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