Combination Of Linezolid Research Articles

MRSA Otorrhea: A Case Series and Review of the Literature

Methicillin-resistant Staphylococcus aureus (MRSA) has become an increasingly common cause of difficult-to-treat head and neck infections. We report a retrospective analysis of 3 cases of MRSA otorrhea treated in our clinic between 2007 and 2009. Culture analysis of otorrhea isolates revealed MRSA infections with identical drug sensitivities. Treatment success was achieved using combinations of linezolid with gentamicin ear drops for 3 to 4 weeks or trimethoprim/sulfamethoxazole (TMP/SMX) with gentamicin drops for 6 weeks. This study illustrates the importance of determining individual drug sensitivities for optimal treatment and maintaining current knowledge of the local MRSA strains. Empiric combination therapy of TMP/SMX with gentamicin is an effective first-line treatment for MRSA otorrhea. Regional differences in clindamycin sensitivities warrant clinical discretion. Fluoroquinolones should be avoided because of high rates of resistance unless culture sensitivity determines that they are appropriate. First-line agents for severe infections include combination therapy with vancomycin or linezolid.

Treatment with Linezolid or Vancomycin in Combination with Rifampin Is Effective in an Animal Model of Methicillin-Resistant Staphylococcus aureus Foreign Body Osteomyelitis

Rifampin monotherapy was compared to the combination of linezolid or vancomycin with rifampin in an experimental rat model of methicillin-resistant Staphylococcus aureus (MRSA) chronic foreign body osteomyelitis. MRSA was inoculated into the proximal tibia, and a titanium wire was implanted. Four weeks after infection, rats were treated intraperitoneally for 21 days with rifampin alone (n = 16), linezolid plus rifampin (n = 14), or vancomycin plus rifampin (n = 13). Thirteen animals received no treatment. At completion of treatment, qualitative cultures of the wire and quantitative cultures of the bone (reported as median values) were performed. Quantitative cultures from the control, rifampin monotherapy, linezolid-plus-rifampin, and vancomycin-plus-rifampin groups revealed 4.54, 0.71, 0.10, and 0.50 log₁₀ CFU/gram of bone, respectively. The bacterial load was significantly reduced in all treatment groups compared to that in the control group. Rifampin resistance was detected in isolates from 10, 2, and 1 animal in the rifampin, linezolid-plus-rifampin, and vancomycin-plus-rifampin groups, respectively. Cultures of the removed wire revealed bacterial growth in 1 and 2 animals in the rifampin and linezolid-plus-rifampin groups, respectively, with no growth in the vancomycin-plus-rifampin group and growth from all wires in the untreated group. In conclusion, we demonstrated that combination treatment with linezolid plus rifampin or vancomycin plus rifampin is effective in an animal model of MRSA foreign body osteomyelitis in the context of retention of the infected foreign body.

Aqueous and Vitreous Penetration of Linezolid and Levofloxacin After Oral Administration

To evaluate the time course of drug concentrations achieved in aqueous (AQ), vitreous (V), and serum (S) compartments after oral administration of linezolid and levofloxacin. Randomized, clinical trial. Clinical practice. Sixteen patients (16 eyes) undergoing vitrectomy who had not had a prior pars plana vitrectomy in the study eye were randomly assigned to one of 4 groups. AQ, V, and S samples were obtained from all subjects after single concomitant doses of linezolid 600 mg and levofloxacin 750 mg between 1 and 12 h before the procedure: group A = 1-3 h; group B = 3-6 h; group C = 6-9 h; group D = 9-12 h. AQ, V, and S concentrations of linezolid and levofloxacin. Overall mean concentrations ± standard deviation (μg/mL) achieved by linezolid in AQ, V, and S compartments were 3.32 ± 2.06, 2.98 ± 1.87, and 7.91 ± 3.94, respectively. Overall mean concentrations ±standard deviation (μg/mL) achieved by levofloxacin in AQ, V, and S compartments were 2.19 ± 1.92, 1.95 ± 1.27, and 7.38 ± 3.47, respectively. Single concomitant doses of linezolid and levofloxacin achieved AQ and V concentrations above the minimum inhibitory concentration for 90% of common ocular gram-positive and gram-negative pathogens up to 12 h after administration. The combination of linezolid and levofloxacin represents a viable option for the prophylaxis and management of endophthalmitis.

Antistaphylococcal Activity of ACHN-490 Tested Alone and in Combination with Other Agents by Time-Kill Assay

Synergy time-kill studies of 47 methicillin-resistant Staphylococcus aureus strains with differing resistance phenotypes showed that combinations of subinhibitory concentrations of ACHN-490 and daptomycin yielded synergy against 43/47 strains at 24 h, while the combination was indifferent against the remaining 4 strains. ACHN-490 and ceftobiprole showed synergy in 17/47 strains tested at 24 h, while 6/47 strains showed synergy for subinhibitory combinations of ACHN-490 and linezolid.

A case of psoas abcess due to methicillin-resistant Staphylococcus aureus in type 2 diabetic patient successfully treated with linezolid in combination with rifampicin and sulfamethoxazole/trimethoprim

A case of psoas abcess due to methicillin-resistant Staphylococcus aureus in type 2 diabetic patient successfully treated with linezolid in combination with rifampicin and sulfamethoxazole/trimethoprim

Gram-Pozitif Patojenler Üzerine Linezolidin, Vankomisin, Teikoplanin, Fusidik Asit ve Siprofloksasin ile Kombinasyonlarının In Vitro Aktivitesi

Gram-Pozitif Patojenler Üzerine Linezolidin, Vankomisin, Teikoplanin, Fusidik Asit ve Siprofloksasin ile Kombinasyonlarının In Vitro Aktivitesi

The Use of Daptomycin and Linezolid to Treat Vancomycin-Intermediate Staphylococcus haemolyticus Infection in a Premature Infant

Infections with staphylococcal species, especially coagulase-negative staphylococci are common after neurosurgical procedures. We report a case of a coagulase-negative staphylococci infection of a ventricular shunt site in a 105-day-old, premature infant born at 25 weeks gestation with multiple medical problems. The patient was successfully treated with a combination of daptomycin and linezolid for the persistent infection, which was increasingly resistant to vancomycin. The patient was initially treated with a combination of vancomycin and rifampin; however, the course of therapy had to be changed when the bacteria was identified as having intermediate resistance to vancomycin. Therapy was initially changed to linezolid monotherapy, but culture results continued to be positive for the bacteria, necessitating removal of an external ventricular drain and combination therapy of daptomycin and linezolid for 2 weeks before insertion of a new ventricular shunt. The patient received 4 weeks of therapy with no further positive results of the culture analysis. To our knowledge, this is the first published case report of the use of daptomycin to successfully treat a central nervous system infection in a premature infant.

Treatment of vancomycin-intermediate Staphylococcus aureus (VISA) endocarditis with linezolid

We report a case of infective endocarditis due to vancomycin-intermediate Staphylococcus aureus (VISA). This was treated with a combination of intravenous linezolid and fusidic acid. Cure was achieved without surgical intervention.

Efficacy and tolerance of rifampicin–linezolid compared with rifampicin–cotrimoxazole combinations in prolonged oral therapy for bone and joint infections

Both linezolid and cotrimoxazole are antibiotics that are well suited for oral therapy of bone and joint infections (BJI) caused by otherwise resistant Gram-positive cocci (GPC) (resistance to fluoroquinolones, maccolides, betalactamines). However, in this context, no data are currently available regarding the safety and tolerance of these antibiotics in combination with rifampicin. The objective of this study was to compare the efficacy and safety of a combination of rifampicin and linezolid (RLC) with those of a combination of rifampicin and cotrimoxazole (RCC) in the treatment of BJI. Between February 2002 and December 2006, 56 adult patients (RLC, n = 28; RCC, n = 28), including 36 with infected orthopaedic devices (RLC, n =18; RCC, n =18) and 20 with chronic osteomyelitis (RLC, n =10; RCC, n = 10), were found to be eligible for inclusion in this study. Patients who discontinued antibiotic therapy within 4 weeks of commencing treatment were considered to represent cases of treatment failure and were excluded. Rates of occurrence of adverse effects were similar in the two groups, at 42.9% in the RLC group and 46.4% in the RCC group (p = 1.00), and led to treatment discontinuation in four (14.3%) RLC and six (21.4%) RCC patients. Cure rates were found to be similar in the two groups (RLC, 89.3%, RCC, 78.6%; p = 0.47). Prolonged oral RLC and RCC therapy were found to be equally effective in treating patients with BJI caused by resistant GPC, including patients with infected orthopaedic devices. However, the lower cost of cotrimoxazole compared with linezolid renders RCC an attractive treatment alternative to RLC. Further larger clinical studies are warranted to confirm these preliminary results.

LONG-TERM LINEZOLID TREATMENT IN A YOUNG CHILD WITH EXTENSIVELY DRUG-RESISTANT TUBERCULOSIS

Treatment of extensively drug-resistant tuberculosis (XDR-TB) is a challenge. We describe a young child with pulmonary XDR-TB who did not respond to an aggressive multidrug-resistant TB treatment regimen, but was cured with linezolid in combination with other reserve antituberculous drugs. No serious adverse events were observed during 19 months of treatment for XDR-TB.

In Vitro 24-Hour Time-Kill Studies of Vancomycin and Linezolid in Combination versus Methicillin-Resistant Staphylococcus aureus

Many clinicians are trying unique strategies, including vancomycin and linezolid in combination, for treatment of patients who do not respond to conventional therapy against methicillin (meticillin)-resistant Staphylococcus aureus. In our study, which illustrated in vitro activity only, no synergistic activity was seen when the two agents were combined. Conversely, antagonistic activity occurred in three of five strains when linezolid was added to vancomycin. Our results indicate that vancomycin and linezolid in combination should be avoided.

Rifampin and Linezolid in the Treatment of Methicillin-Resistant Staphylococcus aureus Preseptal Cellulitis

Methicillin-resistant Staphylococcus aureus (MRSA) preseptal cellulitis is an aggressive ophthalmic infection of increasing frequency. Previously reported cases were successfully treated with first line drugs such as vancomycin or Bactrim (trimethoprim and sulfamethoxazole); however, such drugs have limited efficacy in treating cutaneous MRSA. The authors report the first 2 known cases of MRSA-mediated preseptal cellulitis that resolved with systemic linezolid and rifampin following failed intravenous vancomycin treatment after incision and drainage of the abscess. The authors conclude that in cases of cutaneous MRSA infections that respond poorly to vancomycin, linezolid and rifampin combination therapy may provide an alternative therapeutic option.

Development of a Validated Stability-Indicating LC Assay and Stress Degradation Studies of Linezolid in Tablets

This paper describes the validation of an isocratic LC method for the assay of linezolid in tablets. Validation parameters such as linearity, precision, accuracy, specificity, limit of detection, limit of quantitation and robustness were determined. LC was carried out by reversed phase technique on an RP-18 column with a mobile phase composed of 1% acetic acid:methanol:acetonitrile (50:25:25, v/v/v). Linezolid and your combination drug product were exposed to acid, base, oxidation, dry heat and photolytic stress conditions. A linear response (r > 0.9999) was observed in the range of 8.0–20.0 μg mL−1. The retention time of linezolid was 4.6 min. The method showed good recoveries and intra- and inter-day relative standard deviations were less than 1.0%. The LOD and LOQ were 0.21 and 0.63 μg mL−1, respectively. The developed LC method for determination of related substances and assay determination of linezolid can be used to evaluate the quality of regular production samples. It can also be used to test the stability samples of linezolid.

Hyperbaric Oxygen as Adjunctive Therapy in Experimental Mediastinitis

Mediastinitis is a dreaded complication of cardiac surgical procedures. The purpose of our study was to research the role of hyperbaric oxygen therapy (HBO) in the treatment of experimental mediastinitis and to investigate whether it potentiates the antibiotic effects of linezolid, teicoplanin, and vancomycin. The study included nine groups; an uncontaminated and a contaminated untreated control groups, and seven contaminated groups that received HBO or systemic antibiotics with linezolid, vancomycin, or teicoplanin, or a combination therapy consisting of one of these antibiotics and HBO. There were six adult male Wistar rats in each group. Contaminated groups were inoculated with 0.5 mL 10(8) CFU/mL methicillin resistant Staphylococcus aureus in the mediastinal and in the sternal layers. The antibiotic treatment continued 7 d. Twelve hours later at the end of the treatment, the rats were sacrificed, a sternotomy was performed for each rat and tissue samples from the upper ends of the sternum were aseptically obtained and evaluated microbiologically. There was no difference between the therapeutic efficacy of linezolid, teicoplanin, or vancomycin (P>0.05). When the groups were analyzed separately, treatment with a combination of HBO and antibiotic therapy reduced the bacterial count in comparison with HBO or antibiotic treatment alone (P<0.05). The combination of teicoplanin or vancomycin and HBO, respectively, was not more effective in reducing the bacterial count in comparison with the combination of linezolid and HBO (P>0.05). Linezolid and teicoplanin therapy was found as effective as standard vancomycin therapy for methicillin resistant Staphylococcus aureus (MRSA) mediastinitis. Adjunctive HBO offered additional benefit to the antibiotic treatment of mediastinitis.

Serotonergic Antidepressants and Linezolid: A Retrospective Chart Review and Presentation of Cases

To report the results from a retrospective chart review looking at the combination of linezolid and serotonergic antidepressants and to report two cases of serotonin syndrome which were identified at our hospital. During the retrospective chart review one case of serotonin syndrome was identified. A 65-year-old female was receiving escitalopram for the treatment of depression prior to admission. Linezolid therapy was initiated on admission and two days later the patient had a tonic-clonic seizure. Escitalopram was discontinued and the patient did not have any further seizure activity. In a second case, a 37-year-old male was receiving citalopram during hospitalization and was started on concomitant linezolid. The patient had myoclonus and was observed to be tremulous throughout therapy with linezolid. Ten days after discontinuation of linezolid the patient continued to have symptoms until the withdrawal of citalopram. The Naranjo probability scale scores the first case as possibly related and the second case as probably related to the combination. It has been well documented in the literature that the combination of linezolid and serotonergic antidepressants may cause serotonin syndrome. In this retrospective chart review only one patient of 53 (1.8%) had symptoms highly suggestive of serotonin syndrome. A second patient continued to have symptoms of serotonin syndrome even after withdrawal of linezolid. This retrospective review and subsequent case reports confirm the rare, but serious, potential of serotonin syndrome associated with the combination of linezolid and serotonergic antidepressants.

Effectiveness and tolerability of prolonged linezolid treatment for chronic osteomyelitis: A retrospective study

Background:Linezolid is an oxazolidinone agent which is apparently well designed for treating chronic osteomyelitis, but data on effectiveness and tolerability as prolonged therapy is currently lacking. Objective:The purpose of this study was to assess the effectiveness and tolerability of linezolid in the treatment of chronic osteomyelitis. Methods:The charts of hospitalized patients who had been treated with linezolid for >4 weeks because of chronic osteomyelitis and were followed up for ≥12 months after the end of treatment were retrospectively reviewed for clinical outcome and tolerability. Cure was defined as the absence of clinical, biological, or radiological evidence of infection throughout the posttreatment follow-up. Linezolid tolerability was assessed on the basis of hematologic properties during treatment. Results:Of the 66 patients included, all were white (mean [SD] age, 67.7 [18.1] years; 41 men and 25 women; mean [SD] weight, 80.7 [18.6] kg). Thirty-seven (56.1%) patients had infection due to implants including 27 prosthetic joints. Pathogens were predominantly methicillin-resistant staphylococci (49/72 strains, 68.1 %). Every patient was administered N linezolid (600 mg BID) treatment for 6 to 8 days as inpatients, and then, as outpatients, they were switched to PO treatment. Fifty (75.8%) patients received a combination of linezolid and other antimicrobial agents, including rifampin (32 [48.5%]). Surgery was performed in 52 (78.8%) patients. The median hospital stay was 14 days (mean [SD], 19 [11.4] days [range, 7–70 days] ). The median duration of treatment was 13 weeks (mean [SD], 14.3 [8.2] weeks [range, 5–36 weeks]). At the end of treatment, 56 (84.8%) patients were cured, and during the post-treatment follow-up (median duration, 15 months [range, 12–36 months]), 4 relapses occurred, resulting in an overall successful cure for 52 (78.8%) patients.Reversible anemia was reported in 21 patients (31.8%), of whom 16 (24.2%) required blood transfusions. Median time from treatment initiation to anemia onset was 7.3 weeks (range, 4–12 weeks). Peripheral neuropathy was reported in 6 (9.1%) patients, of whom 4 remained symptomatic for up to 24 months after linezolid discontinuation. Other reported adverse events included nausea (6 [9.1%]), diarrhea (1 [1.5%]), and headache (2 [3.0%]), although none of these patients discontinued treatment. Conclusions:In this retrospective chart review, treatment with linezolid as monotherapy or in combination with antimicrobials and/or surgery was associated with cure of chronic osteomyelitis in 84.8% of subjects at 12 weeks after the end of treatment and 78.8% at follow-up. Adverse events were reported in 51.5% of subjects, and 34.8% of subjects discontinued the study because of adverse events. The potential for severe complications justifies close monitoring of these patients.

Treatment of prosthetic valve infective endocarditis due to multi-resistant Gram-positive bacteria with linezolid

Clinical experience with linezolid in the treatment of infective endocarditis either alone or in combination with other agents is limited. We describe our experience in the treatment of two patients with IE due to multi-resistant Gram-positive bacteria. One patient with MRSE and one with VRE endocarditis were treated with regimens containing linezolid. The killing kinetics of linezolid in combination with gentamicin or vancomycin against isolates of Staphylococcus epidermidis and Enterococcus faecalis were analysed in vitro. Clinical response and eradication of bacteraemia was achieved with linezolid therapy in both patients. Time-kill curve studies showed that linezolid was bacteriostatic against the MRSE and VRE isolates used. Combination with gentamicin or vancomycin did not produce synergy or antagonism but at best only marginal additive effect. Although bacteriostatic, linezolid provides an important therapeutic option in IE due to multi-resistant Gram-positive pathogens. It challenges the conventional wisdom that bactericidal synergy is required for the effective treatment of most cases of IE due to Gram-positive organisms.

Linezolid for the treatment of multidrug-resistant tuberculosis

In vitro studies have shown good activity of linezolid against Mycobacterium tuberculosis, including multidrug-resistant strains. However, clinical experience with linezolid in tuberculosis is scarce. We report our clinical experience with five consecutive patients with multidrug-resistant tuberculosis infection treated with combination regimens that included linezolid. Two patients had multidrug-resistant Mycobacterium bovis infection, with resistance to 12 antituberculous agents (one of them with HIV co-infection and <50 CD4 cells/mm(3)). The other three patients were infected by multidrug-resistant M. tuberculosis strains, with resistance to all first-line drugs and other second-line drugs. All patients received linezolid in combination with thiacetazone, clofazimine or amoxicillin/clavulanate. Susceptibility tests showed linezolid MIC values < or =0.5 mg/L against all tuberculosis strains tested (standard proportion method, Middlebrook agar 7H10). In all cases, tuberculosis cultures from respiratory samples were sterile after 6 weeks of therapy. Three patients have clinical and microbiological cure of tuberculosis with a combination regimen with linezolid (range: 5-24 months). One patient was lost to follow-up at month 5. The remaining patient has completed 11 months of therapy and is still on treatment. Four patients developed anaemia and needed blood transfusions. In two of these patients, the linezolid daily-dose (600 mg twice a day) was successfully reduced to 50% (300 mg twice a day) to decrease toxicity while maintaining efficacy. Peripheral neuropathy (two patients) and pancreatitis (one patient) were other adverse events observed during linezolid treatment. In our experience, linezolid has been a valid alternative drug in the management of multidrug-resistant tuberculosis. The prolonged use of linezolid is frequently associated with toxicity, mainly anaemia and peripheral neuropathy, that requires special management.

Endogenous Endophthalmitis Treated With Systemic Ciprofloxacin and Linezolid

Endogenous endophthalmitis is a serious sight-threatening condition. The role of intravitreal antibiotics is controversial. We present a case of endogenous endophthalmitis successfully treated with a combination of systemic ciprofloxacin and linezolid.

In Vitro and In Vivo Synergistic Activities of Linezolid Combined with Subinhibitory Concentrations of Imipenem against Methicillin-Resistant Staphylococcus aureus

Indifference or moderate antagonism of linezolid combined with other antibiotics in vitro and in vivo have mainly been reported in the literature. We have assessed the in vitro activities of linezolid, alone or in combination with imipenem, against methicillin-resistant Staphylococcus aureus (MRSA) strains using the dynamic checkerboard and time-kill curve methods. Linezolid and low concentrations of imipenem had a synergistic effect, leading us to evaluate the in vivo antibacterial activity of the combination using the rabbit endocarditis experimental model. Two MRSA strains were used for in vivo experiments: one was a heterogeneous glycopeptide-intermediate clinical S. aureus strain isolated from blood cultures, and the other was the S. aureus COL reference strain. Animals infected with one of two MRSA strains were randomly assigned to one of the following treatments: no treatment (controls), linezolid (simulating a dose in humans of 10 mg/kg of body weight every 12 h), a constant intravenous infusion of imipenem (which allowed the steady-state concentration of about 1/32 the MIC of imipenem for each strain to be reached in serum), or the combination of both treatments. Linezolid and imipenem as monotherapies exhibited no bactericidal activity against either strain. The combination of linezolid plus imipenem showed in vivo bactericidal activity that corresponded to a decrease of at least 4.5 log CFU/g of vegetation compared to the counts for the controls. In conclusion, the combination exhibited synergistic and bactericidal activities against two MRSA strains after 5 days of treatment. The combination of linezolid plus imipenem appears to be promising for the treatment of severe MRSA infections and merits further investigations to explore the mechanism underlying the synergy between the two drugs.