A 7 year old presents to the emergency department with fever and an expanding area of redness over his left calf. He has had fever for only 8 hours with a maximum temperature of 39 degrees C. He had a bug bite on his left calf three days ago. It now appears to be infected and painful. There is no pus, but overnight, there is a large area of redness noted with slight swelling. Because of these symptoms, he is brought to the emergency room.

Exam VS T 38.5, HR 90, RR 24, BP 100/65. He is alert and not toxic. His HEENT, heart, lung and abdominal exam findings are unremarkable. His left lower extremity is negative for any lymphangitis or lymphadenopathy. There is a 6 by 12 cm oval region of erythroderma with a sharply demarcated border over his mid lateral calf. There is a central skin sore which does not appear to excessively swollen. There is no fluctuance or drainage. There is mild tenderness within the red region. There is no bony tenderness and he is able to ambulate normal.

A culture of the central skin lesion is obtained. A blood culture is also obtained. He is given a dose of IV clindamycin and he is prescribed a course of oral clindamycin. His conditions improves the next day. His skin sore culture grows beta hemolytic group A streptococci. His blood culture is negative. His antibiotic treatment is changed to penicillin and he has a full recovery.

Antibiotics are one of the most important classes of medications prescribed by physicians. When you consider the major classes of pharmacologic agents which are used to treat children, you will find that there are only a few classes of drugs which are used frequently. These include antipyretic/analgesics, antibiotics, bronchodilators and a few others which are less common such as corticosteroids, anesthetics, cardiac medications, etc. Thus, out of the three large classes of drugs which are frequently used for children, antibiotics are a major group. Proper antibiotic prescribing is an important medical practice skill.

The most important item of information is to be able to use an antibiotic which satisfactorily cures the patient of an infection. While the mechanism of action of the different antibiotics are important, this is not as important in most instances. Antibiotic therapy is initiated in three basic ways: 1) empiric therapy, 2) specific therapy, 3) prophylaxis.

Empiric therapy is the selection of treatment based on clinical and laboratory information with the exception of culture and sensitivity information. Specific therapy is the selection of an antibiotic based on the culture and sensitivity testing of the organism causing the infection. Prophylaxis is the use of antibiotics to prevent an infection which is anticipated.

Empiric therapy is based on a three step process: 1) identifying a clinical entity, 2) knowing which organisms cause this entity, 3) selecting an antibiotic which covers these organisms. Some physicians use a two step process which is to identify the clinical entity, then select an antibiotic which is commonly used for this entity. I would prefer that students and physicians in training learn the three step process because it is a deeper level of understanding. The three step method is a universal approach which will always work as the future challenges us with changes in antimicrobial resistance patterns, newly developed antibiotics, insurance company drug coverage restrictions, side effect profiles, allergies, compliance issues, etc. The two step process is similar to following a cook book without understanding it.

Many students have learned simple rules to select antibiotics. Unfortunately, simple rules usually DO NOT work. A commonly taught rule is that penicillins and cephalosporins (which inhibit peptidoglycan synthesis) work for gram positive organisms, while aminoglycosides (which inhibit bacterial ribosome function) work for gram negative organisms. This is often true, but it is an oversimplification which has too many exceptions for this rule to be useful. This rule is based on the premise that gram positive organisms are more dependent on peptidoglycan cell wall synthesis (that's why they stain gram positive), while gram negative organisms are not as dependent on peptidoglycan cell wall synthesis. Staphylococcus aureus is a gram positive organism which is highly resistant to penicillin. Staph aureus is usually sensitive to penicillinase resistant penicillins and cephalosporins, but resistance to these is becoming more frequent (25% or more). Aminoglycosides such as gentamicin cover Staph aureus with a much higher frequency than cephalosporins. Neisseria gonorrhoeae is a gram negative organism for which the treatment of choice is ceftriaxone. Neisseria gonorrhoeae used to be treated with penicillin, but the emergence of PPNG (penicillinase producing Neisseria gonorrhoeae) has rendered penicillin ineffective. Staphylococcus epidermidis is a gram positive organism which is highly resistant to penicillins and cephalosporins. Staph epi must generally be treated with vancomycin.

Are there any simple rules which work? Unfortunately, no. However, it is a certainty that antibiotic resistance patterns will change and new antibiotics will be developed. The best way to learn the three step process is to do it frequently. If you do it again and again, it will become routine and relatively easy.

Empiric therapy is generally used first. Handbooks on antimicrobial therapy are commonly available. Such a handbook will provide useful information in learning the three step process. Most handbooks have three separate listings:

1. A list of clinical infections and most commonly used antibiotics for these infections.

2. A list of clinical infections and the common organisms which cause these infections.

3. A list of organisms and their usual sensitivity and resistance patterns (this is often a table). Similarly, most hospitals publish annual sensitivity and resistance percentages of the organisms which have been cultured in the clinical laboratory. These hospital results would be the most current and community specific sensitivity and resistance patterns for the organisms that are likely to be affecting your patients.

The first listing (#1 above) is the two step method of selecting antibiotics. Once a clinical entity is identified, then an antibiotic from this listing can be selected.

Items #2 and #3 above, are necessary for the three step method. Although this may seem a longer process at first, it will provide students and physicians in training with a better understanding of antibiotic use. After utilizing the three step method frequently, you will become very good at this, and most antibiotic decisions in the future will not require the assistance of a handbook, The three step process described below:

Step 1. Identification of a clinical entity. A history and examination provides clinical information. Sometimes laboratory and imaging information may also be necessary to add more certainty to a diagnosis. Such an entity may be cellulitis, otitis media, pneumonia, osteomyelitis, gastroenteritis, pelvic inflammatory disease, urinary tract infection, rule out sepsis, etc.

Step 2. What organisms cause this entity? For an entity such as cellulitis, we know that the most common organisms are group A streptococci and staphylococcus aureus.

Step 3. Select an antibiotic which covers the organisms which are potentially causing the infection. Group A strep is sensitive to all penicillins and cephalosporins. Staph aureus is usually sensitive to cephalosporins and penicillinase resistant penicillins such as oxacillin and cloxacillin. However, there is growing staph aureus resistance to these drugs (currently about 25% or more). Staph aureus is about 95% sensitive to clindamycin and this also covers group A strep. Thus, clindamycin appears to be the best choice to treat cellulitis in this instance. Another consideration is the severity of the infection. For a life threatening infection such as bacterial meningitis, there must be the certainty of 100% coverage. Thus, initial broad spectrum or multiple antibiotics may need to be used empirically. As opposed to a less serious infection such as otitis media or impetigo, in which case 80% coverage certainty may be sufficient.

It is possible to stratify this further. A more experienced physician examines the cellulitis and indicates that this cellulitis is caused by group A strep which more commonly causes large areas of erythroderma surrounding a single skin sore. Staph aureus cellulitis is usually associated with suppuration and a smaller area of redness and induration surrounding a central abscess. Thus, clinically, one could be more certain that this is a group A strep cellulitis which can be treated with penicillin. In the case, the patient was initially treated with IV clindamycin because high antibiotic levels are immediately achieved to be followed by a course of oral clindamycin. When the results of the culture returned identifying the organism and its sensitivity to penicillin, the patient could then be changed to specific therapy with penicillin.

Specific therapy utilizes culture and sensitivity information which is usually available 1 to 3 days later. The general principle is to select the antibiotic which is the most effective with the least side effects. Additionally, it may be preferable to select the antibiotic with the most narrow spectrum to reduce the likelihood of significantly altering the patient's normal flora. Sometimes, physicians may be limited by cost and compliance issues. For example, there may be two possible treatments; one which is B.I.D. costing $80 and another which is Q.I.D costing $10. One is less expensive, but it may be more difficult to ensure compliance. Such decisions are judgments which physicians must make in conjunction with patient preferences.

Prophylaxis is the utilization of antibiotics for an infection which is anticipated. An example would be a dog bite wound in which an infection is anticipated several days later. In addition to cleansing and irrigating the wound, antibiotics may be able to reduce the patient's risk of infection. Patients with vesicoureteral reflux are at greater risk for urinary tract infections. Thus, placing these patients on prophylactic antibiotics (usually once a day or twice a day) will reduce their likelihood of acquiring a UTI. Patients with rheumatic fever and subsequent rheumatic heart disease are at risk for worsening heart disease if another group A streptococcal infection is acquired. Thus, such patients are placed on daily oral penicillin or monthly long acting benzathine penicillin injections to prevent group A streptococcal infections.

New antibiotics will be developed in the future. As a preliminary discussion, antibiotics can be classified into 7 groups: penicillins, cephalosporins, aminoglycosides, sulfonamides, quinolones, macrolides and other.

Penicillins

Penicillins inhibit bacterial cell wall formation by inhibiting peptidoglycan synthesis. Penicillins can be further classified into three groups: penicillin, broad spectrum penicillins and anti-staph aureus penicillins. Penicillin typically covers group A and group B streptococci, most pneumococci, Neisseria meningitidis, Pasteurella multocida, Listeria and most anaerobes (with the exception of bacteroides fragilis). Broad spectrum penicillins include amoxicillin, ampicillin, carbenicillin, ticarcillin, piperacillin, azlocillin, mezlocillin, etc. This group covers more gram negative organisms such as E. coli, Proteus, Klebsiella, etc. With the exception of amoxicillin and ampicillin, the other broad spectrum penicillins cover pseudomonas as well. Broad spectrum penicillins can be combined with penicillinase inhibitors such as clavulanate and sulbactam. These combinations drug such as Augmentin (amoxicillin/clavulanate), Unasyn (ampicillin/sulbactam), Timentin (ticarcillin/clavulanate) and Zosyn (piperacillin/tazobactam) cover most staph aureus (but not MRSA) and other penicillinase producing organisms such as beta-lactamase producing Haemophilus influenzae B.

It should be noted that amoxicillin is metabolized to ampicillin in the bloodstream. Thus, these two antibiotics have identical coverage. Amoxicillin is better absorbed from the GI tract which is why amoxicillin should be favored via the PO route (except for GI infections) over ampicillin, and ampicillin should be favored via the IV route (amoxicillin is no longer available IV).

The anti-staph aureus penicillins are also called the penicillinase resistant penicillins which include methicillin, oxacillin, nafcillin, cloxacillin, dicloxacillin. These drugs are targeted against staph aureus which is why this group should more accurately called the anti-staph aureus penicillins. Methicillin resistant staph aureus (MRSA) is resistant to all the penicillins in this group. About 25% or more of staph aureus are currently MRSA. The term "penicillinase resistant penicillins" is a misnomer. It is true that staph aureus is penicillin resistant because of penicillinase production, but the term "penicillinase resistant penicillins" implies that they will cover all penicillinase producing organisms, but they do not cover penicillinase producing Neisseria gonorrhoeae, Haemophilus influenzae, Bacteroides fragilis, and many other penicillinase producing organisms. Thus, this group should be more appropriately called the anti-staph aureus penicillins, because the only penicillinase producing organism which they cover to a moderate degree is staph aureus.

Cephalosporins

Cephalosporins are structurally similar to penicillins with a similar mechanism of action. Cephalosporins are difficult to learn because there are many of them and new ones are frequently introduced. The "generation" of cephalosporins is only slightly helpful. In general, all cephalosporins cover all penicillin sensitive organisms with the exception of Listeria and Pasturella. Coverage for group B streptococci is better with penicillin than with cephalosporins. Cephalosporins also cover many gram negative organisms such as E. coli, Klebsiella, Proteus, etc. Cephalosporins also cover staph aureus, but only to a similar degree as the anti-staph aureus penicillins (i.e., MRSA is cephalosporin resistant as well). Two generalizations that usually hold true are: 1) lower generations of cephalosporins cover staph and strep better than the higher generation cephalosporins (but staph and strep coverage with high generation cephalosporins is still generally adequate), and 2) higher generations of cephalosporins have extended coverage of gram negative organisms. Unfortunately, the "generation" of cephalosporins does not provide clinicians with specific properties which permit us to use any drug in the same generation. Within the higher generations, each cephalosporin has specific properties which make one more useful than others. In my view, using the generation of the cephalosporin is NOT the best way to learn how to use cephalosporins. The best way to select cephalosporins, is to learn the properties of a single first generation cephalosporin, then find other useful clinical properties of another cephalosporin which provides clinicians with a useful clinical advantage. If a cephalosporin has no clinically useful advantages which separate it from other cephalosporins, then we should purge it from our memory.

The prototype first generation cephalosporin is cefazolin (Kefzol and Ancef are trade names), which is for IV use. Cephalexin (Keflex trade name) is an oral first generation cephalosporin with an essentially identical spectrum. These drugs have the basic cephalosporin coverage described above.

What if we needed coverage for anaerobes? Then we would use IV cefotetan (Cefotan) or cefoxitin (Mefoxin), since these cephalosporins cover most anaerobes (but not 100%). Thus, these cephalosporins would be preferred for appendectomy prophylaxis.

What if we needed Haemophilus influenzae or Moraxella catarrhalis coverage? Then we would use IV cefuroxime (Zinacef), cefotaxime (Claforan) or ceftriaxone (Rocephin). We could also use oral cefuroxime (Ceftin) or cefaclor (Ceclor).

What if we needed to cover meningitis? We need the additional property of penetration through the blood brain barrier into the CNS and CSF. Although cefuroxime covers all the meningitis organisms, it does NOT penetrate the blood brain barrier as well as cefotaxime and ceftriaxone, therefore, one of these two latter drugs would be preferable.

What if we needed pseudomonas coverage? Then we would use ceftazidime (Fortaz) since this is one of the few cephalosporins with pseudomonas coverage.

What if we wanted to treat an infection as an outpatient, but we wanted to be certain that high antibiotic levels would be maintained for at least 24 hours (similar to an over night hospitalization for IV antibiotics)? Then we would use ceftriaxone (Rocephin) since it has a long half-life and its usual dosing interval is every 12 to 24 hours. Thus, giving a single dose of IM or IV ceftriaxone, results in antibiotic levels which would be similar to an overnight hospitalization with IV antibiotics, at a substantially lower cost since it can be done as an outpatient.

Thus, as a simplification, the only IV cephalosporins we need to know for pediatrics are cefazolin (first generation), cefotetan (better anaerobe coverage), ceftriaxone (extended coverage which includes Haemophilus influenzae and Moraxella, good blood brain barrier penetration, and a long duration of action), and ceftazidime (pseudomonas coverage). The only oral cephalosporins we need to know are cephalexin (first generation), cefuroxime (extended coverage) and perhaps cefixime (once a day dosing often recommended for UTI). Other cephalosporins are less important. We will still be exposed to them, because other physicians will prescribe them, and there are additional subtle factors which may slightly favor other cephalosporins. But for most clinical applications, the above will suffice.

Aminoglycosides

Aminoglycosides inhibit bacterial ribosomal function. Aminoglycosides are more toxic than penicillins and cephalosporins. Thus, they must be maintained within a certain therapeutic range. At high levels, aminoglycosides are nephrotoxic and ototoxic. These drugs are also weak neuromuscular blocking agents so they can cause respiratory depression or apnea if given in to a patient with neuromuscular compromise (e.g., early infant botulism, Guillain Barre syndrome, severe myopathies, etc.).

Aminoglycosides are generally directed at gram negative organisms (especially the Enterobacteriacae, also known as stool germs). However, aminoglycosides also cover gram positive organisms such as Staph aureus and many streptococci. In fact, while Staph aureus may be 25% resistant to the anti-staph aureus penicillins and cephalosporins, Staph aureus resistance to aminoglycosides is 10% or less.

Gentamicin is the most basic aminoglycoside. Other aminoglycosides with extended coverage include tobramycin and amikacin. Note the spelling of Gentamicin compared to tobramycin. The difference is the "micin" (no "y"). Gentamicin is commonly misspelled. Tobramycin and amikacin have extended gram negative coverage which includes most pseudomonas.

Sulfonamides

Most sulfonamides inhibit various steps in metabolic pathways such as those which inhibit folate metabolism. The popular combination drug trimethoprim-sulfamethoxazole inhibits folate metabolism at two points. Sulfonamides are inexpensive and they have a broad spectrum. Sulfonamides are usually used for gram negative infections such as urinary tract infections; however, they cover many gram positives, such as Staph aureus well. This is an ideal combination of effective broad coverage and low cost, except that sulfonamides have a slightly higher risk of severe drug reactions such as Stevens-Johnson syndrome. Additionally, sulfonamides result in acute hemolytic reactions in some patients with G6PD deficiency. Since we usually don't know who has G6PD deficiency and Stevens-Johnson syndrome can result in death or severe morbidity, these factors have tempered the popularity of sulfonamides. Law suits involving sulfonamides suggest that malpractice occurs when the clinicians fails to warn the patient of adverse reactions such as hemolytic reactions and Stevens-Johnson syndrome. Thus, if you intend to prescribe a sulfonamide to a patient, you must inform them of these risks (blood reaction if they have a hidden blood problem, or a severe allergic reaction which can result in death). In most instances after being informed of such risks, patients will prefer alternative antibiotics which have similar coverage and less side effects. In most instances, other antibiotics can provide the same coverage with less risk and similar cost. However, in patients with allergies to other antibiotics, sulfonamides may be useful. Additionally, if the patient's medical history indicates that they have used a sulfonamide in the past without problems, then their risk of an adverse reaction is substantially lower.

Quinolones

This class of antibiotics are related structurally to nalidixic acid. These drugs inhibit bacterial DNA synthesis by inhibiting B-subunit of DNA gyrase, an essential enzyme that allows DNA supercoils to be relaxed and reformed. Quinolones such as ciprofloxacin, norfloxacin and levofloxacin are very broad spectrum with coverage against Staph aureus (including MRSA), pneumococcus, Haemophilus influenzae, Mycoplasma, Chlamydia, gram negative enterics, Pseudomonas, etc.. Their main indication is in resistant urinary tract infections, but their broad spectrum makes them effective in other conditions. Their use is limited in pediatrics since they are currently contraindicated in children and pregnant women, because these drugs have impaired bone growth in laboratory animals.

Carbapenems

This new class of antibiotics target bacterial cell wall synthesis by inhibiting the transpeptidase enzymes required for peptidoglycan cross-linking. These drugs are very broad spectrum similar to high generation cephalosporins. Examples include imipenem and meropenem. These drugs have not been used commonly in pediatrics since they are most commonly used in highly resistant adult infections.

Macrolides and others.

The typical macrolide is erythromycin. These drugs inhibit bacterial ribosomal function. These drugs cover most streptococci and some Staph aureus. They also cover many atypical organisms such as Mycoplasma, Chlamydia, Legionella, Bordetella, Yersinia, Campylobacter, and Tularemia. Erythromycin ethylsuccinate (EES) and erythromycin estolate (also known as erythromycin propyl-laurel sulfate, or Ilosone) are commonly used. EES has less hepatic toxicity. Erythromycin estolate gets higher tissue levels and is commonly recommended for pertussis. Newer and more expensive erythromycins such as azithromycin and clarithromycin have broader coverage, less side effects and more convenient dosing. Azithromycin is dosed once a day for 5 days to give 10 days of clinical efficacy.

The tetracycline family (tetracycline, doxycycline, minocycline, etc.) shares some properties with erythromycins in that they inhibit bacterial ribosomal function and cover many of the same atypical organisms. Tetracyclines tend to be photosensitizers which limits their use in Hawaii. Tetracycline use is discouraged in children because it causes staining of teeth, hypoplasia of dental enamel, and abnormal bone growth in children.

Vancomycin is a glycopeptide which inhibits bacterial cell wall synthesis. It is available for IV since it is not absorbed from the GI tract. Vancomycin is broad spectrum and its major pediatric application is to cover resistant Staph aureus (MRSA) and resistant pneumococci. Vancomycin use is associated with a "red man syndrome" which is a histamine like reaction that can be inhibited by pretreatment with diphenhydramine and slowing the IV administration rate of the vancomycin. Vancomycin can also be given orally for pseudomembranous colitis caused by Clostridium difficile.

Clindamycin inhibits bacterial ribosomal function. It covers most streptococci and Staph aureus. Clindamycin covers most MRSA, but not 100%. If 100% coverage for Staph aureus is needed, then vancomycin is indicated. Clindamycin is a useful for the outpatient treatment of cellulitis and other infections commonly caused by group A strep and Staph aureus. Staph aureus resistance to clindamycin is present, but it is uncommon. Many clinicians treat cellulitis and other suspected outpatient Staph aureus conditions with clindamycin instead of cephalosporins since resistance to cephalosporins is too frequent. Clindamycin is also used for coverage of anaerobes including Bacteroides fragilis.

Chloramphenicol inhibits bacterial ribosomal function. Chloramphenicol is used infrequently because it has the potential to cause irreversible bone marrow suppression. It more commonly causes reversible bone marrow suppression which is not nearly as severe. Chloramphenicol covers all anaerobes similar to Clindamycin. Chloramphenicol crosses the blood brain barrier well and penetrates into the CSF, so it was frequently used to treat meningitis. Chloramphenicol has the unusual property of attaining high serum levels from oral administration. Most other drugs require IV administration to get high serum levels. When I was a resident in the early 80's, all children with bacterial meningitis would be treated initially with ampicillin and chloramphenicol. If the organism was resistant to ampicillin, then chloramphenicol would be used. These children could actually be switched over to oral chloramphenicol if starting an IV was difficult. CBCs would be checked daily or every other day to check for bone marrow suppression. Cephalosporins and vancomycin have largely replaced these older drugs to treat meningitis.

Metronidazole (Flagyl) is a anti-parasitic anti-amebic drug, but it also has nearly complete coverage of anaerobes. Thus, when 100% anaerobe coverage is required, the options include metronidazole, clindamycin or chloramphenicol. The broad spectrum penicillins in combination with clavulanate or sulbactam may also cover anaerobes sufficiently.

Questions

1. How many generations of cephalosporins are there?

2. Can the generation of the cephalosporin (in itself) be the sole selection criteria for a particular clinical situation?

3. List some organisms which cause the following entities: osteomyelitis, bacterial meningitis.

4. What empiric antibiotic(s) could be used to cover the organisms in the above question?

5. Select an empiric antibiotic for a 10 year old female who has a small pneumonia on chest x-ray. She is afebrile and has a frequent non-productive cough.

6. Select an empiric antibiotic for an 18 month old female with fever and pyuria on UA (i.e., suspected UTI)?

7. You decide to prescribe an erythromycin to a patient. You could prescribe erythromycin ethylsuccinate (EES) which is $10 for 40 tabs (1 tab q.i.d. for 10 days), or you could prescribe azithromycin (Zithromax) which is $70 for 6 tabs (two tabs today, then one tab daily for 4 more days). What considerations should be made in making such a decision?

References

1. Beers MH, Berkow R (eds). The Merck Manual of Diagnosis and Therapy, Seventeenth Edition, Centennial Edition. 2001, Internet Edition Provided By MEDICAL SERVICES, USMEDSA, US. www.merck.com/pubs/mmanual

Answers to questions

1 and 2. There are at least four, and probably five, and possibly six. No doubt in the future, there will be more. How do these cephalosporins differ from each other and what characteristic places them in a given generation? The answer to this question is not an easy one. If you enter "fourth generation cephalosporin" into Medline's search engine, you will find some articles on fourth generation cephalosporins. Similarly, searches for fifth and sixth generation cephalosporin yields some articles. If I was a slick marketer of drugs, I would simply call my new cephalosporin "Tenth Generation" and almost everyone would buy it. However, what specific characteristic of the cephalosporin makes it clinically useful over other cephalosporins? If the drug was a tenth generation cephalosporin, but it had no clinical advantage over an existing third generation cephalosporin, then there is no need for a such a tenth generation cephalosporin. The generation is not nearly as important as the specific property of the cephalosporin which makes it clinically useful over another cephalosporin.

3. Osteomyelitis: Most likely Staph aureus. Bacterial meningitis: Pneumococcus, meningococcus, Haemophilus influenzae type B (HiB).

4. For osteomyelitis, we could cover the Staph aureus with an anti-Staph aureus penicillin such as oxacillin, nafcillin or methicillin or a first generation cephalosporin such as cefazolin. However, resistance to these drugs is currently about 25% to 30%. Although there is a good chance the patient will respond, in 25% to 30% of cases, this treatment will fail and the patient will suffer the consequences of inadequate treatment which would include: death from sepsis, Staph pneumonia, spread of the osteomyelitis, chronic osteomyelitis requiring an amputation, etc. None of these complications are minor, therefore, 75% coverage is inadequate. We need 100% coverage empirically since osteomyelitis is a serious infection. Thus, IV vancomycin is the treatment of choice here. For the bacterial meningitis case, we need an antibiotic to effectively cover these organisms and additionally, we need an antibiotic that will penetrate the blood brain barrier into the CSF. Chloramphenicol would be satisfactory here, but we don't use this because of its side effects. IV ceftriaxone or cefotaxime would penetrate the CSF well and cover meningococcus and HiB, and most pneumococcus, but pneumococcus has a small frequency of high level resistance to cephalosporins, so vancomycin must be added.

5. What organism is most likely? Mycoplasma or viral. Pneumococcus is unlikely since she is afebrile. The best antibiotic choice would be an erythromycin.

6. Although trimethoprim/sulfamethoxasole (Bactrim or Septra) is commonly recommended because of its broad coverage for this indication, this drug causes Stevens-Johnson syndrome more commonly than others. If the parents accept this increased risk, then this should be documented on the chart. Most parents are not willing to accept this increased risk since other antibiotics are available. Amoxicillin will probably work, but there is a high frequency of resistance which is generally not a probably for simple cystitis, but in a febrile 18 month old, there may be some degree of pyelonephritis as well. Resistance to cephalosporins is infrequent. Thus, an acceptable answer here would also be a first generation cephalosporin such as cephalexin. IM ceftriaxone can also be given at the initial patient encounter to ensure high initial antibiotic levels and initial compliance.

7. Cost, compliance, convenience, efficacy, etc. While EES is $10 and azithromycin is $70, some patients may choose to pay more if the more expensive drug has significant advantages. Additionally, since most patients have drug plans, the difference may be negligible (e.g., $5 vs. $10). Compliance is essential for the drug to be effective. EES must be taken four times a day for 10 days while azithromycin is once a day for five days. Additionally, EES may have more GI side effects. Clearly a once a day medication is more convenient than a q.i.d. medication. If both medications are efficacious, perhaps it is best to discuss these differences with the patient and give them some input in the decision.