The emergence of antibiotic resistance by mutation.

The emergence of antibiotic resistance by mutation.

Clin Microbiol Infect. 2007 Jan

Woodford N,
Ellington MJ.

Antibiotic Resistance Monitoring and Reference Laboratory, Centre for Infections, Health Protection Agency, London, UK.

The emergence of mutations in nucleic acids is one of the major factors underlying evolution, providing the working material for natural selection. Most bacteria are haploid for the vast majority of their genes and, coupled with typically short generation times, this allows mutations to emerge and accumulate rapidly, and to effect significant phenotypic changes in what is perceived to be real-time. Not least among these phenotypic changes are those associated with antibiotic resistance. Mechanisms of horizontal gene spread among bacterial strains or species are often considered to be the main mediators of antibiotic resistance. However, mutational resistance has been invaluable in studies of bacterial genetics, and also has primary clinical importance in certain bacterial species, such as Mycobacterium tuberculosis and Helicobacter pylori, or when considering resistance to particular antibiotics, especially to synthetic agents such as fluoroquinolones and oxazolidinones. In addition, mutation is essential for the continued evolution of acquired resistance genes and has, e.g., given rise to over 100 variants of the TEM family of beta-lactamases. Hypermutator strains of bacteria, which have mutations in genes affecting DNA repair and replication fidelity, have elevated mutation rates. Mutational resistance emerges de novo more readily in these hypermutable strains, and they also provide a suitable host background for the evolution of acquired resistance genes in vitro. In the clinical setting, hypermutator strains of Pseudomonas aeruginosa have been isolated from the lungs of cystic fibrosis patients, but a more general role for hypermutators in the emergence of clinically relevant antibiotic resistance in a wider variety of bacterial pathogens has not yet been proven.

PMID: 17184282 [PubMed - in process]

Doctors Prescribing Antibiotics Without Patient Examination

Study: Doctors call in more antibiotics without exams

By Rita Rubin, USA TODAY

Created: 12/6/2006 10:56:47 AM
Updated: 12/6/2006 10:57:58 AMPrescribing antibiotics has become so common that many doctors literally are just phoning it in, a new analysis of insurance claims suggests.

Prescribing antibiotics has become so common that many doctors literally are just phoning it in, a new analysis of insurance claims suggests.

Researchers found that 40% of people who filled an antibiotic prescription had not seen a doctor in at least a month, raising the possibility that their symptoms were the result of a viral infection, which doesn't respond to antibiotics, instead of a bacterial infection, which does.

Though antibiotics generally are benign, overprescribing has helped produce drug-resistant "superbugs."

"The study is just a broad indicator of too great a willingness to prescribe," says author William Marder, senior vice president and general manager of Thomson Medstat, a health care information company based in Ann Arbor, Mich.

Thomson Medstat analyzed 1.5 million insurance claims for antibiotic prescriptions in 2004 - the most recent information available - for children and adults under 65 covered by an employer health plan.

Marder called for new treatment guidelines for doctors who increasingly are likely to evaluate patients by phone and the Internet. "It will be critical for physicians to develop the skills necessary to communicate effectively with patients" they can't examine, he writes.

Already, though, says Dartmouth pediatrics professor James Sargent, there are many situations where doctors call in antibiotic prescriptions and refills "without cause for alarm."

For example, Sargent said via e-mail, his practice often calls in prescriptions for antibiotic drops for pinkeye and pills for sore throats in people who have a family member diagnosed with strep throat.

Randall Stafford, associate professor at Stanford's Prevention Research Center, acknowledges that phoned-in antibiotic prescriptions are OK in some situations, such as for women with a repeat urinary tract infection. Still, he called Marder's findings "concerning."

"The standard of care is to have adequate information to make reliable decisions," Stafford says. "Usually, that requires a physical exam."

Article

Cefazolin Sodium Injection

Cefazolin Sodium Injection

About your treatment

Your doctor has ordered cefazolin, an antibiotic, to help treat your infection. The drug will be either injected into a large muscle (such as your buttock or hip) or added to an intravenous fluid that will drip through a needle or catheter placed in your vein for 30 minutes, two to four times a day.

Cefazolin eliminates bacteria that cause many kinds of infections, including lung, skin, bone, joint, stomach, blood, heart valve, and urinary tract infections. This medication is sometimes prescribed for other uses; ask your doctor or pharmacist for more information.

Your health care provider (doctor, nurse, or pharmacist) may measure the effectiveness and side effects of your treatment using laboratory tests and physical examinations. It is important to keep all appointments with your doctor and the laboratory. The length of treatment depends on how your infection and symptoms respond to the medication.

Precautions

Before administering cefazolin:

tell your doctor and pharmacist if you are allergic to cefazolin, any other cephalosporin [e.g., cefaclor (Ceclor), cefadroxil (Duricef), or cephalexin (Keflex)], penicillins, or any other drugs.
tell your doctor and pharmacist what prescription and nonprescription medications you are taking, especially other antibiotics, probenecid (Benemid), and vitamins.
tell your doctor if you have or have ever had kidney, liver, or gastrointestinal disease (especially colitis).
tell your doctor if you are pregnant, plan to become pregnant, or are breast-feeding. If you become pregnant while taking cefazolin, call your doctor.

if you have diabetes and regularly check your urine for sugar, use Clinistix or TesTape. Do not use Clinitest tablets because cefazolin may cause false positive results.

Administering your medication

Before you administer cefazolin, look at the solution closely. It should be clear and free of floating material. Gently squeeze the bag or observe the solution container to make sure there are no leaks. Do not use the solution if it is discolored, if it contains particles, or if the bag or container leaks. Use a new solution, but show the damaged one to your health care provider.

It is important that you use your medication exactly as directed. Do not stop your therapy on your own for any reason because your infection could worsen and result in hospitalization. Do not change your dosing schedule without talking to your health care provider. Your health care provider may tell you to stop your infusion if you have a mechanical problem (such as a blockage in the tubing, needle, or catheter); if you have to stop an infusion, call your health care provider immediately so your therapy can continue.

Side effect

Cefazolin may cause side effects. If you are administering cefazolin into a muscle, it may be mixed with lidocaine (Xylocaine) to reduce pain at the injection site. Tell your health care provider if any of these symptoms are severe or do not go away:

diarrhea
stomach pain
upset stomach
vomiting

If you experience any of the following symptoms, call your health care provider immediately:
skin rash

itching
hives
unusual bleeding or bruising
difficulty breathing
sore mouth or throat

If you experience a serious side effect, you or your doctor may send a report to the Food and Drug Administration's (FDA) MedWatch Adverse Event Reporting program online
or by phone [1-800-332-1088].

Storing your medication

Your health care provider probably will give you a several-day supply of cefazolin at a time. If you are receiving cefazolin intravenously (in your vein), you probably will be told to store it in the refrigerator or freezer.

Take your next dose from the refrigerator 1 hour before using it; place it in a clean, dry area to allow it to warm to room temperature.

If you are told to store additional cefazolin in the freezer, always move a 24-hour supply to the refrigerator for the next day's use.

Do not refreeze medications.

If you are receiving cefazolin intramuscularly (in your muscle), your health care provider will tell you how to store it properly.

Store your medication only as directed. Make sure you understand what you need to store your medication properly.

Keep your supplies in a clean, dry place when you are not using them, and keep all medications and supplies out of reach of children. Your health care provider will tell you how to throw away used needles, syringes, tubing, and containers to avoid accidental injury.

In case of emergency/overdose

In case of overdose, call your local poison control center at 1-800-222-1222. If the victim has collapsed or is not breathing, call local emergency services at 911.

Signs of infection

If you are receiving cefazolin in your vein or under your skin, you need to know the symptoms of a catheter-related infection (an infection where the needle enters your vein or skin). If you experience any of these effects near your intravenous catheter, tell your health care provider as soon as possible:

tenderness
warmth
irritation
drainage
redness
swelling
pain

Brand names

Ancef®

Last Revised - 08/01/2006

Medline Plus

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CEFAZOLIN SODIUM USP

Action And Clinical Pharmacology: Cefazolin is a cephalosporin antibiotic for parenteral administration. Cefazolin exerts its bactericidal effect by inhibiting bacterial cell wall synthesis. Cefazolin is about 85% bound to serum protein. The peak level in serum is approximately 32 to 42 mg/mL after an i.m. injection of 500 mg. Over 80% of injected cefazolin is excreted in the urine during the first 24 hours after i.m. injection; most is excreted during the first 4 to 6 hours. tag_Indications

Indications Indications And Clinical Uses: In the treatment of the following infections when caused by susceptible strains of the listed organisms: Respiratory tract infections caused by S. pneumoniae, K. pneumoniae, H. influenzae, S. aureus (penicillin-sensitive and penicillin-resistant) and group A beta-hemolytic streptococci.

Urinary tract infections caused by E. coli, P. mirabilis, K. pneumoniae and some strains of enterobacter, and enterococci. See Note below.

Skin and soft tissue infections caused by S. aureus (penicillin-sensitive and penicillin-resistant), group A beta-hemolytic streptococci and other strains of streptococci.

Bone and joint infections caused by S. aureus. Septicemia caused by S. pneumoniae, S. aureus (penicillin-sensitive and penicillin-resistant), P. mirabilis, E. coli and K. pneumoniae. See Note below.

Endocarditis caused by S. aureus (penicillin-sensitive and penicillin-resistant) and group A beta-hemolytic streptococci. Determine susceptibility of the causative organism to cefazolin by performing appropriate culture and susceptibility studies. Note: Most strains of Enterococci, indole positive Proteus (P. vulgaris).

E. cloacae, M. morganii, P. rettgeri and methicillin-resistant Staphylococci are resistant.

Serratia, Pseudomonas and A. calcoaceticus (formerly Mima and Herellea species) are almost uniformly resistant to cefazolin.

Perioperative Prophylaxis: In patients undergoing potentially contaminated surgical procedures, and in patients in whom infection would pose a serious risk (e.g., during open-heart surgery and prosthetic arthroplasty), the preoperative, intraoperative and postoperative administration of cefazolin may reduce the incidence of certain postoperative infections. Identification of the causative organisms should be made by culture should signs of infection occur, so that appropriate therapy may be instituted.

Contra-Indications: In patients with known allergy to the cephalosporin group of antibiotics. tag_Warning

Warnings Manufacturers' Warnings In Clinical States: Use with caution in penicillin-allergic patients. There is clinical evidence of partial cross-allergenicity of the penicillins and the cephalosporins. There are instances of patients who have had reactions to both penicillins and cephalosporins (including fatal anaphylaxis after parenteral use). Clinical and laboratory evidence of partial cross-allergenicity of the 2 drug classes exists.

Cefazolin should be administered cautiously and then only when absolutely necessary to any patient who has demonstrated allergy, particularly to drugs. Immediate emergency treatment with epinephrine is indicated for serious anaphylactoid reactions. As indicated, oxygen, i.v. steroids, and airway management, including intubation, should also be employed.

There have been reports of pseudomembranous colitis with the use of cephalosporins. It is therefore important to consider its diagnosis in patients who develop diarrhea in association with antibiotic use.

Precautions: The overgrowth of nonsusceptible organisms may result from the prolonged use of cefazolin. It is essential that the patient be carefully observed.

In patients with a history of lower gastrointestinal disease, particularly colitis, cefazolin should be prescribed with caution. Clinitest tablets solution, but not enzyme-based tests such as Clinistix and Tes-Tape, may falsely indicate glucose in the urine of patients on cefazolin.

Positive direct and indirect Coombs' tests have been reported during treatment with cefazolin. These may also occur in neonates whose mothers received cephalosporins before delivery. The clinical significance of this effect has not been established.

Renal Impairment: Caution should be exercised in treating patients with pre-existing renal damage although cefazolin has not shown evidence of nephrotoxicity.

Patients with low urinary output due to impaired renal function should be administered reduced daily dosages of cefazolin. (See Dosage, Patients with Reduced Renal Function.) Blood levels of cefazolin in dialysis patients remain fairly high and should be monitored.

Probenecid may decrease renal tubular secretion of cefazolin when used concurrently with cefazolin, resulting in increased and prolonged cefazolin blood levels.

In beta-hemolytic streptococcal infections, treatment should be continued for at least 10 days, to minimize possible complications associated with the disease.

Pregnancy: The safety of the use of cefazolin during pregnancy has not been established.

Lactation: Very low concentrations of cefazolin are found in the milk of nursing mothers. Cefazolin should be administered with caution to a nursing woman.

Children: The safety of the use of cefazolin in prematures and infants under 1 month of age has not been established.

Drug Interactions: The renal tubular secretion of cefazolin may be decreased when probenecid is used concurrently, resulting in increased and prolonged cefazolin blood levels.

Adverse Reactions: The following reactions have been reported: Gastrointestinal: diarrhea, oral candidiasis (oral thrush), vomiting, nausea, stomach cramps, anorexia. During antibiotic treatment symptoms of pseudomembranous colitis can appear. There have been rare reports of nausea and vomiting.

Allergic: Allergic reactions occur infrequently and include: anaphylaxis, eosinophilia, itching, drug fever, skin rash. Hematologic: neutropenia, anemia, leukopenia, thrombocythemia, positive direct and indirect antiglobulin (Coombs') tests.

Hepatic and Renal: Without clinical evidence of renal or hepatic impairment transient increases in AST, ALT, BUN and alkaline phosphatase levels have been observed. Transient hepatitis and cholestatic jaundice have been reported rarely, as with some penicillins and some other cephalosporins. Local: Phlebitis at the site of injection has occurred rarely. Infrequently there is pain at the site of injection following i.m. injection. Some induration has been reported. Other: vulvar pruritus, genital moniliasis, vaginitis and anal pruritus.

Symptoms And Treatment Of Overdose: Symptoms and Treatment: There is a lack of experience with acute cefazolin overdosage. Supportive therapy should be instituted according to symptoms in cases of suspected overdosage. tag_DosageDosage

Dosage And Administration: After reconstitution cefazolin may be administered either i.m. or i.v. In both cases total daily dosages are the same. Cefazolin has been administered in dosages of 6 g/day in serious infections such as endocarditis. Treatment should be continued for at least 10 days in beta-hemolytic streptococcal infections to minimize possible complications associated with the disease.

Patients with Reduced Renal Function: After an initial loading dose appropriate to the severity of the infection, the following reduced dosage schedule is recommended (see Table II).

Perioperative Prophylactic Use: The recommended dosage regimen to prevent postoperative infection in contaminated or potentially contaminated surgery is: a) 1 g i.v. or i.m. administered 1/2 hour to 1 hour prior to the start of surgery so that at the time of the initial surgical incision adequate antibiotic levels are present in the serum and tissues. b) For lengthy operative procedures (e.g., 2 hours or more) 0.5 to 1 g administered i.v. or i.m. during surgery.

(Administration should be modified according to the duration of the operative procedure and the time of greatest exposure to infective organisms.) c) Postoperatively, 0.5 to 1 g i.v. or i.m. every 6 to 8 hours for 24 hours postoperatively. The prophylactic administration of cefazolin may be continued for 3 to 5 days following the completion of surgery in which the occurrence of infection may be particularly devastating (e.g., open-heart surgery and prosthetic athroplasty).

Children: A total daily dosage of 25 to 50 mg/kg of body weight, divided into 3 or 4 equal doses, is effective for most mild to moderately severe infections in children. For severe infections total daily dosage may be increased to 100 mg/kg of body weight. The use of cefazolin in prematures and in infants under 1 month is not recommended since the safety for use in these patients has not been established.

Pediatric Dosage Guide: See Tables III and IV. Treatment with 60% of the normal daily dose may be administered in divided doses every 12 hours to children with mild to moderate renal impairment (Ccr 0.67 to 1.17 mL/s). Children with moderate to severe renal impairment (Ccr 0.33 to 0.87 mL/s) should be given 25% of the normal daily dose in equally divided doses every 12 hours, and children with severe renal impairment (Ccr 0.08 to 0.33 mL/s) should receive 10% of the normal daily dose every 24 hours. All dosage recommendations apply after an initial loading dose.

Administration:

Note: See Reconstitution and Dilution directions below: I.M.: Inject the reconstituted solution into a large muscle mass. Pain on injection of cefazolin occurs infrequently.

I.V.: Direct (bolus) Injection: Inject the appropriately diluted reconstituted solution slowly over 3 to 5 minutes directly into a vein or through tubing for patients receiving parenteral fluids. (See list of solutions for i.v. infusion.)

Intermittent or Continuous Infusion: The reconstituted solution can be administered along with primary i.v. fluid management programs in a volume control set or in a separate secondary i.v. bottle. (See list of solutions for i.v. infusion.)

Reconstituted Solutions: Parenteral drug products should be shaken well when reconstituted, and inspected visually for particulate matter prior to administration. The drug solutions should be discarded if particulate matter is evident in reconstituted fluids. Reconstituted solutions may range in color from pale yellow to yellow without a change in potency. Reconstituted cefazolin may be stored for 24 hours at controlled room temperature not exceeding 25°C, or for 72 hours under refrigeration (2 to 8°C), protected from light. Cefazolin solution reconstituted with bacteriostatic diluent and used for i.m. administration as multiple-dose containers should be used within 6 days when stored under refrigeration. The pharmacy bulk vial is intended for multiple dispensing for i.v. use only, employing a single puncture. Following reconstitution, the solution should be dispensed and diluted for use within 8 hours. Any unused reconstituted solution should be discarded after 8 hours.

I.M. Injection: Single Dose Vials: Reconstitute according to Table V. Shake well.

Direct I.V. (bolus) Injection: Single Dose Vial: Reconstitute as directed above. Shake well. A minimum of 10 mL of Sterile Water for Injection should be used to dilute the reconstituted solution.

Pharmacy Bulk Vial: Pharmacy Bulk Vials should be used for i.v. use only. Add, according to Table VI, Sterile Water for Injection, Bacteriostatic Water for Injection, or Sodium Chloride Injection. Shake well. The vial is intended for single puncture and multiple dispensing, and the vial contents should be used within 8 hours.

Intermittent or continous i.v. infusion, reconstituted cefazolin may be further diluted as follows: Single Dose Vials: Reconstitute according to Table V. Shake well.

Further dilute the reconstituted cefazolin in 50 to 100 mL of Sterile Water for Injection or 50 to 100 mL of one of the following solutions: Sodium Chloride Injection 0.9%, Dextrose Injection 5% or 10%, Dextrose 5% in Lactated Ringer's Injection, Dextrose 5% and Sodium Chloride Injection 0.9% (also may be used with Dextrose 5% and Sodium Chloride Injection 0.45% or 0.2%), Lactated Ringer's Injection, Ringer's Injection, Sodium Bicarbonate 5% in Sterile Water for Injection. Pharmacy Bulk Vial: Reconstitute according to Table VI. Shake well.

Further dilute aliquots in 50 to 100 mL of Sterile Water for Injection or one of the solutions listed above. The further diluted solutions above should be used within 24 hours at room temperature or 72 hours under refrigeration from the time of initial puncture.

Extended Use of I.V. Admixtures: Although i.v. admixtures may often be physically and chemically stable for longer periods, due to microbiological considerations, they are usually recommended for use within the maximum of 24 hours at room temperature or 72 hours when refrigerated (2 to 8°C). Hospitals and institutions, that have recognized admixture programs and use validated aseptic techniques for preparation of i.v. solutions, may extend the storage times for cefazolin in admixtures with 5% Dextrose Injection or 0.9% Sodium Chloride Injection in Viaflex bags in 80 mg/mL concentrations to 30 days when stored under refrigeration (2 to 8°C) and in 5 mg/mL concentrations to 72 hours when stored under refrigeration (2 to 8°C).

Availability And Storage: 500 mg: Each clear glass vial of sterile powder contains: cefazolin 500 mg. Preservative-free. 1 g: Each clear glass vial of sterile powder contains: cefazolin 1 g.

Preservative-free. 10 g: Each pharmacy bulk vial of sterile powder contains: cefazolin 10 g.

Preservative-free. The availability of the pharmacy bulk vial is intended for hospitals with a recognized i.v. admixture program. Store between 15 and 25°C, protect from light.

RxMed

Single Dose Of Antibiotics Before Surgery

Single Dose Of Antibiotics Before Surgery Sufficient To Help Prevent Infection

Main Category: Infectious Diseases / Bacteria / Viruses News

Article Date: 26 Nov 2006 - 23:00pm (PST)

A single dose of antibiotics prior to surgery appears to prevent infections occurring at the surgical site as effectively as a 24-hour dosing regimen, and with reduced antibiotic costs, according to an article in the November issue of Archives of Surgery, one of the JAMA/Archives journals. Infections remain an important complication of surgical procedures despite increased knowledge about prevention and technological advances in modern surgery, according to background information in the article.

Prophylactic antibiotics--preventive antibiotics given before surgery--have been shown to decrease the occurrence of infection at the site of the surgery. However, due to rising health care costs and concerns about antimicrobial resistance, hospitals have been under pressure to use fewer antibiotics. Most guidelines for the use of prophylactic antibiotics recommend using only one dose prior to surgery; however, surgeons might not comply with this recommendation, sometimes giving patients more than one dose or using broad-spectrum (targeting many types of bacteria) rather than the recommended narrow-spectrum drugs. Silvia Nunes Szente Fonseca, M.D., M.P.H., Hospital Sao Francisco, Ribeirao Preto, Sao Paolo, Brazil, and colleagues studied infection rates before and after the implementation of a one-dose prophylactic antibiotic protocol at a local hospital. "We previously described the successful implementation of an antibiotic prophylaxis program in our hospital, discontinuing prophylactic antibiotic usage after 24 hours and correcting the timing of the first dosage," the authors write. "We decided to reduce all antibiotic prophylaxis to one dose because this measure could safely promote savings for our institution."

Under the new protocol, for most procedures, patients are given one 1-gram dose of the antibiotic cephazolin at the same time anesthesia is administered. The protocol was approved by surgeons prior to implementation; education was provided to surgical and medical staff. To assess the effectiveness of this approach, the researchers examined infection rates and costs for 6,140 consecutive patients who had surgery between February 2002 and October 2002 and 6,159 consecutive patients who had surgery between December 2002 and August 2003, following the implementation of the one-dose protocol.

The correct protocol was followed in 6,123 (99 percent) of the surgeries performed after the new guidelines were implemented. Surgical site infections occurred in 127 (2 percent) of surgeries performed under the 24-hour protocol and 133 (2.1 percent) performed under the one-dose protocol. The number of vials of cephazolin purchased decreased from 1,259 in the first time period to 467 in the second, a 63 percent decline that represented a monthly cost savings of $1,980 for this drug alone. The cooperation and encouragement of hospital administration and clinical staff, as well as educational efforts, contributed to the success of the new protocol, the authors write. "We were able to demonstrate that one-dose prophylaxis is feasible," they conclude. "In this era of restricted hospital budgets and increased bacterial resistance, one-dose prophylaxis may provide a way to improve performance by lowering costs." ### (Arch Surg. 2006;141:1109-1113.)

This study was supported by the Waldemar Barnsley Pessoa Foundation and Maternidade Sinha Junqueira Foundation.

Please see the article for additional information, including other authors, author contributions and affiliations, financial disclosures, funding and support, etc. Contact: Silvia Nunes Szente Fonseca

JAMA and Archives Journals

Dalbavancin: A review for dermatologists.

Dalbavancin: A review for dermatologists.
1: Dermatol Online J. 2006 May 30;12(4):6.

Scheinfeld N.

Department of Dermatology, St Lukes Roosevelt Hospital, New York.

Most complicated skin and skin structure infections (cSSSI) are caused by Staphylococcus aurens (SA) and streptococcus (SC). More and more isolates of SA and SC are resistant to methicillin (MRSA) and there are concerns that SA will become resistant to vancomycin (VRSA), the current standard of treatment. Dalbavancin (BI397) is a novel semisynthetic lipoglycopeptide that was designed to improve uon the natural glycopeptides currently available, vancomycin and teicoplanin. Phase-III clinical trials comprising more than 1,500 patients evaluating once-weekly dalbavancin in skin and soft tissue infections (SSTIs) associated with Gram-positive bacteria met the primary endpoint of non-inferiority in patients whose clinical response was evaluated at 2 weeks following therapy when compared to linezolid, cefazolin, or vancomycin, the three most widely administered standard-of-care agents for SSTIs. The side effect profile of dalbavancin is mild, with headache and pyrexia being the most adverse effects.

Once-a-week dosing with dalbavancin may obviate the need for the continued presence of IV lines in some patients, which could translate into fewer local infections and blood stream infections and which could facilitate transfer of the patients to skilled nursing facilities. Unlike other new antibiotics, such as oritavancin and tigecycline, dalbavancin is not active against vancomycin-resistant enterococcus or VRSA. Its approval by the FDA is expected soon. The extent to which dalbavancin will supplant vancomycin and whether it will be preferred other newer agents such as linezolid.

PMID: 17083861 [PubMed - in process]

* * * * * *

Dalbavancin: a new option for the treatment of gram-positive infections.

1: Ann Pharmacother. 2006 Mar;40(3):449-60. Epub 2006 Feb 28

NEW DRUG DEVELOPMENTS
Dalbavancin: A New Option for the Treatment of Gram-Positive Infections Shu-Wen Lin, MS PharmD
at time of writing, Specialty Resident in Infectious Diseases, Department of Pharmacy Services, University of Michigan Health System; Clinical Instructor, Department of Clinical Sciences, College of Pharmacy, University of Michigan, Ann Arbor, MI; now, Clinical Pharmacist, Infectious Diseases, Department of Pharmacy Services, Hahnemann University Hospital, Philadelphia, PA
Peggy L Carver, PharmD
Clinical Pharmacist in Infectious Diseases, Department of Pharmacy Services, University of Michigan Health System; Associate Professor, Department of Clinical Sciences, College of Pharmacy, University of Michigan
Daryl D DePestel, PharmD
Clinical Pharmacist in Infectious Diseases, Department of Pharmacy Services, University of Michigan Health System; Clinical Assistant Professor, Department of Clinical Sciences, College of Pharmacy, University of Michigan
Reprints: Dr. DePestel, Departments of Pharmacy Services and Clinical Sciences, University of Michigan Health System, UH B2D 301/0008, 1500 E. Medical Center Dr., Ann Arbor, MI 48109-0008, fax 734/936-7027, daryldd@umich.edu

OBJECTIVE:

To review the pharmacology, microbiology, chemistry, in vitro susceptibility, pharmacokinetics, clinical efficacy, safety, tolerability, dosage, and administration of dalbavancin, a new semisynthetic lipoglycopeptide.

DATA SOURCES:

A MEDLINE search, restricted to the English language, was conducted from 1966 through January 2006. Supplementary sources included program abstracts from the Interscience Conference on Antimicrobial Agents and Chemotherapy, American Society of Microbiology, and the Infectious Diseases Society of America from 2000 to 2005 and information available from the manufacturer's Web site.

STUDY SELECTION AND DATA EXTRACTION:

In vitro and preclinical studies, as well as Phase I, II, and III clinical trials, were evaluated to summarize the microbiology, pharmacology, clinical efficacy, and safety of dalbavancin. All published trials and abstracts citing dalbavancin were selected.

DATA SYNTHESIS:

Dalbavancin, a novel lipoglycopeptide, has a mechanism of action similar to that of other glycopeptides. It has in vitro activity against a variety of gram-positive organisms, but no activity against gram-negative or vancomycin-resistant enterococci that possess VanA gene. Due to its prolonged half-life (6-10 days), dalbavancin can be administered intravenously once weekly. In Phase II and III clinical trials, dalbavancin was effective and well tolerated for the treatment of skin and soft-tissue infections, catheter-related bloodstream infections, and skin and skin-structure infections. To date, adverse events are mild and limited; the most common include pyrexia, headache, nausea, oral candidiasis, diarrhea, and constipation.

CONCLUSIONS:

Dalbavancin appears to be a promising antimicrobial agent for the treatment of gram-positive infections. A new drug application was filed with the Food and Drug Administration (FDA) in December 2004. The FDA issued an approvable letter in 2005 for dalbavancin. If approved, dalbavancin is expected to be launched in the first quarter of 2006.

Key Words: BI397, dalbavancin, glycopeptide, gram-positive

Published Online, February 28, 2006. DOI 10.1345/aph.1G158

The Annals of Pharmacotherapy

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Dalbavancin activity against selected populations of antimicrobial-resistant Gram-positive pathogens.

Diagn Microbiol Infect Dis. 2005 Dec;53(4):307-10.

Streit JM,
Sader HS,
Fritsche TR,
Jones RN.

The JONES Group/JMI Laboratories, North Liberty, IA 52317, USA.

Dalbavancin, a dimethylaminepropyl amide derivative of the lipoglycopeptide A40926, was tested against 375 antimicrobial-resistant Gram-positive pathogens collected worldwide during 2001-2003. The isolates were tested by reference and Clinical Laboratory Standards Institute broth microdilution susceptibility methods, and dalbavancin was compared with over 20 other antimicrobials. Vancomycin resistance determinants among enterococci were identified using PCR primer sets for vanA and vanB. Dalbavancin was generally more potent than vancomycin or teicoplanin. Dalbavancin was highly active against penicillin- and ceftriaxone-resistant Streptococcus pneumoniae strains (MIC(90), < or =" 0.016">

PMID: 15922534 [PubMed - indexed for MEDLINE]

Inappropriate Use of Antibiotic Prophylaxis to Prevent Infective Endocarditis in Obstetric Patients

Inappropriate Use of Antibiotic Prophylaxis to Prevent Infective Endocarditis in Obstetric Patients

Sean B. Pocock, MD, MPH1 and Katherine T. Chen, MD, MPH1
From the 1Department of Obstetrics and Gynecology and Epidemiology, Columbia University, New York, New York.

OBJECTIVE:

To evaluate infective endocarditis prophylaxis practices during the intrapartum period and to assess obstetric providers’ adherence to the American Heart Association and American College of Obstetrics and Gynecology guidelines for infective endocarditis prophylaxis.

METHODS:

We performed a chart review of pharmacy, electronic nursing, and physician records to report this case series of obstetric patients who received infective endocarditis prophylaxis during the intrapartum period at a single tertiary referral care center during a 1-year study period from August 1, 2004, to July 31, 2005.

RESULTS:

Fifty patients received antibiotics for infective endocarditis prophylaxis. Three of the 50 patients who received infective endocarditis prophylaxis had high-risk cardiac lesions and three other patients had moderate-risk cardiac lesions and evidence for intrapartum infection. Thus, only six patients (12.0%, 95% confidence interval 4.5%–24.3%) met the American Heart Association and American College of Obstetricians and Gynecologists criteria for an appropriate indication for infective endocarditis prophylaxis. Of these six patients who had an appropriate indication for infective endocarditis prophylaxis, only three (50.0%, 95% confidence interval 11.8%–88.2%) received appropriate antibiotic regimens.

CONCLUSION:

Antibiotics are frequently given to obstetric patients during pregnancy. Although many obstetric patients receive antibiotics for recommended indications, some patients, as our study shows, do not. A concerted effort by all practitioners and institutions to reduce the amount of inappropriate antibiotics given to obstetric patients will have positive public health effects in addition to benefiting individual mothers and neonates.

LEVEL OF EVIDENCE: II-3

Obstetrics & Gynecology

The dearth of new antibiotic development

The dearth of new antibiotic development: why we should be worried and what we can do about it.

eMJA The Medical Journal of Australia

Patrick G P Charles and M Lindsay Grayson

2004

Abstract

The emergence and spread of multidrug-resistant pathogens has increased substantially over the past 20 years.

Over the same period, the development of new antibiotics has decreased alarmingly, with many pharmaceutical companies pulling out of antibiotic research in favour of developing “lifestyle” drugs.

Reasons given for withdrawing from antibiotic development include poor “net present value” status of antibiotics, changes in regulations requiring larger drug trials and prolonged post-marketing surveillance, clinical preference for narrow-spectrum rather than broad-spectrum agents, and high new-drug purchase costs.

Major improvements in infection control in Australia are needed to prevent further spread of resistant clones, buying some time to develop urgently needed new antibiotic agents.

Perpetuating a culture of “pharma bashing” will simply lead to more pharmaceutical companies withdrawing from the market. A change in the health and research culture is needed to improve cooperation between public, academic and private sectors.

Article

Antibiotic resistance is a natural phenomenon — resistant strains of Staphylococcus aureus were encountered soon after the introduction of penicillin into clinical medicine in 1941 by Florey, Chain and colleagues.1-3 The story of penicillin’s discovery and then manufacture in sufficient quantities to treat injured troops at the D-Day landing in 1944 is also notable, because it was probably the last time an antimicrobial was developed to such an initial extent by anyone other than a large pharmaceutical company.4 To our knowledge, since the time of Florey, no government (regardless of its rhetoric) has developed a single new antimicrobial, and, while many clinicians criticise the activities of the big drug manufacturers, it is these companies that have been responsible for almost all new antimicrobial research and development during the past half-century.5 Although antibiotic development was rapid between the 1950s and the 1970s, with multiple new drugs being developed, many of these gains have been eroded over the past 30 years because of the rapid emergence of and spread of resistance to antimicrobials.6 Here, we explain what lies behind the developing resistance and why, despite a seemingly crowded current antibiotic market, the true picture is that our antibiotic development pipeline has been reduced to a trickle. We propose some problem-based solutions that could help prevent, or at least delay, a return to the dangers of the pre-antibiotic era.

Why do we need new antibiotics?

Burgeoning resistance

The increasing prevalence of resistant pathogens is mainly related to either the emergence of new strains or the spread of existing resistant clones. The specific mechanisms of drug resistance are important in determining its likely reversibility. For instance, plasmid-mediated resistance (eg, ampicillin resistance in Escherichia coli) is more likely to be reversible when exposure to the relevant antibiotic is withdrawn than chromosomally mediated resistance (eg, fluoroquinolone resistance in gram-negative bacteria), which is often a “one-way street”, with reversal much less likely.7

Although the emergence of resistant clones is crucial, the factor responsible for most resistance problems is patient-to-patient spread of existing resistant clones, usually on the hands of healthcare workers or on shared equipment in hospitals,8-11 aided by the increasing immunological frailty of many hospital inpatients.7

Inappropriate antibiotic use is a key driver of resistance, but the reasons for such use can be complex.7 In developed countries, the obsession with “zero risk” has distorted the decision-making process for many clinicians, with broad-spectrum antibiotics being used even when not indicated. Pharmaceutical marketing often targets such clinician insecurity, and rational debate is not always helped by the growing band of “microbiology accountants”, who report the percentage of resistant strains among their laboratory collections of pathogens rather than the likelihood of resistant pathogens among patients presenting with a particular disease.

Appropriate antibiotic prescribing has also been affected by the threat of bioterrorism.12 For instance, although the anthrax strain used in the 2001 US anthrax attacks was susceptible to both tetracyclines and penicillin, 32 000 government workers and other contacts were treated with oral ciprofloxacin for up to 60 days as prophylaxis, just in case the strain was capable of producing β-lactamase.13

Underpowered response?

The current antibiotic market is fairly crowded with agents, but many of these are “me-too” antibiotics — drugs from the same class developed by competing companies (eg, fluoroquinolones and third-generation cephalosporins). There has been a decline in registration of new antibiotics. A summary of new antibiotics and older antibiotics with new indications or treatment options is given in Box 1.

Several of the “new” antibiotics were actually discovered in the 1980s. Their development stalled because of poor initial results or problems with toxicity, but, more recently, desperation has led to renewed research interest in these drug classes, especially agents for treating gram-positive pathogens (Box 2). For example, daptomycin was initially studied in the early 1990s but was “shelved” due to toxicity, especially its potential to cause myositis. Its use at a lower dose has now been reassessed.18,19

Oritavancin, tigecycline and ramoplanin are the only truly new antibiotic agents that are likely to enter the Australian market in the next 5 years, with only tigecycline likely to be active against gram-negative bacteria.20,21 Because of this and the worsening problem of multiresistant Acinetobacter spp., Pseudomonas aeruginosa and Klebsiella spp., clinicians have been forced to use more toxic older agents such as colistin (Box 1).22

Why is the new-antibiotic pipeline running dry?

Large pharmaceutical companies are primarily responsible for new antibiotic development, with 93% of new agents developed between 1980 and 2003 coming from this source, rather than small biotechnology companies or small pharmaceutical manufacturers.5 The cost of researching and developing any new drug is generally in excess of US$500 million, and it usually takes about 8–10 years from the time a drug is first developed to the time it is released for sale.5,6 Naturally, pharmaceutical companies will only take this risk if there is reasonable likelihood of recouping development costs and making a profit. The pharmaceutical industry is under considerable financial pressure, with many companies believing they need to get bigger to survive and to afford the research needed for drug licensing. However, with more than 40 companies merging and consolidating over the past 20 years, there are now only about eight companies still undertaking some antibiotic research and development.23,24 This is because, during the past 10–15 years, a number of key factors (discussed below) have combined to reduce pharmaceutical companies’ interest in antibiotic development.

Relatively low “net present value”

For an increasing number of pharmaceutical companies, antibiotics are financially less attractive to develop than drugs for other indications (Box 3). Antibiotics are generally used for short periods for specific, relatively narrow indications. In comparison, other agents (eg, lipid-lowering agents) are often commenced at a relatively young age, are taken by a large proportion of the population for many years without much restriction, and are not subject to the emergence of resistance. Further, in contrast to the restrictions placed on antibiotics, there are few guidelines (or physician experts) advising against widespread use of these agents.25

Conducting clinical trials is one of the major expenditures in developing any new drug, and a separate clinical trial is needed for each potential indication for a drug. The complexity of conducting clinical trials for antibiotics adds to the costs associated with their development and licensure.

Such financial considerations are often summarised by a drug’s “net present value” (NPV). This is what the drug’s future is worth in today’s money. Usually, the NPV is then risk-adjusted (rNPV), based on the extent to which the drug has been developed. For instance, an antibiotic in Phase III trials carries less risk than one early in development (most antibiotics in Phase III trials have an 87% “success rate”).24 Thus, it is no surprise that antibiotics have a lower rNPV than many other drug classes. In fact, in some industry estimates, injectable antibiotics rank well behind musculoskeletal, neuroscience and oncology agents and vaccines in terms of rNPV.24

Stricter standards for equivalence

Most antibiotic trials are “equivalence” trials, whereby the new drug is required to have equivalent or similar efficacy to an older, comparator agent that is already licensed for the relevant indication. The amount to which the efficacy of the new agent can differ from the comparator and still be considered sufficiently similar to be “equivalent” is called the “delta” value. Until recently, the standard for most antibiotic trials in which a drug’s efficacy was estimated to be 80%–90% was a delta value of 15% — that is, as long as the new antibiotic was within 15% of the efficacy of the comparator (ie, no more than 15% better or worse) it was considered statistically equivalent. Such trials would generally be used to support the licensure of the new drug for the studied indication. Because of concerns about possible “downward” drift in efficacy over time, some regulatory authorities have proposed that the delta value be reduced to 10%. The effect of this proposal would be to more than double the number of patients who need to be enrolled in antibiotic trials to demonstrate the new standard of “equivalence” (eg, for a study of community-acquired pneumonia, 1500–2200 patients would be required instead of 600–1000).25 Increased patient recruitment would add to trial costs.

Further, for some relatively uncommon, but important, indications, this increase in required patient recruitment would be unachievable from a clinical perspective, or would result in the trial becoming so prolonged that the comparator drug may no longer be considered appropriate due to the emergence of antibiotic resistance. It is believed that the proposed change in the trial delta value was a key reason for at least two major manufacturers withdrawing from antibiotic research prior to 2002.26

Risk of rapidly emerging antibiotic resistance

While the presence of antibiotic resistance among key clinical pathogens can be an important driver of new antibiotic development, it can also be a disincentive. This is especially the case if resistance to a new agent is emerging quickly, so that clinical trials cannot be completed without a substantial number of the enrolled patients being infected with new, highly resistant strains. This mostly affects trials associated with relatively rare clinical conditions (eg, bacterial meningitis or endocarditis), for which trials may take many years and require many enrolment sites to complete. However, it is often these uncommon, clinically devastating diseases that most require the development of new antibiotics to overcome the reduced efficacy of older agents.
Cross-class resistance can be a particular problem, as the development of resistance to either the new agent or the older comparator during a trial can make the assessment of either equivalence or superiority clinically irrelevant, and thus devalue the trial.

Clinical preference for narrow-spectrum agents

Given the costs associated with drug development, many companies attempt to design agents with a broad antibacterial spectrum to make them more suitable for a wide variety of indications. However, to avoid rapid emergence of resistance, many infectious disease experts often prefer that new antibiotics be used for specific, narrow indications for which the efficacy of older agents has become a problem. Thus, while pharmaceutical companies are pressing for multi-indication use to recoup their development costs, regulatory authorities frequently limit a new drug’s indications.

Varying licensure regulations

Conducting clinical trials to obtain multi-indication licensure is complicated by the fact that licensing requirements can vary between the United States, the United Kingdom, Europe, Australia and South America. Although there have been attempts to streamline these regulatory requirements, differences remain, so that pharmaceutical companies invariably target their most profitable market (generally the United States) when designing trials, even though other markets may have a greater disease burden and clinical need for the new agent.7 The World Health Organization and other agencies have tried to help standardise regulatory requirements, but progress has been slow.

Relatively high purchase price

Invariably, new agents are more expensive to users than their older comparators, as they are still under patent protection, and companies attempt to recoup their development costs during the patent period. In Australia, the initial high cost of some agents often leads to restrictions on their use both in hospitals and by the Pharmaceutical Benefits Scheme. In some developing countries, this high cost of a new drug encourages pharmaceutical companies that make generic drugs to ignore patent law and produce the drug at reduced cost, thereby often further eroding the new drug’s market.7

Increased post-marketing surveillance

Post-marketing surveillance of new drugs has been a growing requirement of most regulatory authorities over the past 20 years. For some agents, this has been vital in identifying important toxicities (eg, hepatotoxicity associated with trovafloxacin), but, for others, it has identified potential adverse effects that, although important, would not overly limit use of the drug if the clinical indication were sufficiently worthy (eg, the possibility of elevated liver enzyme levels and some blurred vision associated with use of telithromycin).23,24 However, the requirement for companies to maintain detailed post-marketing surveillance programs adds to a drug’s development costs and reduces its NPV, as some commercial risk persists after a drug is licensed.

How can we improve the situation?

In the near future, there appears to be little that can be done to overcome the current and impending shortage of new agents. Instead, there must be a greater focus on appropriate infection control measures to limit the spread of resistant clones within hospitals and reduce the emergence of new resistant strains by restricting unnecessary antibiotic use in humans and in agriculture.7,27

In Australia, the current hyperendemic spread of methicillin-resistant S. aureus within most large hospitals is a reflection of past apathy and woeful infection control measures in the 1970s and 1980s. The same mistakes must not be repeated with vancomycin-resistant enterococci, S aureus with reduced vancomycin susceptibility, and multiresistant Acinetobacter.28-30

Governments need to prioritise funding for effective infection control measures, such as patient cohorting and isolation (ie, greater access to single rooms) and improved hand hygiene among healthcare workers through the use of alcohol/chlorhexidine-based handrub to minimise transmission of resistant pathogens.11 Neglecting these issues will inevitably undermine current healthcare gains.

To encourage renewed interest in antibiotic research and development, a number of approaches have been suggested, many of which we believe could be effective:

Standardise regulation and licensure. Standard requirements for drug regulation in the United States, United Kingdom, Europe and other regions could have substantial benefits by reducing the number of clinical trials needed to obtain widespread licensure.

Specify appropriate antibiotic comparators. The proposal for a 10% delta value arose in response to concerns about downward drift in comparator efficacy. An alternative way of reducing the likelihood of inadequate efficacy would be for regulatory agencies to specify the appropriate antibiotic comparator required for each indication. This approach would allow the 15% delta value (and thus the current number of patients required for each trial) to be maintained.

Broaden the funding base for drug research and development. To reduce the financial risk of developing new drugs, antibiotic research and development could be co-funded by pharmaceutical companies, governments and public academic institutions.27 Tax incentives for companies to perform work in identifying new drugs might help.7

Increase cooperation between academic institutions and pharmaceutical companies. More research into the mechanisms of antibiotic resistance and bacterial physiology would allow the development of antimicrobials with new mechanisms of action, as occurred with the recently discovered CBR703 class of molecules, which inhibit bacterial RNA polymerase.31

Fast-track drug licensure when needed. For high-priority diseases, where resistance is a major clinical problem, a new system of fast-tracking licensure of potential agents is necessary to enhance clinical availability while continuing to monitor potential adverse reactions. The current system of fast-tracking drugs for treating HIV could serve as a useful model.7

Extending the duration of patent protection (so-called “exclusivity”) has also been proposed as a way of encouraging antibiotic research and development. However, we believe this is unlikely to be particularly effective, as the later years of a drug’s patent are heavily discounted in the NPV calculation because of the emergence of resistance and higher likelihood of generic pharmaceutical companies ignoring patent regulations and producing the drug at lower cost.

Conclusion

Declining antibiotic research and development at a time of increasing emergence and spread of resistant pathogens poses a major challenge to our society if we are to avoid a return to the pre-antibiotic era for many infections. Perpetuating a culture of “pharma bashing” will simply lead to more pharmaceutical companies withdrawing from the market. Crucial to success will be a change in the health and research culture towards greater cooperation between the public, academic and private sectors. Improving infection control initiatives will buy some time, but, given the lag between antibiotic development and eventual availability, we need to develop a sensible strategy soon to avoid problems in the next one to two decades.

e Medical Journal of Australia

Antibiotic-Associated Colitis

Antibiotic-Associated Colitis

Antibiotic-associated colitis is inflammation of the large intestine caused by the growth of unusual bacteria that results from the use of antibiotics.

Many antibiotics alter the balance among the types and quantity of bacteria in the intestine, thus allowing certain disease-causing bacteria to multiply and replace other bacteria. The type of bacteria that most commonly overgrows and causes infection is Clostridium difficile. Clostridium difficile infection releases two toxins that can damage the protective lining of the large intestine.

Almost any antibiotic can cause this disorder, but clindamycinSome Trade Names CLEOCIN, penicillins such as ampicillinSome Trade Names OMNIPENPOLYCILLINPRINCIPEN, and cephalosporins such as cephalexinSome Trade Names KEFLEXare implicated most often. Other commonly involved antibiotics include erythromycinSome Trade Names E-MYCINERYTHROCINILOSONE, sulfonamides such as sulfamethoxazoleSome Trade Names GANTANOL, chloramphenicolSome Trade Names CHLOROMYCETIN, tetracyclineSome Trade Names ACHROMYCIN VTETRACYNSUMYCIN, and quinolones such as norfloxacinSome Trade Names NOROXIN.

Clostridium difficile infection is most common when an antibiotic is taken by mouth, but it also occurs when antibiotics are injected or administered intravenously. The risk of developing antibiotic-associated colitis increases with age.

Symptoms

Symptoms usually begin while the person is taking antibiotics. However, in one third of people who have this disorder, symptoms do not appear until 1 to 10 days after treatment has stopped, and in some people, symptoms do not appear for as long as 6 weeks afterward.

Symptoms vary according to the degree of inflammation caused by the bacteria, ranging from slightly loose stools to bloody diarrhea, abdominal pain, and fever. The most severe cases may involve life-threatening dehydration, low blood pressure, toxic megacolon (see Inflammatory Bowel Diseases: Complications), and perforation of the large intestine

Diagnosis

The diagnosis of antibiotic-associated colitis is confirmed when one of the toxins produced by Clostridium difficile is identified in a stool sample. A toxin is found in about 20% of people with mild antibiotic-associated colitis and in more than 90% of those with severe antibiotic-associated colitis. Sometimes two or three stool samples must be obtained before the toxin is detected.

A doctor can also diagnose antibiotic-associated colitis by inspecting the lower part of the inflamed large intestine (the sigmoid colon), usually through a sigmoidoscope (a rigid or flexible viewing tube). A colonoscope (a longer flexible viewing tube) is used to examine the entire large intestine if the diseased section of intestine is higher than the reach of the sigmoidoscope. These procedures, however, usually are not required.

Treatment

If a person with antibiotic-associated colitis has diarrhea while taking antibiotics, the drugs are discontinued immediately unless they are essential. Drugs that slow the movement of the intestine, such as diphenoxylate, generally are avoided because they may prolong the disorder by keeping the disease-causing toxin in contact with the large intestine. Antibiotic-induced diarrhea without complications usually subsides on its own within 10 to 12 days after the antibiotic has been stopped. When it does, no other therapy is required. However, if mild symptoms persist, cholestyramineSome Trade Names QUESTRANmay be effective, probably because it binds itself to the toxin.

For most cases of more severe antibiotic-associated colitis, the antibiotic metronidazoleSome Trade Names FLAGYLis effective against Clostridium difficile. The antibiotic vancomycinSome Trade Names VANCOCINis reserved for the most severe or resistant cases. Symptoms return in up to 20% of people with this disorder, and treatment with antibiotics is repeated. If diarrhea returns repeatedly, prolonged antibiotic therapy may be needed. Some people are treated with preparations of lactobacillus given by mouth or bacteroides given rectally to restock the intestine with normal bacteria; however, these treatments are not used routinely.

Rarely, antibiotic-associated colitis is so severe that the person must be hospitalized to receive intravenous fluids, electrolytes (such as sodium, magnesium, calcium, and potassium), and blood transfusions. A temporary ileostomy (a surgically created connection between the small intestine and an opening in the abdominal wall that diverts stool from the large intestine and rectum) or surgical removal of the large intestine occasionally is needed in these severe cases as a lifesaving measure.

Merck