elucidated molecular mechanism of antimicrobial drug resistance. The first section recounts the increased occurrence of vancomycin resistance in the world; the second section briefly discusses the mechanistic study of vancomycin resistance; the third section presents the currently established design principles of multivalent vancomycins; the fourth section examines the structural-activity relationships of multivalent vancomycins; the fifth section describes relevant studies on multivalent antibiotics; and the last section summarizes advantages and limitations of multivalent antibiotics.

Anti-Bacterial Agents↗

Vancomycin-induced Stevens-Johnson syndrome.

Stevens-Johnson syndrome is a rare immunologic reaction that may involve skin or various mucosal surfaces. The etiology may range from multiple pharmacologic agents to viral infections. Associated findings can range from minimal skin and mucosal involvement to extensive dermal exfoliation, nephritis, lymphadenopathy, hepatitis, and multiple serologic abnormalities. We report a 36 year-old caucasian male who developed a pruritic, raised maculopapular eruption on Day 17 of intravenous vancomycin for treatment of probable bacterial endocarditis. The vancomycin was discontinued. The patient had received a prosthetic aortic valve subsequent to acute rheumatic valve disease 20 years earlier, but had been well until development of endocarditis. The rash became more extensive to involve the torso, abdomen, legs, and arms. His fever persisted, and he developed neutropenia and eosinophilia. Axillary and inguinal lymphadenopathy, pharyngeal irritation, lip swelling, conjunctival injection, and elevated liver function studies also developed following cessation of the vancomycin. Eight days after eruption and fever began, corticosteroid therapy was instituted, with subsequent improvement of symptoms in less than 24 hours. Allergic reactions to vancomycin have included Stevens-Johnson syndrome rarely, and only one other case of adenopathy has been recorded. Most reactions have been in patients with severe renal insufficiency. We believe this patient is the first case of vancomycin-induced Stevens-Johnson syndrome in a previously healthy patient to be complicated by lymphadenopathy, hepatitis, and multiple serologic abnormalities.

Adult↗

Vancomycin-resistant Enterococcus faecalis in a bone-marrow transplant recipient.

Since 1988 a number of reports on the emergence of vancomycin-resistant enterococci have been published. We describe an additional case of colonization of and subsequent infection with a vancomycin-resistant Enterococcus faecalis in a bone-marrow transplant recipient, who had never before received vancomycin therapy. The strain was resistant to most antibiotics tested, including low-level resistance to gentamicin and cross-resistance to teicoplanin. It was sensitive to amoxicillin and the lipopeptide antibiotic daptomycin. The origin, the mode of acquisition and the incidence of vancomycin-resistant enterococci are still unknown. The clinical and bacteriological features of the cases reported thus far and the genetic and biochemical basis of vancomycin resistance are discussed.

Adult↗

Incorporation and release of vancomycin from poly(D,L-lactide-co-glycolide) microspheres.

Spherical monolithic microspheres, with a honeycomb-like internal architecture, composed of PLCG 50:50 and PLCG 75:25 and containing a range of vancomycin loadings, have been fabricated using a W/O emulsification with solvent evaporation technique. Microspheres were generated in high yield (80 wgt%) and vancomycin incorporation, confirmed using the displacement of DSC thermograms, had no significant effect on microsphere size distribution (5-50 microns). The vancomycin encapsulation efficiency was high (> 64%) and release profiles were characterized by a substantial initial burst release and a subsequent low-level sustained release extending up to 30 days depending upon the fabrication polymer, % vancomycin loading and incubation medium used. In both Hank's buffer and newborn calf serum the mean total cumulative release of vancomycin from microspheres increased significantly with theoretical percentage loading.

Animals↗

Multiple-dose activated charcoal in an accidental vancomycin overdose.

BACKGROUND: Multiple-dose activated charcoal may enhance the enterocapillary clearance of vancomycin. CASE REPORT: A 17-day-old female neonate born with congenital meningomyelocele and Arnold-Chiari malformation was iatrogenically overdosed with a 500 mg intravenous bolus of vancomycin during a shunt operation. The Red Man's Syndrome developed within minutes, characterized by sudden hypotension, skin rash and cyanosis. Serum vancomycin level at one hour after the injection was 165.7 micrograms/mL, as measured by an enzyme immunoassay method (EMIT). Multiple dose activated charcoal, 1 g/kg, was first given five hours after injection, and continued every four hours for 12 doses. The half-life of vancomycin during charcoal administration was calculated to be 9.4 h or less than the reported 13.4-33.7 h half-life in normal neonates. The neonate's renal function tests and brainstem auditory responses remained normal. CONCLUSIONS: Gastrointestinal dialysis with multiple-dose activated charcoal without cathartics appeared to shorten the elimination half-life of vancomycin.

Anti-Bacterial Agents↗

Nosocomial infection with vancomycin-dependent enterococci.

We report three patients infected with unique strains of vancomycin-dependent enterococci. Two were first infected by genetically identical strains of vancomycin-resistant enterococci (VRE). All three patients had much greater exposure to vancomycin and third-generation cephalosporins than did two control groups (patients infected with VRE and hospitalized patients without enterococcal infections). While antimicrobial pressure promotes nosocomial colonization by VRE, prolonged exposure to vancomycin may foster the transition from vancomycin resistance to dependence.

Anti-Bacterial Agents↗

A case of hypersensitivity syndrome to both vancomycin and teicoplanin.

Drug hypersensitivity syndrome to both vancomycin and teicoplanin has not been previously reported. We describe here a 50-yr-old male patient with vertebral osteomyelitis and epidural abscess who developed hypersensitivity syndrome to both vancomycin and teicoplanin. Skin rash, fever, eosinophilia, interstitial pneumonitis, and interstitial nephritis developed following the administration of each drug, and resolved after withdrawing the drugs and treating with high dose corticosteroids. The vertebral osteomyelitis was successfully treated with 6-week course of linezolid without further complications. Skin patch tests for vancomycin and teicoplanin was done 2 months after the recovery; a weak positive result for vancomycin (10% aq.,+at D2 and +at D4 with erythema and vesicles; ICDRG scale), and a doubtful result for teicoplanin (4% aq.-at D2 and+/-at D4 with macular erythema; ICDRG scale). We present this case to alert clinicians to the hypersensitivity syndrome that can result from vancomycin and teicoplanin, with possible cross-reactivity, which could potentially be life-threatening.

Drug Combinations↗

Detection of vancomycin resistant Staphylococcus aureus: a comparative study of three different phenotypic screening methods.

The objective of this study was to investigate screening methodologies, to detect Staphylococcus aureus strains with decreased susceptibility to vancomycin. Three methods were used to screen 160 Staphylococcus aureus clinical isolates along with ATCC quality control strains. Subsequently, MIC of all these 160 strains were determined by NCCLS methodology. The MIC of all the 160 clinical isolates was < or = 4 microg/mL and were classified as vancomycin susceptible by NCCLS criteria but 23 strains were positive by Hiramatshu method, two grew on MHA (5 microg/mL vancomycin) while CDC method correctly identified no vancomycin intermediate S.aureus (VISA) or vancomycin resistant S.aureus (VRSA) strains with reference to there MIC. CDC method was found to be the most appropriate screening methodology for detection of VISA or VRSA for diagnostic laboratories.

Bacteriological Techniques↗

Vancomycin and teicoplanin: something old, something new.

OBJECTIVE: To compare and contrast the pharmacology, activity and clinical efficacy of two glycopeptide antibiotics, vancomycin and teicoplanin. DATA SOURCES: English language literature search using MEDLINE, Index Medicus, relevant textbooks and product information literature. STUDY SELECTION: Over 200 publications were examined extending back to the period of initial Phase I trials with vancomycin. DATA EXTRACTION AND SYNTHESIS: Many publications covered similar ground and came to the same conclusions. In these instances one or two of the best pieces were chosen as cited reference material. Conflicting results and conclusions are discussed and an attempt is made to interpret the findings. CONCLUSION: Vancomycin and teicoplanin show differences in activity both in vitro and in vivo. Vancomycin is superior against coagulase-negative staphylococci and reliable dosage regimens are available. Teicoplanin, however, needs to be given in significantly larger doses than initially thought necessary to maximise clinical efficacy. Teicoplanin has a lower incidence of side effects but in clinical practice this advantage is small. Vancomycin remains the glycopeptide of choice for the treatment of infections due to Gram-positive bacteria.

Anti-Bacterial Agents↗

Gram-positive infections and the use of vancomycin in 550 episodes of fever and neutropenia.

STUDY OBJECTIVE: To determine the appropriate role for vancomycin in neutropenic patients with cancer. To review the incidence, types, and outcome of gram-positive infections in a series of neutropenic patients with cancer. DESIGN: Retrospective review. SETTING: Inpatient units of the Medical and Pediatric Oncology Branches of the National Cancer Institute. PATIENTS: Five hundred and fifty consecutive episodes of fever and neutropenia in patients with cancer randomized prospectively on another study to receive either ceftazidime alone or combination antibiotics for initial empirical therapy. INTERVENTION: Intravenous vancomycin (dosage adjusted by serum levels). MEASUREMENTS AND MAIN RESULTS: Gram-positive organisms were the commonest of the bacterial pathogens isolated (63%). Of the 53 gram-positive organisms accounting for primary infections (isolated at initial presentation), there were 36 staphylococcal isolates (19 coagulase-negative and 17 coagulase-positive), 13 streptococcal isolates (8 non-group D and 5 group D), and 4 polymicrobial isolates. Of the 22 secondary gram-positive infections (occurring after institution of initial antibiotics), there were 10 streptococcal isolates (9 group D and 1 non-group D), 7 staphylococcal isolates (6 coagulase-negative and 1 coagulase-positive), and 5 polymicrobial isolates. Vancomycin was used to treat 26 of the 53 primary infections, but was begun only after knowledge of the isolate in 25. Vancomycin was used to treat 17 of the 22 secondary infections, and begun only after knowledge of the isolate in 14. This approach resulted in no treatment failures for the primary infections, and a single microbiological failure for the secondary infections. There was a tendency towards a greater proportion of secondary gram-positive infections in the monotherapy group compared to the combination therapy group (16 of 282 compared with 6 of 268 respectively, P2 = 0.04 by the chi-squared test); but all were treated successfully. CONCLUSION: Vancomycin need not be included in routine empirical therapy for febrile neutropenic patients, but should be added when clinical or microbiological data suggest the need.

Agranulocytosis↗

Vancomycin therapy in patients with impaired renal function: a nomogram for dosage.

The relation between vancomycin clearance and renal function was studied in 22 patients with various degrees of renal functional impairment and in four normal volunteers. Clearance of vancomycin and creatinine were highly correlated (r = 0.92) among 17 persons not on dialysis. In five dialysis patients vancomycin clearance averaged 0.086 mL/min . kg of body weight (+/- SEM = 0.025). These relations enabled us to construct a nomogram for vancomycin dosage adjustment (based on a mean steady-state serum vancomycin concentration of 15 micrograms/mL) in patients with various degrees of renal functional impairment.

Adolescent↗

A vancomycin drug use evaluation and economic analysis in a cancer treatment centre.

Princess Margaret Hospital is a 140-bed university affiliated cancer treatment centre. Vancomycin was the only formulary agent available for the treatment of methicillin-resistant gram-positive organisms. The high cost and potential toxicity of this drug warranted a closer examination of its use. The purpose of this study was to evaluate vancomycin use and to determine the economic impact when it was used contrary to newly developed hospital guidelines. A sample of 100 vancomycin orders was randomly selected from all prescriptions filled in 1992. The indication, dose, and duration of therapy for each order were compared against the hospital guidelines. The cost savings associated with altering the sample of prescriptions to meet hospital guidelines were then determined. Nine percent of the prescriptions were for nonapproved indications. The actual dose used did not meet criteria in 32% of cases and the length of therapy was beyond the approved duration in 45% of the orders. If the cases had been altered to meet the guidelines then a total savings of $13,581 would have been realized. The projected savings for the entire year (1992) would have been $100,907. The critical problem areas in vancomycin prescribing were the duration of therapy and dose. The results have provided the impetus to initiate a hospital wide prospective Drug Utilization Evaluation (DUE) study to optimize vancomycin prescribing. The program costs would be easily covered by the expected savings.

Cancer Care Facilities↗

Randomized prospective study comparing cost-effectiveness of teicoplanin and vancomycin as second-line empiric therapy for infection in neutropenic patients.

BACKGROUND AND OBJECTIVE: The current health-care philosophy dictates that new therapies should always be evaluated for their economic impact. Along with acquisition cost, the cost of delivery, monitoring, adverse effects and treatment failure must also be considered when determining the total cost of therapy. These auxiliary costs can be significant and greatly alter the overall cost of a drug treatment. We conducted a prospective randomized study to evaluate the efficacy, safety and cost of vancomycin and teicoplanin therapy in patients with neutropenia, after the failure of empirical treatment with a combination of piperacillin/tazobactam and amikacin. DESIGN AND METHODS: Seventy-six febrile episodes from 66 patients with hematologic malignancies under treatment, neutropenia (neutrophils <500/mm3) and fever (38 degrees C twice or 38.5 degrees C once) resistant to the combination piperacillin/tazobactam and amikacin were included in the study. RESULTS: Primary success of second-line therapy was obtained in 35 cases (46%) with no significant difference between vancomycin (17/38) and teicoplanin arms (18/38). No difference in renal or hepatic toxicity related to the antibiotic therapy was observed. The average cost per patient according to glycopeptide used was $450+/-180 for the teicoplanin group and $473+/-347 for the vancomycin group. Interestingly, in the teicoplanin arm, drug acquisition accounted for 97% of the total cost, while in the vancomycin arm administration and monitoring play an important role in overall costs. INTERPRETATION AND CONCLUSIONS: In conclusion, our pharmacoeconomic analysis demonstrates that teicoplanin and vancomycin can be administered in neutropenic hematologic patients with similar efficacy and direct costs.

Amikacin↗

Problems and perils of vancomycin resistant enterococci.

Enterococci have been a therapeutic challenge for haIfa century; first in the management of endocarditis, then associated with the emergence of resistance to streptomycin and later to all aminoglycosides, and now with the increasing levels of resistance to penicillins. A major leap in the problem of antimicrobial resistance occurred more than a decade ago when vancomycin resistant enterococci (VRE) were first identified. This resulted from the acquisition by Enterococcus faecium of vancomycin resistant genes. Five types of vancomycin resistance have since been described (VanA-VanE) and others also appear to exist. VanA and VanB are caused by complex gene clusters that may be plasmid and/or transposon encoded. As a result of the gene cluster, cell wall precursors in the bacteria are formed that do not allow effective vancomycin binding, thus the action of vancomycin to inhibit cell wall synthesis is prevented. Therapy of infections caused by VRE is difficult, but a number of potentially effective antibiotics are now being tested in humans, including quinupristin/dalfopristin, linezolid, evernimomycin, daptomycin and LY333328. Combinations of antibiotics such as ampicillin with quinupristin/dalfopristin or with imipenem, and newer fluoroquinolones are also being evaluated. Until the time when these drugs become available, we must rely on careful monitoring of microbial transmission in hospitals, and we must utilize multi-faceted approaches to prevent the increase in the number and spread of VRE.

Enterococcus↗

[Vancomycin and teicoplanin use as antibiotic prophylaxis in cardiac surgery: pharmacoeconomic study].

BACKGROUND: To assess the economical impact of vancomycin use versus teicoplanin use as antibiotic prophylaxis for patients undergoing cardiac surgery for valve replacement (VR) and coronary artery by-pass (CABS) procedures. PATIENTS AND METHODS: This is an ancillary cost minimization analysis of a double blinded, parallel groups, randomised clinical trial (RCT), with the main objective of comparing the safety and efficacy of these antibiotics. 500 patients were included in the study; 267 in the CABS group and 233 in the VR group. The CABS patients received 1 g vancomicin or 400 mg teicoplanin, plus 150 mg netilmicin. The VR group received a second dose of each drug after extracorporeal circulation. In order to calculate the costs we considered the direct cost of the drug, the i.v. mix and the administration costs, together with personnel and structure costs. We considered two different situations: the administration of drugs within the surgical room theatre and in the medical ward. RESULTS: The demographic data of both groups were comparable. The frequency of severe adverse drug reactions (ADR) were similar (0.4%) in both groups, as well as the post-operative infection rates (8.6%). Differences were seen in the frequencies of low severity ADRs: 20.4% in the vancomycin group and 1.6% in the teicoplanin group. When the antibiotics were administered in the surgical room, among CABS patients the costs were 8,265 pts. for the teicoplanin group and 12,005 pts. for the vancomycin group; while among VR patients, costs were respectively 11,661 pts. and 14,528 pts. Administration costs of teicoplanin and vancomycin within a medical ward setting, however, the costs were 6,740 pts. and 2,809 pts. for CABS patients, and 5,308 pts. and 10,140 pts. for VR patients, respectively. CONCLUSIONS: The costs of antibiotic prophylaxis among cardiac surgery patients heavily depends on the setting and circumstances of drug administration. The minimization cost analysis indicates that teicoplanin is the most cost-effective option if the drug is administered within the surgical area, while vancomycin is the less costly option when administered within the medical ward. However, if the second option is to be chosen, it is necessary to assure the right plasmatic drug levels of the antibiotic at the beginning of the surgical procedure.

Aged↗

[Activity of vancomycin and teicoplanin against clinical isolates of Staphylococcus aureus in the period 1994-1999].

Since the emergence of the methicillin-resistant S. aureus (MRSA) in the 1960's, glycopeptides (Vancomycin and Teicoplanin) has been the drugs of choice and commonly the sole antimicrobial agents available for the treatment of serious MRSA and other Gram-positive infections. The emergence of S. aureus with intermediate vancomycin-resistance after 1997 threatens to return us to the era before the development of the antibiotics. Prevention of the further spread of S. aureus strains with intermediate and eventually with full glycopeptide resistance requires enhanced laboratory methods to detect resistance. A total of 361 S. aureus clinical isolates (177 MRSA and 184 MSSA) obtained from 1994 to 1999 in eleven Bulgarian hospitals located in geographically distinct areas of the country were enrolled in the study. Minimal inhibitory concentrations of Vancomycin and Teicoplanin were determined by agar-dilution method according to NCCLS recommendations. MIC50 and MIC90 for Vancomycin were 0.7 and 1 mg/ml, and for Teicoplanin--0.5 and 0.9 microgram/ml. All staphylococcal isolates showed sensitivity to Vancomycin and Teicoplanin. MICs of both glicopeptides against MRSA and MSSA did not differ significantly.

Anti-Bacterial Agents↗