How To Choose Antibiotics For Staph Aureus Infections

The common thread shared by virtually all antibiotics relevant to podiatry is their activity against S. aureus. After all, S. aureus is by far the predominant infecting organism in lower extremity skin and skin structure infections. The rationale behind choosing an appropriate anti-staphylococcal drug is a daunting task given the ever-changing resistance pattern of this formidable organism. Today, virtually all strains of S. aureus found in lower extremity infections produce beta-lactamase. Beta-lactamase (also known as penicillinase) is an enzyme that cleaves the beta-lactam ring and inactivates the antibiotic. Therefore, empiric therapy for suspected Staph infections should always include a beta-lactamase stable antibiotic. For this reason, it is useful to categorize antibiotics as being either beta-lactamase stable or beta-lactamase susceptible. Drugs such as amoxicillin and ampicillin are beta-lactamase susceptible and should not be relied upon to treat lower extremity Staph infections. Patients will often begin self-treatment with these agents as they may have a few capsules left over from an ear or dental infection. However, they have minimal usefulness in the foot. To overcome bacterial resistance, some drugs combine a beta-lactam antibiotic and a beta-lactamase inhibitor, thus creating a stable, new compound (such as amoxicillin/clavulanate, ampicillin/sulbactam, piperacillin/tazobactam and ticarcillin/clavulanate) with good activity against Staph. A useful side benefit of these additions is the extension of the drug’s spectrum to include B. fragilis, which makes the antibiotics attractive choices when anaerobic bacteria is an issue. Nafcillin, oxacillin, dicloxacillin and, of course, methicillin, also known as the semisynthetic or penicillinase resistant penicillins, are all beta-lactamase stable as are the cephalosporins and carbapenems. Historically, methicillin was one of the first drugs developed to combat the growing number of beta-lactamase producing S. aureus infections. However, methicillin is no longer used due to adverse reactions. The primary reason to be familiar with the drug is because organisms resistant to the entire class have become known as “methicillin resistant.” Other antibiotics are beta-lactamase stable and active against Staph by virtue of the fact that they are not beta-lactam compounds and thus do not contain a beta-lactam ring (see “Other Agents” in “Differentiating Antibiotic Categories” below). Although they have varying degrees of activity against S. aureus, they are often used to help treat patients who have a history of a penicillin allergy. Understanding The Origin And Impact Of MRSA Shortly after its introduction, strains of S. aureus resistant to methicillin began to emerge. Currently, rates of nosocomial methicillin resistant Staph aureus (MRSA) approach 60 percent in many ICUs. Rates of MRSA in the community have likewise been increasing with a recent study putting the number at close to 40 percent. In early reports, community isolates of MRSA had largely affected people with known risk factors for colonization. These risk factors included patients who have been in acute or long term care facilities, individuals who have recently undergone antibiotic therapy and those in proximity to patients infected or colonized with MRSA. However, recent reports describe colonization and transmission in populations lacking risk factors. To understand why some drugs are active against MRSA and others are not, it is helpful to look at the mechanism of resistance. Methicillin resistance is associated with penicillin binding protein 2a (PBP2a). Encoded by the mec A gene, PBP2a has low binding affinity for beta-lactam antibiotics. Therefore, by definition, MRSA is resistant to all currently available beta-lactam antibiotics. Over the years, oxacillin has replaced methicillin on culture and sensitivity reports as the antibiotic one looks to for identifying MRSA. Oxacillin is a more stable drug and is more resistant to degradation in storage. Oxacillin is also more likely to detect heteroresistant strains. Indeed, methicillin has fallen out of use and is no longer commercially available in the United States. The acronym MRSA is still used to describe these isolates because of its historic role. One can differentiate two major types of methicillin resistance in staphylococci; high level resistance and intermediate or borderline resistance. In general, nosocomial strains of MRSA tend to exhibit high-level resistance, showing sensitivity only to drugs like vancomycin and linezolid. Community acquired strains are more likely to exhibit intermediate or borderline resistance, and retain sensitivity to drugs like trimethoprim/sulfamethoxazole, minocycline and occasionally clindamycin. In rare instances, some strains of S. aureus hyperproduce beta-lactamase, thereby exhibiting a sensitivity pattern similar to MRSA. Beta-lactam/beta-lactamase inhibitor compounds such as amoxicillin/clavulanate may show activity against these isolates. The cross reactivity between penicillin and cephalosporins is often a concern especially if a patient has a history of anaphylaxis. The oft-quoted cross-reaction rate of 10 percent is not based on any rigorous trials. The actual number is probably far lower. Recent data suggests that cross reactivity between penicillins and second- or third-generation cephalosporins is probably no higher than between penicillins and other classes of antibiotics. In cases where allergic reaction does occur, the side chain rather than the beta-lactam ring is thought to be the antigen. Case Study One: Prescribing Antibiotics For A Pregnant Patient A situation that commonly causes considerable trepidation is treating an infection in a patient who is pregnant. As the following scenario illustrates, one can safely use antibiotics in the pregnant patient by using published FDA data and having a strong knowledge of what organism predominates in a given situation. A 24-year-old pregnant female is referred to your office by her obstetrician for treatment of an infected ingrown toenail. She has been given a prescription for amoxicillin 500mg q8h. Should you continue the amoxicillin or switch her to another antibiotic? Empiric therapy in this situation is governed by two factors: the most probable infecting organism (beta-lactamase producing S. aureus) and the FDA pregnancy category of the drug to be prescribed. Since amoxicillin is beta-lactamase susceptible, one must switch to an antibiotic that is beta-lactamase stable. The new drug should also come from the safest FDA risk category. Every FDA approved drug is assigned a pregnancy risk category. The categories A, B, C, D and X refer to the potential harm the drug poses to the fetus. Category A. Controlled studies show no risk. Adequate, well-controlled studies in pregnant women have failed to demonstrate a risk to the fetus in any trimester of pregnancy. It’s not surprising that there are no antibiotics in this class. Category B (penicillins, cephalosporins, clindamycin, meropenem, ertapenem, erythromycin/azithromycin, metronidazole). There is no evidence of risk in humans. The chance of fetal harm is remote, but remains a possibility. There are many useful antibiotics in this class. Category C (linezolid, imipenem/ cilistatin, quinolones, trimethoprim/sulfamethoxazole, vancomycin, rifampin). Risk cannot be ruled out, but the potential benefits outweigh the potential risks. Category D (aminoglycosides, tetracyclines). There is positive evidence of risk. These antibiotics are acceptable in life-threatening situations or serious diseases for which safer drugs cannot be used or are ineffective. Category X. Contraindicated in pregnancy. Risks clearly outweigh any possible benefit to the patient. There are no antibiotics in this category. For the aforementioned patient, one may consider several useful anti-staphylococcal agents in category B. For example, a beta-lactamase stable penicillin or a cephalosporin would not only be active against S. aureus, but would be among the safest drugs we could prescribe. Case Study Two: Antibiotic Usage In Patients Undergoing Hemodialysis Once again, empiric therapy is based on knowledge of the most probable infecting organism. However, depending on the antibiotic you choose, dose adjustment may be required. For example, perhaps you are treating a diabetic foot infection with oral antibiotics and wish to prescribe the following combination: – clindamycin 300mg q8h P.O. – ciprofloxacin 500mg q12h P.O. The patient informs you she receives hemodialysis three times a week. What does this mean in terms of antibiotic dose adjustment? Factors influencing dialyzability include the type of dialysis membrane, blood flow rate, dialysate flow rate and ultrafiltration rate. Drug-related factors include molecular weight, protein binding and water solubility. Some antibiotics do not need dose adjustment. They include moxifloxacin, clindamycin, azithromycin, linezolid, minocycline, metronidazole and dicloxacillin. These can be given to dialysis patients at their usual dose. Other drugs require dose adjustment. There are standard adjustments for common oral antibiotics for patients who are undergoing hemodialysis (see “A Review Of Antibiotic Dose Adjustments For Hemodialysis Patients” below). In our scenario, only ciprofloxacin required dose adjustment while clindamycin could still be given at the usual dose. Therefore, the new prescription becomes clindamycin 300mg q6h po and ciprofloxacin 250mg q12h. Case Study Three: Treating Patients With Endocarditis Prophylaxis Infective endocarditis can have devastating consequences. Although American Heart Association Guidelines are clear that prophylaxis is not indicated for elective surgery through surgically prepared skin, they are warranted in the presence of infection. Incision and drainage of abscesses and debridement of infected ulcers can potentially produce a bacteremia which can seed damaged cardiac endothelium and prosthetic valves. By applying the recommendations of the American Heart Association, we can help prevent potentially life threatening complications in at-risk patients. Perhaps a 42-year-old female presents with a Staph abscess on the right hallux which you plan to I&D in your office. She has a history of mitral valve prolapse (MVP) with regurgitation and has been told to take amoxicillin whenever she has dental work performed. She has no known drug allergies. Does this patient require endocarditis prophylaxis and if so, what antibiotic would be appropriate? Although her cardiac condition places her only in the moderate risk category, endocarditis prophylaxis is still recommended. For dental prophylaxis, Strep viridans would be the organism of greatest concern, which is why our patient was advised to take amoxicillin. In our scenario, however, beta-lactamase producing S. aureus is of greatest concern. Being beta-lactamase susceptible, amoxicillin would be an inappropriate choice. For endocarditis to develop, two independent events are required. First, an area of endothelium must be damaged and, second, bacteremia caused by organisms capable of adhering to the damaged endothelium must occur. Endocarditis prophylaxis is recommended for patients who are at a statistically higher risk for endocarditis than people in the general population. The American Heart Association has categorized these risk factors as follows: High Risk Category (endocarditis prophylaxis recommended) 1) prosthetic cardiac valves 2) previous bacterial endocarditis Moderate Risk Category (endocarditis prophylaxis recommended) 1) acquired valvar dysfunction 2) hypertrophic cardiomyopathy 3) mitral valve prolapse with valvar regurgitation and/or thickened leaflets Negligible Risk Category (endocarditis prophylaxis not recommended) 1) previous coronary bypass surgery (CABG) 2) mitral valve prolapse without regurgitation 3) physiologic, functional or innocent heart murmurs 4) previous rheumatic fever without valvar dysfunction 5) cardiac pacemakers and implanted defibrillators For our prophylactic regimen to be effective, it must meet two conditions. First, the antibiotic must be active against the anticipated organism. Second, the antibiotic must reach peak serum concentration at the time of surgery. In the case of methicillin susceptible S. aureus (MSSA), several options are available. Oral No penicillin allergy: Cephalexin 2g PO 1 hour before surgery Penicillin allergy: Clindamycin 600mg PO 1 hour before surgery Parenteral No penicillin allergy: Cefazolin 1g IV 30 minutes before surgery Penicillin allergy: Clindamycin 600mg 30 minutes before surgery Since our procedure will take place in an office setting and our patient relates no allergy to penicillin, the most reasonable option would be to give 1 gram of cephalexin one hour before performing the I&D. A Guide To New Antibiotics Several antibiotics have gained notoriety over the past few years. All of these antibiotics are beta-lactamase stable and all possess qualities which make them useful for treating lower extremity infections. In taking a closer look at these antibiotics, each one has useful features. Ertapenem. This is a long acting parenteral carbapenem. Once a day dosing and its broad spectrum coverage make it well suited for home intravenous antibiotic therapy, especially in diabetic foot infections. Cross resistance to other carbapenems with Pseudomonas has been reported. The usual dose is 1g q24 hours IV Linezolid. As the first member of the oxazolidinone class of antibiotics, linezolid is broadly active against gram-positive bacteria including MRSA and VRE. Since the drug offers 100 percent bioavailability after oral administration, there is no dose adjustment necessary when switching a patient from parenteral to oral therapy. Early reports suggested linezolid was responsible for a high incidence of thrombocytopenia. However, analysis of the HAP (hospital acquired pneumonia) database (n-1,019) shows the use of linezolid does not increase the risk for developing thrombocytopenia versus vancomycin. Monitor CBC weekly especially if there is preexisting myelosupression. The usual dose is 600mg q12h P.O. and IV Cefdinir. This is an oral third generation cephalosporin which is highly stable to beta-lactamase. Published studies have shown cefdinir 300mg q12h to be more active versus beta-lactamase producing S. aureus, and has an overall higher pathogen eradication rate than cephalexin 500mg q6h. The usual dose is 300mg q12h P.O. Moxifloxacin. This is a long-acting quinolone with activity against MSSA (median MIC90= 0.06mg/ml) and B. fragilis (median MIC90= 1.0 mg/ml). No dose adjustment is needed in renal failure. As with other quinolones, moxifloxacin has been shown to prolong the QT interval. The usual dose is 400mg q24h P.O and I.V. In Summary As a general rule, your antibiotic choice should be governed by the organism you expect to find in a given situation. Change or continue the antibiotic based on culture results as soon as possible and avoid prolonged empiric therapy. When sensitivities are known, choose the narrowest spectrum agent with the highest efficacy and the lowest toxicity. Dr. Kosinski is a Professor in the Department of Medicine at the New York College of Podiatric Medicine. He is a member of the Infectious Diseases Society of America and American Society for Microbiology. CE Exam #113 Choose the single best response to each question listed below: 1. Which of the following antibiotics is beta-lactamase susceptible? A) amoxicillin B) amoxicillin/clavulanate C) ticarcillin/clavulanate D) piperacillin/tazobactam 2. Which of the following antibiotics is active against MRSA? A) cephalexin B) linezolid C) amoxicilin/clavulanate D) imipenem/cilistatin 3. Which of the following is the safest to prescribe to a pregnant patient? A) vancomycin B) ciprofloxacin C) cefdinir D) minocycline 4. Which of the follwing does not require dose adjustment for hemodialysis? A) moxifloxacin B) ciprofloxacin C) caphalexin D) amoxicillin/clavulanate 5. Which of the following patients presents the greatest risk for infective endocarditis? A) A 72-year-old woman with a cardiac pacemaker B) A 68-year-old woman with a history of coronary artery bypass surgery C) A 24-year-old college student with a functional heart murmur D) A 58-year-old man with a mitral valve replacement 6. Which of the following is a long acting carbapenem? A) linezolid B) ertapenem C) cefazolin D) cefdinir 7. Which of the following is a member of the oxazolidinone class of antibiotics? A) moxifloxacin B) ertapenem C) cefdinir D) linezolid 8. Which of the following is an oral third generation cephalosporin? A) moxifloxacin B) ertapenem C) cefdinir D) linezolid 9. Which of the following would be the most appropriate choice for a patient with an allergy to penicillin? A) clindamycin B) cefazolin C) ticarcillin/clavulanate D) imipenem/ cilistatin 10. Which of the following drugs has been shown to prolong the QT interval? A) cefdinir B) cephalexin C) moxifloxacin D) linezolid Instructions for Submitting Exams Fill out the postage-paid card that appears on the following page or log on to www.podiatrytoday.com and respond electronically. Within 60 days, you will be advised that you have passed or failed the exam. A score of 70 percent or above will comprise a passing grade. A certificate will be awarded to participants who successfully complete the exam. Responses will be accepted up to 12 months from the publication date.
 

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References 1. Joseph W, Kosinski M .Prophylaxis in Lower Extremity Infectious Diseases. Clinics in Podiatric Medicine and Surgery. Vol 13 No 4 Oct 1996. 2. AS, Taubert KA, Wilson W, Bolger AF, Bayer A, Ferrieri P, et al. Prevention of bacterial endocarditis. Recommendations by the American Heart Association. JAMA 1997;277:1794-801. 3. Gilbert D, Moellering R, Sande M. The Sandford Guide to Antimicrobial Therapy. Antimicrobial Therapy Inc. pub.33th edition. 2003. 4. Linezolid Does Not Increase Risk for Thrombocytopenia in Nosocomial Pneumonia Patients. Poster: B2, American Thoracic Society May 19 2003. 5. Tack K, Littlejohn et.al, Cefdinir v Cephalexin for the Treatment of Skin and Skin-Structure Infections. Clinical Therapeutics. 20:2 1998 244-256. 6. Pickerill KE, Paladino JA, Schentag JJ. Comparison of the Fluoroquinolones Based on Pharmacokinetic and Pharmacodynamic Parameters. Pharmacotherapy 20(4):417-428, 2000. 7. Robinson JL, Hameed T, Carr S. Practical aspects of choosing an antibiotic for patients with a reported allergy to an antibiotic. Clin Infect Dis. 2002 Jul 1;35(1):26-31.