A. Penicillin (PCN)

1. Excellent agent for most streptococci including pneumococcus
   1. Emerging resistance, especially in pneumococcus
   2. Some activity against enterococcus
2. Excellent oral anaerobe activity
3. Excellent anti-syphilis activity
4. Dosing
   1. Intravenous - Standard 600,000 Units PCN G q4-6 hours
   2. High dose IV - 2-4 MU q4-6 hours PCN G
   3. Oral: 250-500mg po qid PCN VK
   4. Probenicid 500mg po qd-qid can be added to increase levels
5. PCNs are important causes of drug induced anaphylaxis (see below)

B. Extended Range Penicillins

1. Ampicillin
   1. Good Enterococcus facaelis coverage, but poor E. faecium coverage
   2. Group A, B, G and other streptococci generally covered well
   3. Covers some Gram negative rods (GNR) and ~60 of H. influenza
   4. Oral availability ~50%; dosing 250-500mg po q6 hours
   5. Intravenous dosing 1-2gm iv q4-6 hours; reduce in renal failure
   6. Drug of choice for Listeria monocytogenes (meningitis) infection
   7. Good oral anaerobe activity (peptostreptococcus, peptococcus, fusobacterium)
2. Ampicillin-Sulbactam (Unasyn®)
   1. Extends spectrum of ampicillin by adding ß-lactamase inhibitor
   2. Covers many methicillin sensitive Staphylococci
   3. Increased coverage of many Gram negative rods (GNRs) compared with ampicillin
   4. Also covers abdominal anaerobes (eg. Bacteroides fragilis)
   5. Parenteral only, dose 1-2gm iv q6 hours (reduce in renal failure)
   6. Piperacillin-tazobactam (Zosyn®) is often preferred for abdominal infections
   7. Useful in diabetic ulcer (usually foot ulcer) infections
3. Amoxicillin [1]
   1. Essentially the same spectrum as ampicillin
   2. Improved oral availability ~100%
   3. Dose is 250-500mg po tid or newer 875mg po bid
4. Amoxicillin-Clavulanate (Augmentin®) [1]
   1. Clavulanate is an orally active ß-lactamase inhibitor (see below)
   2. Extends spectrum to include many Staphylococci
   3. Increased coverage of GNR's
   4. Various formulations are now available
   5. Standard is 875/125mg po bid (sustained release)
   6. Original tablets were 500/125 po tid
   7. New extended release (XR) form with higher amoxicillin available (1000/62.5) 2 tabs bid
   8. Augmentin XR® is approved for acute sinusitis and community acquired pneumonia
   9. Higher dose of amoxicillin should be effective against moderately resistant Pneumococci
   10. Note clavulanate does not affect Pneumococcal resistance to penicillin

C. Anti-Staphylococcal Penicillins

1. Includes methicillin (older, not used), oxacillin and nafcillin (all parenteral)
2. Also includes Dicloxacillin (oral agent) - dose 250-500mg po qid
3. Drugs of choice for methicillin sensitive Staph aureus (better than Vancomycin)
4. Active against MSSA and penicillin sensitive streptococci, but not much else
5. No activity against Gram negative bacteria or enterococci
6. Main use in skin and soft tissue infections
7. High doses may cause nephritis and/or neutropenia

D. Anti-Pseudomonal Penicillins

1. Ticarcillin
   1. Improved Gram negative coverage
   2. Good anaerobic coverage
   3. Lacks coverage against enterococci
2. Ticarcillin-Clavulanate (Timentin®)
   1. Addition of ß-lactamase extends spectrum (as above)
   2. Reasonable agent for mixed infections, including some Pseudomonas ssp.
   3. Avoid in pregnancy
3. Mezlocillin (Mezlin®)
   1. Improved activity against Klebsiella compared with ticarcillin
   2. May be used in fever + neutropenia in combination with aminoglycoside
   3. Parenteral agent only
4. Pipericillin (Pipracil®)
   1. Similar spectrum to mezlocillin
   2. Very good gram negative coverage including many Pseudomonas ssp.
   3. Parenteral agent only
5. Pipericillin-Tazobactam (Zosyn®) [2]
   1. Tazobactam extends range to cover methicillin sensitive Staphylococci
   2. Note that Zosyn® does not have improved anti-pseudomonal coverage over piperacillin
   3. GNR coverage is very good and includes many Pseudomonas ssp.
   4. Zosyn® does have improved activity against B. fragilis and other anaerobes
   5. May be used in severe infections and in fever with neutropenia
   6. Standard dose 3.375gm IV q6 hours; increase to IV q4 hours if Pseudomonas suspected

E. Carbapenams

1. Imipenem (with cilistatin; Primaxin®) [3]
   1. Resistant to ß-lactamases
   2. Must be combined with cilastatin, which prevents renal hydrolysis of imipenem
   3. Extremely broad spectrum, including G positive, negative and anaerobic bacteria
   4. Does not kill Enterococcus faecium and methicillin resistant staphylococci
   5. About 50% of penicillin allergic patients are allergic to imipenem
   6. Pseudomonas and Stenotrophomonas (Xanthomonas) may develop resistance rapidly
   7. Hemodialysis removes most of the drug
   8. Notable incidence of seizures as side effect, particularly with renal insufficiency
   9. Should not be used to treat meningitis, or in patients with renal insufficiency
   10. Dose is 500mg/500mg iv q6 hours with normal renal function
2. Meropenem (Merrem®) [3,4]
   1. Resistant to renal hydrolysis
   2. Activity and clinical efficacy similar to imipenem-cilistatin
   3. Less activity against S. pneumoniae (pneumococcus) than imipenem
   4. May be agent of choice for empiric treatment of serious infections pending organism identification and sensitivity profile
   5. Generally tolerated in PCN allergic patients; test with low dose skin-test and if negative, full dose meropenem can be given 1 hour later [8]
   6. Dose is 1gm iv q8 hours for adults (up to 2gm iv q8 hours in meningitis)
   7. May have least potential for causing seizures and may be used for meningitis
3. Ertapenem (Invanz®) [6]
   1. Long acting carbapenem antibiotic for intra-abdominal, pelvic, skin and skin structure infections
   2. Also approved for community acquired pneumonia
   3. Clinically as efficacious as piperacillin/tazobactam (Zosyn®) in diabetic foot infections [10]
   4. Ertapenem is more effective than cefotetan for prevention of surgical-site infections in patients undergoing elective colorectal surgery [9]
   5. Once daily (1gm IV or IM) dosing
   6. For creatinine clearance <30mL/min, dose is 0.5gm qd
   7. For dialysis patients, dose 0.5gm qd >6 hours prior to dialysis
   8. Similar activity to other penems, but no activity against Pseudomonas or Acinetobacter
   9. Little activity against highly-penicillin resistant pneumococci or MRSA or enterococcus
   10. Minimal advantages over other agents except once daily dosing
4. Doripenem (Doribax®) [3]
   1. Approved for complicated intra-abdominal and urinary tract infections, pyelonephritis
   2. Dose is 500mg IV (over 1 hour) q8 hours x 5-14 days for intra-abdominal, 10 days for UTI
   3. Similar efficacy to meropenem
   4. Headache, nausea, diarrhea, rash were most common adverse events
   5. Usually reserved for resistant and/or polymicrobial compicated infections

F. Other ß-Lactam Derivatives

1. Aztreonam
   1. Monobactam active against many Gram negative aerobic pathogens
   2. No allergy cross-reaction in penicillin allergic patients
   3. No renal toxicity, so may be used instead of aminoglycosides in appropriate patients
   4. Efficacy of aztreonam is highly dependent on specific hospital resistance profiles
2. Cephalosporins

G. ß-Lactamase Inhibitors

1. Clavulanate: combined with amoxicillin = Augmentin® (oral) or Ticarcillin (Timentin®; IV)
2. Sulbactam is added to ampicillin (Unasyn®) for parenteral use
3. Tazobactam is added to piperacillin (Zosyn®) for parenteral use
4. Major improvement on parental antibiotic is coverage of:
   1. Methicillin sensitive staphylococci
   2. ß-lactamase producing H. influenza and M. catarrhalis
   3. Most anaerobic bacteria, including Bacteroides fragilis
   4. Some enteric Gram negative rods
5. Activity of Zosyn® or Timentin® against Pseudomonas is similar to parental drug
   1. Useful for treatment of polymicrobial infections, especially with anaerobes
   2. Particularly well suited to diabetics and other immunosuppressed patients
6. Long duration, low dose treatment with ß-lactams is a risk factor for carriage of resistant pneumococcus [5]

H. Penicillin Allergy [6,7]

1. Penicillin is most common cause of allergic drug reactions and anaphylaxis
   1. Prevalence is ~2% in USA population
   2. Anaphylaxis rates 0.01-0.05%; deaths ~600 annually
   3. For extended range and antistaphylococcal penicillins, rates are similar
   4. Aztreonam and carbapenams rarely (<10%) cause allergies in penicillin allergic patients
   5. Meropenem is usually well tolerated in PCN-allergic patients; skin testing predictive [8]
   6. Cephalosporin allergies occur in <5% of patients with penicillin allergies
   7. <20% of patients reporting allergy to penicillin are truly allergic by skin testing [7]
2. Immunologic Mechanisms
   1. Most pencillin (~95%) is metaboized to penicilloyl hapten, called major determinant
   2. Minor determinants formed from due to other metabolites which form haptens
   3. Most allergic patients have circulating IgE antibodies to major determinants
   4. IgM and IgG anti-penicillin antibodies can cause hemolytic anemia and serum sickness
3. Testing for Penicillin Allergy [7]
   1. Medical history is critical here
   2. In patients with a history, or in very nervous patients, consider skin testing
   3. Immediate hypersensitivity skin testing is useful for predicting allergies
   4. A negative pencillin skin test with no allergy history rules out penicillin allergies
   5. A positive skin test with negative history has 10% risk of severe penicillin reaction
   6. A positive skin test with a positive history has >50% of severe penicillin reaction
   7. A negative skin test with a positive history has ~10% risk of severe penicillin reaction
   8. Nearly all patients with a negative skin test can safely take penicillin [7]
4. Desensitization, though transiently effective, is available

References

1. Augmentin XR. 2003. Med Let. 45(1148):5
2. Piperacillin-Tazobactam. 1994. Med Let. 36(914):7
3. Doripenem. 2008. Med Let. 50(1278):5
4. Meropenam. 1996. Med Let. 38(984):88
5. Guillemot D, Carbon C, Balkau B, et al. 1998. JAMA. 279(5):365
6. Ertapenem. 2002. Med Let. 44(1126):25
7. Salkind AR, Cuddy PG, Foxworth JW. 2001. JAMA. 285(19):2498
8. Romano A, Viola M, Gueant-Rodriguez R, et al. 2007. Ann Intern Med. 146(4):266
9. Itani KM, Wilson SE, Awad SS, et al. 2006. NEJM. 355(25):2640
10. Lipsky BA, Armstrong DG, Citron DM, et al. 2005. Lancet. 366(9498):1695