Comparison of three doses of amikacin on alternate days with a daily dose of meropenem during the same period for the treatment of urinary tract infection with E. coli: a double-blind clinical trial.

OBJECTIVES: Urinary tract infections (UTIs) are very common infections in humans, and Escherichia coli (E. coli) is the commonest pathogen leading to UTIs. The generation of beta-lactamase enzymes in this bacterium results in its resistance against many antibiotics. This study compares three doses of amikacin on alternate days with a daily dose of meropenem in the same period for the treatment of UTIs with E. coli in a double-blind clinical trial. METHODS: The current double-blind clinical trial compares three doses of amikacin on alternate days with a daily dose of meropenem in the same period for the treatment of UTIs with E. coli. The patients were assigned to two groups: Intervention (receiving a single dose of amikacin once a day at 48-h intervals for a week, three doses) and control (receiving meropenem for 1/TDS for a week). RESULTS: The E. coli infection frequency was 61 (21 cases of non-ESBL and 40 cases of ESBL-positive infections) and the frequency of the other infections was 52 (46%). In the patients with ESBL E. coli infection, ciprofloxacin (21; 70%) showed the highest antibiotic resistance, and nitrofurantoin (33; 91.7%) showed the highest sensitivity. The baseline variables between the control and intervention groups indicated no significant difference (p > 0.05). The frequency of signs and symptoms showed no significant difference between the amikacin and meropenem groups in the first 24 h and the first week. In the second week of follow-up, no clinical signs or symptoms were observed in the two groups. CONCLUSION: The results of this study showed that treatment with amikacin, 1 g q48h, for one week (three doses) has the same result as meropenem, 1 g q8h, for one week (21 doses). The results are the same for the treatment of UTIs with ESBL positive and ESBL negative. Amikacin can be used once every 48 h to treat UTIs, is less expensive and can be administered on an outpatient basis. TRIAL REGISTRATION: This study was registered in the Iranian Registry of Clinical Trials (IRCT) with ID number: IRCT20170417033483N2 on the date 2018-02-13.

The nephroprotective properties of taurine-amikacin treatment in rats are mediated through HSP25 and TLR-4 regulation.

Amikacin (AMK) is one of the most effective aminoglycoside antibiotics. However, nephrotoxicity is a major deleterious and dose-limiting side effect associated with its clinical use especially in high dose AMK-treated patients. The present study assessed the ability of taurine (TAU) to alleviate or prevent AMK-induced nephrotoxicity if co-administrated with AMK focusing on inflammation, apoptosis, and fibrosis. Male Sprague Dawley rats were assigned to six equal groups. Group 1: rats received saline (normal control), group 2: normal rats received 50 mg kg-1 TAU intraperitoneally (i.p.). Groups 3 and 4: received AMK (25 or 50 mg kg-1; i.p.). Groups 5 and 6: received TAU (50 mg kg-1; i.p.) concurrently with AMK (25 or 50 mg kg-1; i.p.) for 3 weeks. AMK-induced nephrotoxicity is evidenced by elevated levels of serum creatinine (CRE), blood urea nitrogen (BUN), and uric acid (UA). Histopathological investigations provoked damaging changes in the renal tissues. Heat shock proteins (HSP)25 and Toll-like receptor-4 (TLR-4) elevated levels were involved in the induction of inflammatory reactions and focal fibrosis. The improved activation of TLR-4 may stimulate monocytes to upgrade Interleukin (IL)-18 production rather than IL-10. TAU proved therapeutic effectiveness against AMK-induced renal toxicity through downregulation of HSP25, TLR-4, caspase-3, and IL-18 with up-regulation of IL-10 levels.

Aminoglycosides in critically ill patients: which dosing regimens for which pathogens?

Modifications of antibiotic pharmacokinetic parameters have been reported in critically ill patients, resulting in a risk of treatment failure. We aimed to determine optimised amikacin (AMK), gentamicin (GEN) and tobramycin (TOB) intravenous dosing regimens in this patient population. Patients admitted to the medical ICU and treated with AMK, GEN or TOB were included. Analyses were performed using a parametric population approach. Monte Carlo simulations were performed and the probability of target attainment (PTA) was calculated using Cmax/MIC ≥ 8 and trough concentrations as targets. A total of 117 critically ill hospitalised patients were studied. Median values (interindividual variability, É·2) of clearance were 3.51 (0.539), 3.53 (0.297), 2.70 (0.339) and 5.07 (0.339) L/h for AMK, GEN, TOB, and TOB in cystic fibrosis (CF), respectively. Median values (É·2) of central volume of distribution were 30.2 (0.215), 20.0 (0.109) and 25.6 (0.177) L for AMK, GEN and TOB, respectively. Simulations showed that doses should be adjusted to actual body weight and creatinine clearance (CLCR) for AMK and GEN, and according to CLCR and presence of CF for TOB. In conclusion, our recommendations for treating Pseudomonas aeruginosa infections in this population include using initial doses of 35 mg/kg for AMK or 10 mg/kg for TOB (CF and non-CF patients). GEN demonstrated the best rates of target attainment against Staphylococcus aureus infections with a dose of 5 mg/kg. As high aminoglycoside doses are required in this population, efficacy and safety targets are conflicting and therapeutic drug monitoring remains an important tool to manage this issue.

State-of-the-art treatment strategies for nontuberculous mycobacteria infections.

INTRODUCTION: Non-tuberculous Mycobacteria (NTM) are a group of organisms whose importance in medicine seems to be increasing in recent times. The increasing number of patients susceptible to these diseases make it necessary to expand our knowledge of therapeutic options and to explore future possibilities for the development of a therapeutic arsenal. AREAS COVERED: In this review, the authors provide a brief introduction about the present importance of NTM and describe the present recommendations of the available guidelines for their treatment. They include a description of the future options for the management of these patients, especially focusing on new antibiotics. The authors also look at possibilities for future therapeutic options, such as antibiofilm strategies. EXPERT OPINION: No actual changes have been made to the current recommendations for the management of most NTM infections (except perhaps the availability of nebulized amikacin). However, it is also true that we have increased the number of available antibiotic treatment options with good in vitro activity against NTM. The use of these drugs in selected cases could increase the therapeutic possibilities. However, some problems are still present, such as the knowledge of the actual meaning of a NTM isolate, and will probably be a key part of future research.

New drugs to treat difficult tuberculous and nontuberculous mycobacterial pulmonary disease.

PURPOSE OF REVIEW: Treatment of drug-sensitive tuberculosis (TB) is effective, whereas that of multidrug-resistant and extensively drug-resistant TB as well as nontuberculous mycobacterial (NTM) disease are less so. Therapy in general requires good adherence to potentially toxic drug regimens over prolonged periods. Poor adherence is associated with resistance development and poor outcome. This review will present promising new treatments, both new drugs and regimens, for difficult mycobacterial pulmonary infections. RECENT FINDINGS: A number of new and repurposed drugs including bedaquiline, delamanid, pretomanid, linezolid and clofazimine, and drug regimens, such as the The Evaluation of a Standard Treatment Regimen of Anti-tuberculosis Drugs for Patients With MDR-TB (STREAM) trial regimens, are currently progressing from basic research through clinical trials.

Amikacin Dosing for MDR Tuberculosis: A Systematic Review to Establish or Revise the Current Recommended Dose for Tuberculosis Treatment.

Background: Amikacin has been used for over 40 years in multidrug resistant tuberculosis (MDR-TB), but there is still debate on the right dose. The aim of this review was to search relevant pharmacokinetic (PK) and pharmacodynamic (PD) literature for the optimal dose and dosing frequency of amikacin in MDR-TB regimens trying to optimize efficacy while minimizing toxicity. Methods: A systematic review on the value of amikacin as second-line drug in the treatment of MDR-TB was performed. Results: Five articles were identified with data on PK, hollow-fiber system model for TB and or early bactericidal activity of amikacin. Despite the long period in which amikacin has been available for the treatment of MDR-TB, very little PK data is available. This highlights the need for more research. Conclusions: Maximum concentration (Cmax) of amikacin related to MIC proved to be the most important PK/PD index for efficacy. The target Cmax/MIC ratio should be 10 at site of infection. Cumulative area under the concentration-time curve (AUC) corresponding with cumulative days of treatment was associated with an increased risk of toxicity.

[Effects of the combined therapy of heat sensitive moxibustion and acupoint injection on endometrial receptivity of hypdrosalphinx infertility in the patients after hysteroscopy and laparoscopy].

OBJECTIVE: To explore the effects of the combined therapy of heat sensitive moxibustion and acupoint injection on endometrial receptivity of hypdrosalphinx infertility in the patients after hysteroscopy and laparoscopy on the base of routine post-operative anti-inflammation. METHODS: A total of 210 patients of hypdrosalphinx infertility after hysteroscopy and laparoscopy were divided into a combined therapy group, a heat sensitive moxibustion group and a control group, 70 cases in each one according to the random number table. In the control group, the intravenous drip of cefoxitin sodium was adopted, and the anti-inflammation treatment was given for 1 week after operation. In the heat sensitive moxibustion group, on the basis of the treatment as the control group, the heat sensitive moxibustion was applied after vaginal bleeding stopped. The acupoints were Yaoyangguan (GV 3), Guanyuan (CV 4), Qihai (CV 6), Shenshu (BL 23), Sanyinjiao (SP 6), Yinlingquan (SP 9) and Zigong (EX-CA1). The acupoints were modified according to the different syndromes. In the combined therapy group, on the basis of the regimen as the heat sensitive moxibustion group, after vaginal bleeding stopped, the acupoint injection was given alternatively at bilateral Tiangong (extra, 1.0 cm inferior and bilateral to the cervix) with lidocaine 1 mL, amikacin 2 mL and salvia injection 2 mL. The treatment was given once every day, the treatment for 10 times as one course and a total of 3 courses were required. The endometrial type, thickness, uterine arterial plusatility index (PI) and resistance index (RI) were observed in the patients of each group. RESULTS: After treatment, the numbers of A-type endometrial type in the combined therapy group and the heat sensitive moxibustion group were remarkably higher than those of the control group [57.1% (40/7) vs 31.4% (22/70), 50.0% (35/70) vs 31.4% (22/70), both P<0.05]. The endometrial thickness after treatment was all increased as compared with that before treatment in each group (all P<0.05). The increasing degree in the combined therapy group was better than either the heat sensitive moxibustion group or the control group (both P<0.05). The improvement in the heat sensitive moxibustion group was superior to the control group (P<0.05). PI and RI in the combination group and PI in the control group were decreased after treatment (all P<0.05). The improvements of PI and RI in the combination group were better than those in the heat moxibustion group (both P<0.05), which were superior to those in the control group (all P<0.05). CONCLUSION: In the patients of hypdrosalphinx infertility after hysteroscopy and laparoscopy, the combined therapy of heat sensitive moxibustion and acupoint injection increases endometrial thickness, reduces uterine arterial resistance and improves endometrial receptivity.

Higher versus standard amikacin single dose in emergency department patients with severe sepsis and septic shock: a randomised controlled trial.

Recent studies suggest that intensive care unit patients treated with amikacin frequently do not attain the desired pharmacokinetic/pharmacodynamic (PK/PD) target, i.e. peak amikacin concentration (Cpeak) to minimum inhibitory concentration (MIC) ratio of ≥8, when a single dose of 15 mg/kg is used. No data are available for patients admitted to the emergency department (ED). The aim of this prospective randomised controlled study was to determine PK/PD target attainment in ED patients presenting with severe sepsis or septic shock treated with 15 mg/kg versus 25 mg/kg amikacin. Patients were randomly assigned to receive amikacin 25 mg/kg or 15 mg/kg. Amikacin Cpeak values were determined. The primary outcome was target attainment defined as Cpeak/MIC ≥ 8 both using EUCAST susceptibility breakpoints and actually documented MICs as denominator. A total of 104 patients were included. The EUCAST-based target was attained in 76% vs. 40% of patients assigned to the 25 mg/kg vs. 15 mg/kg dose groups (P <0.0001). Target attainment using actual MICs (median of 2 mg/L, documented in 48 isolated Gram-negative pathogens) was achieved in 95% vs. 94% of patients in the 25 mg/kg vs. 15 mg/kg dose groups (P = 0.969). Risk factors associated with PK/PD target failure were identified in the multivariable analysis. At least 25 mg/kg amikacin as a single dose should be used in ED patients with severe sepsis and septic shock to attain the EUCAST-based PK/PD target. However, when using local epidemiology as denominator, 15 mg/kg appears to be sufficient. [ClinicalTrials.gov ID: NCT02365272.

IMP-6 Carbapenemase-Producing Enterobacteriaceae Bacteremia Successfully Treated with Amikacin-Meropenem in Two Patients.

Infections caused by carbapenemase-producing Enterobacteriaceae (CPE) are becoming increasingly common worldwide. Although CPE infections can be fatal, few reports in the literature have described effective and successful treatments for infectious diseases caused by several types of IMP CPE, and, to our knowledge, no reports have described the successful treatment of IMP-6 CPE infections. We describe two patients who developed bacteremia caused by IMP-6 CPE after surgery for cancer who were successfully treated with amikacin plus high-dose prolonged-infusion meropenem. Both patients were treated over a 2-week period using amikacin 15 mg/kg at various intervals based on therapeutic drug monitoring and meropenem 2000 mg infused over 3 hours every 12 hours. The dosages of amikacin and meropenem were determined based on the creatinine clearance of each patient. Both patients were cured of their bacteremia and did not experience any antibiotic-related adverse effects. Based on the outcomes of these patients, it appears that amikacin plus high-dose prolonged-infusion meropenem may be safe and effective for the treatment of bacteremia caused by IMP-6 CPE.

Efficacy and pharmacokinetics of ME1100, a novel optimized formulation of arbekacin for inhalation, compared with amikacin in a murine model of ventilator-associated pneumonia caused by Pseudomonas aeruginosa.

Background: Arbekacin is an aminoglycoside that shows strong antimicrobial activity against Gram-positive bacteria, including MRSA, as well as Pseudomonas aeruginosa . The therapeutic effectiveness of arbekacin is directly related to C max at the infection site. To maximize drug delivery to the respiratory tract and minimize the systemic toxicity, arbekacin optimized for inhalation, ME1100, is under development. In this study, we investigated the efficacy and pharmacokinetics of ME1100 in a murine model of ventilator-associated pneumonia caused by P. aeruginosa by using a customized investigational nebulizer system. Methods: The mice were treated for 5 min, once daily, with placebo, 3, 10 or 30 mg/mL ME1100 or 30 mg/mL amikacin. Results: In the survival study, the survival rate was significantly improved in the 10 and 30 mg/mL ME1100 treatment groups compared with that in the placebo group. The number of bacteria in the lungs was significantly lower in the 30 mg/mL ME1100 treatment group at 6 h after the initial treatment, compared with all other groups. In the pharmacokinetic study, the C max in the 30 mg/mL ME1100 treatment group in the epithelial lining fluid (ELF) and plasma was 31.1 and 1.2 mg/L, respectively. Furthermore, we compared the efficacy of ME1100 with that of amikacin. Although there were no significant differences in ELF and plasma concentrations between 30 mg/mL of ME1100 and 30 mg/mL of amikacin, ME1100 significantly improved the survival rate compared with amikacin. Conclusions: The results of our study demonstrated the in vivo effectiveness of ME1100 and its superiority to amikacin.

Amikacin therapy for urinary tract infections caused by extended-spectrum ß-lactamase-producing Escherichia coli.

BACKGROUND/AIMS: The number of urinary tract infections (UTIs) caused by extended-spectrum ß-lactamase-producing Escherichia coli (ESBL-EC) is increasing. In an outpatient setting, there are limited therapeutic options to treat ESBL-producing pathogens. We evaluated the outcomes of amikacin outpatient parenteral antibiotic therapy (OPAT) for UTIs caused by ESBL-EC in patients not pre-treated with carbapenem. METHODS: We retrospectively evaluated the outcomes of amikacin OPAT for UTIs caused by ESBL-EC. RESULTS: From November 2011 to October 2012, eight females, who could not be hospitalized for carbapenem treatment, were treated with amikacin OPAT for nine episodes of non-bacteremic ESBL-EC UTIs. Seven of the eight patients had one or more comorbidities. Of the nine UTI cases, three had symptomatic lower UTIs and six had non-bacteremic upper UTIs. In all of the cases, symptomatic and laboratory improvements were observed following amikacin OPAT. One patient showed a delayed relapse with bilateral microabscesses 3 weeks after treatment cessation; however, a clinical and microbiological cure was eventually reached. All of the patients were able to tolerate amikacin OPAT without any significant nephrotoxicity or ototoxicity. CONCLUSIONS: Amikacin OPAT represents a feasible therapeutic option for non-bacteremic UTIs caused by ESBL-EC in settings with limited resources.

Amikacin therapy for urinary tract infections caused by extended-spectrum beta-lactamase-producing Escherichia coli

BACKGROUND/AIMS: The number of urinary tract infections (UTIs) caused by extended-spectrum beta-lactamase-producing Escherichia coli (ESBL-EC) is increasing. In an outpatient setting, there are limited therapeutic options to treat ESBL-producing pathogens. We evaluated the outcomes of amikacin outpatient parenteral antibiotic therapy (OPAT) for UTIs caused by ESBL-EC in patients not pre-treated with carbapenem. METHODS: We retrospectively evaluated the outcomes of amikacin OPAT for UTIs caused by ESBL-EC. RESULTS: From November 2011 to October 2012, eight females, who could not be hospitalized for carbapenem treatment, were treated with amikacin OPAT for nine episodes of non-bacteremic ESBL-EC UTIs. Seven of the eight patients had one or more comorbidities. Of the nine UTI cases, three had symptomatic lower UTIs and six had non-bacteremic upper UTIs. In all of the cases, symptomatic and laboratory improvements were observed following amikacin OPAT. One patient showed a delayed relapse with bilateral microabscesses 3 weeks after treatment cessation; however, a clinical and microbiological cure was eventually reached. All of the patients were able to tolerate amikacin OPAT without any significant nephrotoxicity or ototoxicity. CONCLUSIONS: Amikacin OPAT represents a feasible therapeutic option for non-bacteremic UTIs caused by ESBL-EC in settings with limited resources.

Even high-dose extended infusions may not yield desired concentrations of ß-lactams: the value of therapeutic drug monitoring.

A 35-year-old patient in intensive care with severe burn injury developed episodes of sepsis. Blood culture yielded a multidrug-resistant Pseudomonas aeruginosa and treatment was commenced with amikacin (minimum inhibitory concentration (MIC) 2-4 mg/L, dose 20 mg/kg adjusted body weight 24-hourly) and meropenem (MIC 8 mg/L, dose 2 g IV 8-hourly and later 6-hourly). Despite the use of extended infusions with ß-lactam therapeutic drug monitoring and doses that were more than 2.5 times higher than standard meropenem doses, resistance emerged. This case report describes the application of therapeutic drug monitoring to optimize ß-lactam therapy in a difficult-to-treat critically ill patient.

Delivery of aerosolized liposomal amikacin as a novel approach for the treatment of nontuberculous mycobacteria in an experimental model of pulmonary infection.

Pulmonary infections caused by nontuberculous mycobacteria (NTM) are an increasing problem in individuals with chronic lung conditions and current therapies are lacking. We investigated the activity of liposomal amikacin for inhalation (LAI) against NTM in vitro as well as in a murine model of respiratory infection. Macrophage monolayers were infected with three strains of Mycobacterium avium, two strains of Mycobacterium abscessus, and exposed to LAI or free amikacin for 4 days before enumerating bacterial survival. Respiratory infection was established in mice by intranasal inoculation with M. avium and allowing three weeks for the infection to progress. Three different regimens of inhaled LAI were compared to inhaled saline and parenterally administered free amikacin over a 28 day period. Bacteria recovered from the mice were analyzed for acquired resistance to amikacin. In vitro, liposomal amikacin for inhalation was more effective than free amikacin in eliminating both intracellular M. avium and M. abscessus. In vivo, inhaled LAI demonstrated similar effectiveness to a ∼25% higher total dose of parenterally administered amikacin at reducing M. avium in the lungs when compared to inhaled saline. Additionally, there was no acquired resistance to amikacin observed after the treatment regimen. The data suggest that LAI has the potential to be an effective therapy against NTM respiratory infections in humans.

Effectiveness of antibiotic combination therapy as evaluated by the Break-point Checkerboard Plate method for multidrug-resistant Pseudomonas aeruginosa in clinical use.

Multidrug-resistant Pseudomonas aeruginosa (MDRP) strains are defined as having resistance to the following 3 groups of antibiotics: carbapenems, aminoglycosides, and fluoroquinolones. Antibiotic combinations have demonstrated increased activity in vitro compared with a single agent. As an in vitro method of determining the combination activity of antibiotics, the Break-point Checkerboard Plate (BC-plate) can be used routinely in clinical microbiology laboratories. We evaluated the effectiveness of the BC-plate for MDRP infections in clinical settings. We retrospectively selected cases of MDRP infection treated with combination therapy of antibiotics in Tokyo Medical University Hospital (1015 beds), Tokyo, Japan, from November 2010 to October 2012. A total of 28 MDRP strains were clinically isolated from 28 patients during the study period. This study design is a case series of MDRP infection. Six infections among the 28 patients were treated based on the results of the BC-plate assay, and the 6 strains tested positive for MBL. One patient had pneumonia, 3 had urinary tract infections, 1 had vertebral osteomyelitis, and 1 had nasal abscess. The combination of aztreonam with amikacin demonstrated the most frequently recognized in vitro effect (5 patients). Next, aztreonam with ciprofloxacin and piperacillin with amikacin revealed equivalent in vitro effects (3 patients, respectively). The clinical cure rate was 83.3% (5/6 patients). Antibiotic combination therapy based on the results of the BC-plate assay might indicate the effective therapy against MDRP infection in clinical settings.

[The treatment outcomes of 21 cases of rapidly growing mycobacteria related pulmonary disease].

OBJECTIVE: To explore the efficacy of the chemotherapeutic regimen with clarithromycin (CTM) and amikacin (AMK) as the main drugs in the therapy of rapidly growing mycobacteria (RGM) related pulmonary disease. METHODS: The clinical efficacy of 21 patients with RGM related pulmonary disease was retrospectively analyzed from January 2008 to October 2011 in Guangzhou Chest Hospital. The individual chemotherapeutic regimen was mainly based on azithromycin (ATM) 0.5 g/d or CTM 0.5 - 1.0 g/d, AMK 0.4 - 0.6 g/d according to the medication history and antimicrobial susceptibility tests. After 6 months of treatment, symptomatic improvement, changes of imaging findings, sputum cultures and adverse effects were observed. RESULTS: In the 21 cases of RGM related pulmonary disease, drug resistance to amikacin (9 cases) and clarithromycin (5 cases) were relatively low as compared to other antituberculous drugs. Lesions involving more than 3 lung fields were seen in 17 cases, cough and phlegm in 21, bloody sputum in 18, chest pain and shortness of breath in 15, and fever in 15 cases. After 2-week treatment, fever disappeared and shortness of breath improved in all the cases. Cough and phlegm improved in 12 and bloody sputum improved in 16 cases. After 6-month treatment, lesion absorption occurred in 12 cases, lung cavity became smaller in 9 cases and sputum culture became negative in 8 cases. Of the 16 cases sensitive to CTM, 11 was smear-negative, and of the 12 cases sensitive to AMK, 11 was smear-negative. Common adverse effects included gastrointestinal symptoms, liver damage and blood abnormalities. CONCLUSIONS: Patients with RGM related pulmonary disease had low rates of drug resistance to CTM and AMK. However, individual chemotherapy regimen based on CTM and AMK showed unsatisfactory clinical efficacy. More sensitive drugs combined with potent chemotherapy regimen are needed for the treatment of this disease.

Guidelines for aminoglycoside use and applicability to geriatric patients.

OBJECTIVES: The authors had for objective to evaluate the applicability of AFSSAPS guidelines for aminoglycoside use to geriatric patients. METHODS: Theoretical doses and dosing regimens allowing reaching target concentrations in this population were calculated by applying a pharmacokinetic model to 30 geriatric patients treated by amikacin. RESULTS: The dose allowing reaching a maximum concentration of 60 mg/L was 1.217 mg on average. The time required to reach a blood concentration lower than or equal to 2.5mg/L was 62.5±70.4 hours. Forty-six percent of patients had a trough concentration greater than 2.5 mg/L, 48 hours after administration. For these patients, the time between critical minimum inhibitory concentration (MIC) and toxicity threshold concentration was 21.9±14.9 hours. CONCLUSION: Reaching a target concentration can be problematic in geriatric patients. It is frequently necessary to use dosing intervals greater than 48 hours. The effectiveness and safety of these regimens remain uncertain.

Chitosan sponges for local synergistic infection therapy: a pilot study.

BACKGROUND: Although bacterial antibiotic resistance is increasing, fewer new antibiotics are being developed to compensate. Localized delivery of synergistic antiseptics and antibiotics with a chitosan sponge device may offer an alternative infection treatment. QUESTIONS/PURPOSES: In this pilot study, we asked whether antiseptic and antibiotic combinations provided in vitro synergism against Staphylococcus aureus, whether synergism reduces cell viability, and whether their combination releases drugs at inhibitory levels. METHODS: To investigate the pharmacodynamics among three combinations of the antiseptic chlorhexidine digluconate (CHX) with the antibiotics amikacin, daptomycin, and vancomycin (VAN) (n=1), we determined the fractional inhibitory concentration (FIC) index against S aureus Cowan I. The determined synergistic combination of CHX and VAN was evaluated for cell compatibility using NIH/3T3 fibroblasts (n=3) and the drug release profile from a chitosan sponge device (n=5). RESULTS: With an FIC index<0.5, the combination of CHX+VAN exhibited synergism against S aureus. CHX concentrations≥3.91 µg/mL resulted in fibroblast viability decrease, whereas the combination of CHX+VAN did not decrease fibroblast viability until their concentrations reached ≥7.81 µg/mL. The CHX and VAN release profile, both individually and in combination, was an initial bolus with no difference between eluate concentrations after Day 5. CONCLUSIONS: CHX+VAN combination may be delivered locally by a chitosan sponge that synergistically inhibits S aureus growth. CLINICAL RELEVANCE: The use of synergism between combined antibiotic and antiseptics delivered at high local concentrations with an implanted chitosan sponge may provide a useful alternative infection treatment option.

The optimal aminoglycoside and its dosage for the treatment of severe Enterococcus faecalis infection. An experimental study in the rabbit endocarditis model.

Aminoglycosides are recommended for the treatment of Enterococcus faecalis infections, especially in severe and bacteremic infection. However, the optimal aminoglycoside or the optimal dosage remains uncertain. This study aimed to compare the activity of four aminoglycosides against E. faecalis (gentamicin, netilmicin, tobramycin, and amikacin) and two dosages of gentamicin. One clinical strain of E. faecalis was used to induce aortic endocarditis in the study rabbits. Each aminoglycoside was infused daily over 3 days with a computer-regulated flow simulating human pharmacokinetics of 15 mg/kg/day for amikacin, 6 mg/kg/day for netilmicin, and 3 mg/kg/day for gentamicin and tobramycin. Additionally, two dosages of gentamicin (simulating 3 or 6 mg/kg/day) were compared over 1 or 3 days of treatment. The in vivo efficacy was assessed according to the bacterial count in vegetations, in comparison with a control group. Of the four aminoglycosides tested, only gentamicin and netilmicin showed significant antibacterial efficacy after 3 days of treatment. After only 1 day of treatment, the high dosage of gentamicin (6 mg/kg/day) was more effective than the standard dosage (3 mg/kg/day). Among the tested aminoglycosides, gentamicin showed the best efficacy, with the best results after 24 h of treatment for the highest dosage.