Friday, August 15, 2008

Isolation, Structure, and Antibacterial Activity of Philipimycin

Isolation, Structure, and Antibacterial Activity of Philipimycin, A Thiazolyl Peptide Discovered from Actinoplanes philippinensis MA7347.

J Am Chem Soc. 2008 Aug

Zhang C, Occi J, Masurekar P, Barrett JF, Zink DL, Smith S, Onishi R, Ha S, Salazar O, Genilloud O, Basilio A, Vicente F, Gill C, Hickey EJ, Dorso K, Motyl M, Singh SB.

Bacterial resistance to antibiotics, particularly to multiple drug resistant antibiotics, is becoming cause for significant concern. The only really viable course of action is to discover new antibiotics with novel mode of actions. Thiazolyl peptides are a class of natural products that are architecturally complex potent antibiotics but generally suffer from poor solubility and pharmaceutical properties. To discover new thiazolyl peptides potentially with better desired properties, we designed a highly specific assay with a pair of thiazomycin sensitive and resistant strains of Staphylococcus aureus, which led to the discovery of philipimycin, a new thiazolyl peptide glycoside. It was isolated along with an acid-catalyzed degradation product by bioassay-guided fractionation. Structure of both compounds was elucidated by extensive application of 2D NMR, 1D TOCSY, and HRESIFT-MS/MS. Both compounds showed strong antibacterial activities against Gram-positive bacteria including MRSA and exhibited MIC values ranging from 0.015 to 1 mug/mL. Philipimycin was significantly more potent than the degradation product. Both compounds showed selective inhibition of protein synthesis, indicating that they targeted the ribosome. Philipimycin was effective in vivo in a mouse model of S. aureus infection exhibiting an ED 50 value of 8.4 mg/kg. The docking studies of philipimycin suggested that a part of the molecule interacts with the ribosome and another part with Pro 23, Pro 22, and Pro 26 of L11 protein, which helped in explaining the differential of activities between the sensitive and resistant strains. The design and execution of the bioassay, the isolation, structure, in vitro and in vivo antibacterial activity, and docking studies of philipimycin and its degradation product are described.

PMID: 18698773 [PubMed - as supplied by publisher]

Thursday, August 07, 2008

Tobramycin-induced hepatotoxicity

Tobramycin-induced hepatotoxicity

Ann Pharmacother. 2007 Dec

Nisly SA, Ray SM, Moye RA.
College of Pharmacy and Health Sciences, Butler University, Indianapolis, IN, USA.

OBJECTIVE: To report a case of tobramycin-induced hepatotoxicity.

CASE SUMMARY: A 20-year-old female was hospitalized for treatment of Pseudomonas aeruginosa bacteremia and osteomyelitis. Empiric intravenous antibiotic therapy with piperacillin/tazobactam, vancomycin, and ciprofloxacin was started, and based on the results of culture and sensitivity testing, was changed to intravenous ceftazidime and tobramycin 70 mg every 8 hours on hospital day 3. Liver enzyme levels then increased over days 3-6. Tests for hepatitis A, B, and C were all nonreactive, and HIV testing was negative. On day 8, therapy was changed from ceftazidime to piperacillin/tazobactam and the tobramycin dose was increased to 100 mg every 8 hours. Due to a continued increase in total bilirubin, aspartate aminotransferase, and alanine aminotransferase, piperacillin/tazobactam was discontinued and aztreonam was started on day 10. All antibiotics were stopped on day 12 and the elevated liver parameters began to decrease. Aztreonam and ciprofloxacin were restarted on day 16, and most laboratory test results returned to baseline levels by day 19; total bilirubin and alkaline phosphatase decreased to lower than baseline values.

DISCUSSION: This case illustrates a possible occurrence of tobramycin-induced hepatotoxicity. Liver enzymes rose when tobramycin therapy was initiated, markedly increased when the tobramycin dose was increased, then resolved upon discontinuation of therapy. Other medication-related causes were ruled out by temporal relationship or rechallenge (aztreonam). Use of the Naranjo probability scale indicated a possible relationship between hepatotoxicity and tobramycin therapy. Other adverse reaction scales specific for evaluation of drug-induced liver disease were also used. Both the Council for International Organizations of Medical Sciences and Maria and Victorino scales indicated a probable likelihood of tobramycin-induced hepatotoxicity. This patient was not rechallenged with tobramycin due to the highly suggestive timeline present, lack of specific symptoms, and unnecessary risk to the patient.

CONCLUSIONS: Although no other case reports on this interaction have been published through October 9, 2007, historical data from tertiary sources reveal the possibility of aminoglycoside-induced hepatotoxicity; therefore, tobramycin-induced hepatotoxicity cannot be ruled out in this patient. Clinicians should be aware of this adverse event.

Annals of Pharmacotherapy

Neuralgic Amyotrophy Associated with Antibiotic Therapy

Neuralgic Amyotrophy Associated with Antibiotic Therapy

Ann Pharmacother. 2008 Aug

Finstad K, Guajardo JR, Scoville C.
Department of Child Health, University Hospital and Clinics, Columbia, MO.

OBJECTIVE: To report a case of neuralgic amyotrophy associated with antibiotic therapy.

CASE SUMMARY: A 22-year-old male with cystic fibrosis had been nonadherent to treatment for 4 years; when he returned to the clinic with symptoms, his forced expiratory volume in 1 second dropped from 84% predicted to 43% predicted. He was admitted to the hospital for treatment after failing to improve on oral ciprofloxacin and inhaled tobramycin. Treatment was initiated with intravenous tobramycin 560 mg daily and piperacillin/tazobactam 4.5 g infused every 6 hours. He continued inhaled tobramycin 300 mg twice daily, his home doses of pancreatic replacement enzymes and vitamins, albuterol 2.5 mg by high flow nebulizer (HFN) 4 times daily, and dornase alpha 2.5 by HFN daily. Sputum cultures were positive for methicillin-resistant Staphylococcus aureus, and intravenous vancomycin 1 g every 8 hours was added to the treatment regimen on hospital day 7. The patient developed bilateral shoulder pain followed by decreased function of his upper extremities 2 days later. He was treated with oral ibuprofen 600 mg every 6 h and oral cyclobenzaprine 5 mg daily, which improved his pain, but the shoulder stiffness remained throughout his hospital stay and persisted for 2 months following discharge. These symptoms resolved but recurred rapidly (within 24 h) and were more debilitating following a second exposure to the same antibiotics at the same doses 8 months later when the patient was readmitted for treatment of another cystic fibrosis-related pulmonary exacerbation.

DISCUSSION: To our knowledge, this is the first case report illustrating neuralgic amyotrophy triggered by exposure to the antibiotics vancomycin, tobramycin, and piperacillin/tazobactam. After analysis of the case, ruling out other possibilities and using the Naranjo probability scale, we found that there is a highly probable likelihood that the symptoms presented by our patient were secondary to his drug therapy. Neuralgic amyotrophy is a rare condition of unknown etiology that has never before been associated with administration of these antibiotics, individually or in combination. Because of the specifics of the clinical history, we were unable to ascertain whether this complication was due to a single antibiotic or to the combination. It is quite possible that vancomycin was the only culprit, but impossible to ensure with the available evidence.

CONCLUSIONS: Clinicians should be aware of this adverse reaction when facing similar complex neurologic symptoms in patients who are receiving the antibiotic treatment described here, especially vancomycin.

PMID: 18682542 [PubMed - as supplied by publisher]

Wednesday, August 06, 2008

Tigecycline: a critical update.

Tigecycline: a critical update.
J Chemother. 2008 Jul

Shakil S, Akram M, Khan AU.
Interdisciplinary Biotechnology Unit, Aligarh Muslim University, India.

Tigecycline is the first Food and Drug Administration (FDA) approved glycylcycline antibiotic. It has shown remarkable in vitro activity against a wide variety of gram-positive, gram-negative and anaerobic bacteria including many multidrug resistant (MDR) strains. However, it has minimal activity against Pseudomonas aeruginosa and Proteus spp. To date, little resistance to tigecycline has been reported. Clinical trials studying complicated skin and skin-structure infections (cSSSIs) demonstrated that tigecycline has equivalent efficacy and safety compared with the combination of vancomycin and aztreonam. For complicated intra-abdominal infections (cIAIs), tigecycline was found to be as effective as imipenem/cilastatin. Adverse events related to tigecycline therapy, i.e. nausea and vomiting, were tolerable. Currently available data suggest that tigecycline may play an important role in the future as a monotherapy alternative to older broad-spectrum antibiotics, such as advanced generation cephalosporins, carbapenems, fluoroquinolones, piperacillin/tazobactam, and gram-positive directed agents (e.g. daptomycin, linezolid and quinupristin/dalfopristin) for which resistance is being increasingly reported from all parts of the world.

PMID: 18676218 [PubMed - in process]

Monday, August 04, 2008

Daptomycin, a lipopeptide antibiotic in clinical practice.

Daptomycin, a lipopeptide antibiotic in clinical practice.
Curr Opin Investig Drugs. 2008 Aug

Weis F, Beiras-Fernandez A, Schelling G.
Department of Anesthesiology, University Hospital Grosshader, Marchioninistrasse 15, 81377, Munich, Germany.

Gram-positive cocci are one of the leading causes of infections in clinical medicine. Since the invention of antibiotic substances, multidrug resistance is a major problem in the treatment of such infections. Methicillin-resistant Staphylococcus aureus (MRSA) is responsible for 60% of nosocomial infections in the US. The first-choice drug used in these cases is the glycopeptide vancomycin; however, vancomycin is associated with a significant number of adverse side effects, such as nephro- and ototoxicity. Thus, the discovery of new drugs against MRSA and other multidrug-resistant cocci is of utmost interest. Daptomycin, a lipopeptide, is one of these new drugs and has been successfully used in the treatment of complicated skin and skin-structure infections and right-sided endocarditis. Because of its potency and pharmacological profile, it is increasingly used for new indications not yet approved by the FDA. The purpose of this article is to provide an overview of daptomycin, with particular emphasis on potential new indications for which it could be used in the future.


Bacteriophage therapy in children: Facts and prospects

Bacteriophage therapy in children: Facts and prospects

Med Sci Monit. 2008 Aug

Fortuna W, Miedzybrodzki R, Weber-Dabrowska B, Gorski A.
Bacteriophage Laboratory, Ludwik Hirszfeld Institute of Immunology and Experimental Therapy, Polish Academy of Sciences, Wroclaw, Poland and Phage Therapy Unit, Healthcare Center, Institute of Immunology and Experimental Therapy, Polish Academy of Sciences, Wrocław, Poland.

Data from the World Health Organization confirm a decrease in the effectiveness of antibiotic therapy. The spread of bacteria resistant to several groups of antibiotics creates more problems in the treatment of various diseases, especially in children. It is possible that pharmacological agents may prove to be ineffective in curing infections caused by resistant pathogens, and this could lead to a post-antibiotic era. It is necessary to extend the arsenal of the available therapeutic tools. Bacteriophages have long been used therapeutically and prophylactically in children. In the beginnings of phage therapy, enthusiasm prevailed over the rational methods used in contemporary controlled studies. Many people dealing with phages described cases of successful therapy, but did not conduct comparative studies. Nevertheless, phage administration seems to be safe, even in children after intravenous administration. The therapeutic and prophylactic application of phages is now experiencing a renaissance of interest. The authors' own recent analysis demonstrated the cost effectiveness of phages over antibiotic especially in the treatment of infections caused by multidrug-resistant bacteria. It can be concluded that the results of the therapeutic and prophylactic application of phages against multi-drug resistant pathogens are encouraging. It seems clear that bacteriophages need further evaluation regarding the control of bacterial infection in children.


A new lipoglycopeptide: telavancin.

A new lipoglycopeptide: telavancin.

Expert Opin Pharmacother. 2008 Aug

Nannini EC, Stryjewski ME.
Sanatorio Parque, Division of Infectious Diseases, Argentina.

The increase in infections caused by resistant Gram-positive organisms has led to an urgent need for new antibiotics. Telavancin is a rapidly bactericidal lipoglycopeptide with multiple mechanisms of action, including concentration-dependent inhibition of bacterial cell wall synthesis and disruption of the functional integrity of the cell membrane. Telavancin is active against a wide variety of Gram-positive organisms including Staphylococcus aureus with resistance to methicillin, reduced susceptibility to vancomycin, and full resistance to vancomycin. Telavacin is approximately 90% protein bound; it has a serum half-life of around 8 h and a prolonged postantibiotic effect, allowing once daily administration. Telavancin is eliminated principally through the urine, requiring dose adjustment in patients with renal impairment. The efficacy and safety of telavancin was demonstrated in a large program of patients with complicated skin and skin structure infections. Development of resistance has not been detected in clinical strains. Adverse events include taste disturbance, nausea and vomiting; a small proportion of patients experienced reversible increase in serum creatinine. Two large Phase III studies in patients with healthcare associated pneumonia were recently completed. Telavancin has the potential to become an important therapeutic option to treat serious infections produced by resistant Gram-positive cocci, particularly those caused by methicillin-resistant S. aureus.

Expert Opinion