1 Antibiotics and Outpatient Infections David Kramer, M.D.2 Antibiotic Therapy Factors in Choosing an Antibiotic • Clinical syndrome • Host characteristics • Focused history • Antibiotic characteristics When you are choosing an agent to use, you are looking at what clinical symptoms the patient has, who is this patient, an immunocompromised or normal host. You are taking a little bit more of a detailed history to include infectious risks, and you are thinking about the antibiotic itself. 3 Assessment of Clinical Syndromes Identify predominant symptoms and signs Determine the site of infection Identify disease process Determine likely causative organisms Identify likely susceptibility pattern In a clinical syndrome, you are trying to identify what is the predominant symptom and signs. You are trying to see where the site of infection is. Is this infection in the joint? Is this infection in the bone? Where are we treating this infection? Does this patient have a central nervous system infection? Then, identify the disease process because if you identify that this is osteomyelitis, it is a little bit different than if you think that the patient has pyogenic arthritis. The causative organisms might change and then what you need do, is you need to think of what the disease is, what are the most likely pathogens associated with this disease and what is their susceptibility pattern in the area where you practice. This is essential. To pick a drug, you have to know what organism you are dealing with. Because if not, you are really doing it blindly. So you have to have an idea of what organisms cause what specific diseases so that then you can make a good choice about antibiotic therapy.4 Host Characteristics Age Underlying conditions Medical devices Nutritional status When you look at hosts, you need to know the age of the patient. A 10-year-old is different from a neonate. The pathogeen are different. Think about underlying conditions. Is this a patient with cystic fibrosis with pneumonia, or is this a well child with pneumonia? Different pathogens. So you are thinking about that host. Does this patient have an indwelling catheter? Does the patient have a prosthetic heart valve? All these things make it a little different to know which antibiotic to choose. Then, is the patient malnourished because that might be a cause for immunodeficiency. 5 Focused History Travel Exposures Immunizations Drug abuse Sexual activity When you are looking at a focused history, you need to know if the patient you are seeing with fever for 10 days has just come back from a safari in Africa, or is this a patient who has just been in the community where there is a lot of influenza. So you are going to ask about travel, about exposure to people who have contagious diseases such as tuberculosis, or whether the child is exposed to more infections because he is in daycare. Are immunizations up to date? That is very important. That patient may have measles if they have never been immunized and there is an increase in your community of Hemophilus influenza type E,. which is now very rare but can occur. Is this adolescent an IV drug abuser? Unfortunately, this happens occasionally and it brings in another set of organisms and diseases we have to think about, and then sexual activity brings up another whole host of organisms and disease processes.6 Antibiotic Selection Factors Spectrum of activity Absorption Distribution Metabolism Excretion Adverse Effects Safety Routes of administration Drug-drug interactions Cost Palatability Effect on Resident Flora Selective Pressure on environment When we finally make that decision to select an antibiotic, we must ask, "Does the antibiotic cover the organisms that I am thinking about? Is it well absorbed? Does it get to the site of infection? Oral vancomycin is not good to treat Staph aureus because it does not get absorbed from the GI tract. What are the adverse effects? How safe is this drug? Do I have to monitor drug levels? What is the route of administration? Can I give it orally? Is it as good orally as it is IV? Are there other interactions with other drugs, I might not want to use erythromycin because it might change the levels of the cyclosporin? How much does it cost? Is there a cheaper alternative? Does it taste good? Because if it doesn't taste good nobody, is going to take it. And no matter how good the antibiotic is for that infection, if it is not taken, it is not of use. Then, things that we think of in a more global setting are what will this do to the patient's flora, and will this alter the flora and then transmit resistant organisms? So, usually when you are selecting an antibiotic, you are looking at all of these factors and then making the decision based on the best antibiotic.7 General Principles of Antibiotic Therapy May initiate with broad spectrum awaiting culture results Obtain pertinent cultures to narrow therapy Use narrowest spectrum antibiotic as possible The general principle is that you initiate broad spectrum antibiotics awaiting culture results, then based on culture results, you can narrow therapy. It is really best to use the narrowest spectrum antibiotic possible for the infection, especially now in the era of increasing antimicrobial resistance. We really want to keep the very broad spectrum antibiotics for when we need them. Ceftriaxone for treatment of otitis should not be used because we have other, much narrower, alternatiive for otitis media and I want to save ceftriaxone to have an antibiotic to treat the patient who comes in with meningitis. If you don't use it in this fashion, I think that we are going to end up with a lot of ceftriaxone resistance, and you are going to have a lot of patients for which we have no antibiotics. So use the narrowest spectrum possible. The ideal antibiotic would be one that would be broad enough to cover everything we want to cover, but very narrow to also not cause resistance. It would have a very good absorption. It would have a long half-life, preferably that could be given in a once a day or b.i.d. dosing. I actually prefer a b.i.d. dosing schedule. Once a day, if a patient forgets to take it, then you could be without an antibiotic for a long period of time. I want an antibiotic that has no side effects. I want one that is very cheap and one that has a great taste that the child will actually say, "Mom. It's my antibiotic time. I want to take it." Unfortunately, it doesn't exist. There is no perfect antibiotic. Unfortunately, there are good antibiotics or there are better antibiotics, but there is no perfect one. There is no magical antibiotic for every infection.8 Penicillins Agent Activity Clinical Uses Penicillin G oral anaerobes Gp A streptococcus pharyngitis Penicillin V streptococci RF prophylaxis Benzathine Eikenella Syphilis Procaine Pasteurella Treponema aspiration pathogen specific The different classes of antibiotics. I am starting with the penicillins and they are divided into the name of the antibiotic, their activity and then the clinical uses. Penicillin is a very useful antibiotic still. Very active against oral anaerobes, streptococci and the treatment of choice for Eikenella infections. Eikenella is an organism that lives in the mouth, and with boxers or people who punch each other in the mouth, you can get infections with Eikenella in the hand. That is not uncommon. Occasionally bites from animals can have Eikenella. Pasteurella. Bites from animals. Penicillin is also for syphilis. Penicillin is still very useful. We use it as the treatment of choice for group A strep pharyngitis. We use it for rheumatic fever prophylaxis. It is the therapy of choice for syphilis. For aspiration pneumonia, it is still a very good agent to use initially in that patient that may have aspirated in the community, not the patient that has aspirated and has hospital acquired organisms. But definitely, that patient coming from the communiit with an aspiration pneumonia. If you have a specific infection with any of these pathogens, then that is when you would use the penicillin.9 Penicillin -Adverse Effects Allergic reactions Hemolytic anemia Interstitial nephritis Seizures and hyperkalemia in patients with underlying renal disease Adverse effects. The one that you most commonly hear about is allergic reactions. A lot of people say that they are penicillin allergic. I think that if you are penicillin allergic, you're really going to take out all of the penicillins and most of the cephalosporins if you are truly allergic with anaphylaxis. So when the patient says they had a rash from penicillin or a rash from amoxicillin, I investigate it further. I would hesitate to label a patient as allergic to penicillin. Is it hives, not hives? I try to bring pictures so the patient can see if it was hives or not. Or was there wheezing, no wheezing? Was it true anaphylaxis? Try to limit the labeling of patients as penicillin allergic if they just had a rash. 10 Penicillinase-Resistant Penicillins Agents Activity Clinical Uses Methicillin Nafcillin Oxacillin Cloxacillin Dicloxacillin S. aureus S. epidermidis less active for penicillin susceptibbl bacteria S. aureus infectiion After the penicillins were introduced, Staph aureus became very rapidly resistant to penicillin. The penicillinase-resistant penicillins were developed basically for treatment of Staph aureus infections. These include methicillin, nafcillin, oxacillin and oral agents such as cloxacillin and dicloxacillin. Their activity is for Staph aureus. Occasionally, some Staph epidermidis may be susceptible but the penicillinase-resistant penicillins are less active against penicillin susceptible bacteria, especially anaerobes. The clinical uses are limited to Staph aureus infections.11 Adverse Effects of Penicillinase Resistaan Penicillins Neutropenia -dose and duration related Cholestasis and cholestatic jaundice Interstitial nephritis -most common with methicillin Poor palatability of oral preparations (dicloxacillin and cloxacillin) Adverse effects. Neutropenia is very common and it really depends on how prolonged the usage is. In patients that we treat for four or six weeks for Staph aureus osteomyelitis with nafcillin, we frequently see neutropenias, and we have to stop that agent and switch to something different like clindamycin. So you should look for neutropenia with prolonged use. If it is going to be a short course, it is very unlikely to produce neutropenia. The other one that I just wanted to mention is interstitial nephritis which is much more common with methicillin than it is with nafcillin or oxacillin. Methicillin may not be available any more. The oral preparations of dicloxacillin and cloxacillin. There is no child who has taste buds that would actually take this preparatiio because it tastes so terrible. The use of dicloxacillin and cloxacillin is limited to the adolescent who can take a pill and not worry about an aftertaste. But in a child, this becomes a very big problem because they are really terrible tasting. 12 Aminopenicillins Agents Activity Clinical Uses Ampicillin Amoxicillin Penicillin susceptiibl Some GNR Enterococcus Listeria H influenzae Borrelia Otitis media Sinusitis UTI Lyme disease The aminopenicillins, ampicillin and amoxicillin, were developed so that they could have a broader spectrum of activity than penicillin. This broader spectrum includes all of the penicillin susceptible ones, some gram negative rods, such as E. coli or occasionally Proteus, enterococcus that is not resistant, Listeria. Listeria in the neonate can cause infection in neonatal meningitis. You cannot use a cephalosporin alone for neonatal meningitis because Listeria would not respond. So ampicillin is the drug of choice for Listeria. If H. influenza is susceptible, you could use ampicillin, although we know that there is increasing resistance. For Lyme disease amoxicillin is a good choice. Clinical uses for amoxicillin. We know it is the drug of choice for otitis and sinusitis. If you have an E. coli that is susceptible in the urinary tract or you have enterococcal urinary tract infection, it is useful, although most people would not start with amoxicillin for a UTI because E. coli is becoming amoxicillin resistant and is the most frequent cause of UTI. Lyme disease is one of the uses you can use it for.13 Adverse Effects of Aminopenicillins Allergic reactions Non-allergic mediated rashes associated with viral infections, particularly EBV Diarrhea C difficile colitis Seizures in patients with renal disease The adverse effects are really non-allergic mediated rashes. The rash from amoxicillin, if it is not hives, is usually not an allergy. Remember that it is particularly evident in patients with EBV. It can cause diarrhea. It can cause C. difficile. Seizures are a very rare side effect. 14 Extended Spectrum Penicillins Agents Activity Clinical Uses Mezlocillin Piperacillinn Ticarcillin Carbenicillin Ampicillin susceptiibl More GNR Pseudomonas GNR infection Extended spectrum penicillins cover more Gram-negative rod infections, and these include, mezlocillin, piperacillin, ticarcillin and carbenicillin. Their activity is the same as ampicillin but they include more Gram-negative rods, and particularly piperacillin and ticarcillin and orally carbenicillin are quite good for Pseudomoona infections if they are susceptible. So their clinical uses are really Gram-negative rod infections. These are frequently antibiotics that are used in hospitalized patients, except for carbenicillin which is a p.o. preparation.15 Adverse Effects of Extended Spectrum Penicillins Allergic reactions Thrombophlebitis High sodium load Hypokalemia Platelet dysfunction and bleeding The extended spectrum penicillin have the same kind of adverse profile. Ticarcillin has a high sodium load so we don't use it in patients that have congenital heart disease or any propensity to go into failure. Ticarcillin can also cause platelet dysfunction and bleeding even with a normal platelet count. 16 Penicillins + Beta Lactamase Inhibitor Agents Activity Clinical Uses Amoxicillin + clavulanate ticarcillin + clavulanate Ampicillin + sulbactam Piperacillin + tazobactam Ampicillin susceptiibl S. aureus Anaerobes H influenzae M catarrhalis Polymicrobic Infecttion Bites Otitis media Sinusitis Nosocomial infectiion Penicillin plus a beta-lactamase inhibitor. We have come up with amoxicillin + clavulanate, ticarcillin + clavulanate, ampicillin + sulbactam and piperacillin + tazobactam. These are all ampicillin susceptible, but because of the clavulanate and the addition of this beta-lactamase inhibitor, they get Staph aureus as well as very good anaerobe coverage. Then because we have ampicillin and the beta-lactamase, we now get H. influennz and Moraxella catarrhalis included in the spectrum. The clinical uses are usually polymicrobic infections. One of the major clinical uses in pediatrics is bites. So that for cat bites, extensive dog bites and even human bites, Augmentin or one of these extended spectrum plus the beta-lactamase inhibitors are the ones that are used in the hospital as well for bites. It is a second line agent for otitis media and sinusitis. And they can be used for nosocomial infection for Gram-negative rods that are susceptible, or in patients infected with Gram-negative rods plus Staph aureus and anaerobes, as in the hospitalized patient who may have an aspiration pneumonia. 17 Adverse Effects of Penicillin +Beta Lactamase Inhibitors Gastrointestinal effects, especially diarrhea All adverse reactions of the penicillin component can occur with combinations The adverse effects are an increased incidence of diarrhea. Then remember that all the adverse effects of penicillin can occur with the combination of preparations. 18 Cephalosporins Cephalosporins are divided into first, second and third generatioons 19 First Generation Cephalosporins Excellent activity against Gram-positive organisms Good activity against enteric Gram-negative bacilli No CNS penetration The first generations have excellent activity against Gramposiitiv organisms and their mainstay is for Staph aureus infections. They have okay activity against enteric Gramnegaativ bacilli, so occasionally you will see that there is an E. coli or Klebsiella that's susceptible to Keflex. But remember that first generation agents have no central nervous system penetratiio so do not use Ancef or Keflex if meningitis is a possibility. That is one of the major reasons we use them very infrequently in neonates or preterm neonates where we can't easily exclude central nervous system infection.20 Second Generation Cephalosporins Retain activity against Gram-positives Enhanced activity against Gram-negatives Some with good anaerobic coverage Limited CNS penetration Second generation cephalosporins retain activity against Staph aureus and the Gram-positives. They have enhanced activity against Gram-negatives, especially Hemophilus and Moraxella. Some of them, especially cefoxitin, have good anaerobic coverage and you may see them used for pelvic inflammatory disease or for abdominal infections because of their anaerobic coverage. Second generation cephalosporins have limited central nervous system penetration and should not be used for meningitis.21 Third Generation Cephalosporins Decreased activity against Gram-positives Much enhanced activity against Gram-negatives Some with antipseudomonal activity Excellent CNS penetration The third generations have much decreased activity against the Gram-positive, so we do not use the third generation cephalosporins, like cefotaxime or ceftriaxone, for infections that are due to Staph aureus. They have much enhanced activity against Gram-negatives. Some, like ceftazidime particularly, have anti-Pseudomonal activity and they have excellent CNS penetration. Therefore, that is why we use them for meningitis.22 First Generation Cephalosporins Agents Activity Clinical Uses cephalothin cephalexin cefazolin cefadroxil Penicillin susceptiibl S. aureus GNR (some) S. aureus infectiion First generation cephalosporins include cephalexin (Keflex), cefazolin (Ancef) and cefadroxil (Duricef) with b.i.d. preparation. Their activity is really for Staph aureus. Their clinical uses are for Staph aureus. Remember that group A strep is also susceptibble So for lacerations or cellulitis or osteomyelitis, where you think Staph aureus is a player, these are good alternative drugs.23 Second Generation Activity Clinical Uses Cefaclor Cefuroxim eCefprozil Loracarbe fCefoxitin 1st gen susceptiibl H. influenzae M. catarrhalis GNR (more) Anaerobes Second-line therapy for otitis media and sinusitti Intraabdominal infections Pelvic inflammatory disease Second generation cephalosporins include cefaclor, cefuroxime, cefprozil, loracarbef. They have the activity of the first generatiio and they include Hemophilus and Moraxella. Some to a better degree than others. The clinical uses are really as second line agents for otitis media and sinusitis. Cefoxitin is a second generation that has increased activity against anaerobes, and is used for intra-abdominal infections and pelvic inflammatory disease. 24 Third Generation Cephalosporins Agent Activity Clinical Uses Cefotaxime Ceftriaxone Ceftazidime* GNR Streptococci Nosocomial infections Meningitis *increased antipseudomonal activity Third generation cephalosporins include cefotaxime, ceftriaxone, and ceftazidime. They truly are Gram-negative rod drugs. They are good for Strep pneumoniae, and that is why we use them for meningitis. But we are seeing increased resistaanc to cephalosporins and their clinical uses should be reserved for nosocomial infections and serious meningitis. Other clinical uses of these can be for Gram-negative rod infections, such as Salmonella in sickle cell patients or Salmoneell infections in general.25 Oral Third Generation Cephalosporins Agent Activity Clinical Uses Cefixime Ceftibuten GNR Poor coverage against S. aureus, pneumococcus Resistant urinary tract infectiion Limited pediatric use Oral third generation cephalosporins include cefixime (Suprax), ceftibuten (Cedax). Their activity is really very good for Gramnegaativ rods. They have extraordinarily poor Staph aureus activity and very poor pneumococcus activity. These basically should really be used for Gram-negative rod infection. This limits their pediatric use because otitis, pharyngitis and sinusitis are not commonly caused by Gram-negative rods. I think that one of the good uses for these agents is for resistant UTIs. So our nephrologists use them quite frequently for complicated UTIs with resistant Gram-negatives that they don't want to put into the hospital and this is a very good oral alternative. Using it routinely for otitis and sinusitis in patients where it really has poor pneumococcal activity really doesn't make much "bugdrrug sense.26 Fourth Generation Cephalosporins Agent Activity Clinical Uses Cefepime S. aureus GNR Pseudomonas Undetermined Cefepime is a new fourth generation. I really have not used it at all yet. Its activity is said to be good for Staph aureus, Gramnegaativ rods and for Pseudomonas and I am really not sure what clinical uses it will have in pediatrics. This is really a relatively new drug that we don't have experience with.27 Oral Cephalosporin Activity PSP PRP H/M GAS SA Cepha lexin Keflex + --+ + Cefad roxil Durice f + --+ + Cefpr ozil Cefzil + -+/-+ + Cefacl or Ceclor + -+/-+ -Cefur oxime Ceftin + -+ + + Cefpo doxim e Vantin + -+ + +/-Lorac arbef Lorabi d + -+/-+ -Cefixi me Supra x +/--+ + -Ceftib uten Cedax +/--+ + -Activity of antibiotics for otitis. Really you have to distinguish between all of these oral cephalosporins and pick the ones that you think have the best activity for the organisms that are prevalent in your community and make a decision according to that. Don't switch between these for second line drugs. There is really no reason to switch. New information on Cedax indicates that it is not very good for pneumococcus, so I think it had a plus there before. You want to change that to a +/-as well as cefixime. Loracarbef and Cefzil as well as cefaclor really are +/-against Hemophilus and none of them are better than high dose amoxicillin for resistant pneumococcus.28 Adverse Effects of Cephalosporins Allergic reactions -15% cross reactivity in penicillin allergic patients Serum sickness reaction (cefaclor) Interstitial nephritis Autoimmune thrombocytopenia Biliary cholestasis and cholelithiasis (ceftriaxone) Fungal overgrowth and infections The adverse effects of cephalosporins. Cross reactivity may be as high as 15% with penicillin allergic patients. It is said that the cross reactivity is much greater with first generation cephalosporins than with second generations and thought to be really not very high at all in third generations. I am very conservattive If the patient truly has an anaphylaxis to penicillin I really do not use any of the cephalosporins. However, some people say that you could very safely use the third generations because they are so different. Ceftriaxone is very unique in that it causes biliary cholestasis and cholelithiasis. Then I really want to point out that these are very a broad spectrum agents, especially the third generations. We do see a lot of fungal overgrowth and this may be a precipitating factor of the nosocomial fungal infections in patients who are hospitalized.29 Disadvantages of Cephalosporins Not cure all drugs Pneumococci may be resistant Increasing resistant of hospital GNR Broad spectrum May lead to changes in normal flora and superinfection High cost Disadvantages. Pneumococci may be resistant. There is increasing resistance of some hospital Gram-negative rods such as Enterobacteriaceae, that are hospital-acquired flora may be resistant to cephalosporins. They are very broad spectrum. They lead to especially fungal superinfection and they are relatively high cost. 30 Causes of Cephalosporin Failure Methicillin-resistant S. aureus Coagulase negative Staphylococcus Listeria monocytogenes Enterococcus spp. C. difficile Rickettsia Chlamydia Cephalosporin failure. The instances where it can fail include methicillin-resistant Staph aureus or coagulase negative Staphylococcus infections because you have an indwelling catheter or a ventriculoperitoneal shunt. Listeria is resistant. For Enterococcus they are not good at all. C. difficile and then Rocky Mountain Spotted fever and chlamydia, especially chlamydia pneumonia.31 Carbapenems Agent Activity Clinical Uses Imipenem Meropenem Ceftriaxone susceptible Resistant GNR anaerobes Resistant infectiion Carbapenems. Imipenem, and meropenem are really extraordinarril broad spectrum drugs that have their use in pediatrics really for resistant infections and particularly have been used for meningitis. For pneumococcus that is resistant to ceftriaxone, sometimes they are susceptible to imipenem or to meropenem. Its activity is really against ceftriaxone susceptible plus resistant Gram-negative rods as well as anaerobes. 32 Adverse Effects of Carbapenems Allergic reactions -cross reactivity in PCN allergic parents Diarrhea Lowers seizure threshold (imipenem) Adverse effects are that if you are penicillin allergic you are going to be allergic to meropenem and imipenem. So it is not an alternative for the penicillin allergic patient. Remember that imipenem lowers the seizure threshold so that for use in meningitis this might become a problem and it is better to use meropenem in those instances. It is really nice to reserve this for when you have a ceftriaxone resistant organism, this is a good alternative. 33 Macrolides Erythromycin Clarithromycin Azithromycin Roxithromycin Dirithromycin Macrolides. Erythromycin is the prototype but now we have clarithromycin, azithromycin. There is increasing use of clarithromycin and azithromycin.34 Erythromycin -Activity Spectrum Clinical Uses Penicillin susceptible S. aureus Mycoplasma Legionella B. pertussis Campylobacter Chlamydia Penicillin allergic ptatients Specific pathogens The spectrum of activity. It is the penicillin susceptible organissms Then you have Staph aureus, although there is an increase in Staph aureus that is resistant to erythromycin and if they're resistant to erythromycin, they're going to be resistant to azithromycin and clarithromycin as well. Organisms that are covered include Mycoplasma pneumoniae, Legionella which is an infrequent cause of infection in children but may occasionally happen, Pertussis. It is our drug of choice for pertussis, Campylobacter, and also chlamydia pneumoniae. So the erythromycins are really good alternatives. The clinical uses are for penicillin allergic patients for pharyngitis. They can be used as second line agents for otitis and sinusitis and against, specific pathogens, it is the drug of choice for pertussis infections. 35 Macrolides -Adverse Effects Gastrointestinal disturbances Hepatotoxicity IV erythromycin -cardiotoxicity hepatotoxicity venous irritation Many drug interactions The adverse effects are really gastrointestinal disturbances and this is why the new macrolides exist. Because clarithromycin and azithromycin have less gastrointestinal intolerance than erythromycin. They may be hepatotoxic and remember that IV erythromycin is a very dangerous drug to use. It can be cardiotoxic and hepatotoxic and causes a lot of venous irritation. It should not be given IV unless you have an infectious disease consult and a very good reason such as Legionella infection in a child. Remember that there are many drug interactions with the erythromycins and these interactions don't go away becaaus you are using the newer preparations. It is terrible for cyclosporin levels but it also interacts with theophylline. 36 New Macrolides Activity Clinical Uses Clarithromyc in azithromycin Erythromycin suscepttibl H influenzae M catarrhalis Non-tuberculous mycobacterium Toxoplasma Cryptosporidium N gonorrhoeae Second line therapy for otitis media and sinusitis Pathogen specific Clarithromycin and azithromycin. Their activity is that of erythromycin susceptible. They have better Hemophilus and Moraxella coverage than penicillin, but they may not achieve adequate middle ear concentrations. It is very interesting that this is a very good use for non-tuberculous mycobacteria. Those patients that have cervical lymphadenitis that we think are secondary to non-tuberculous, might respond to clarithromycin. I may use clarithromycin initially for these patients. Also in patients with HIV with MAI, clarithromycin is a good drug. Toxoplasma also in immunocompromised patients. Azithromycin has the same activity in Cryptosporidium and gonorrhea. The clinical uses are really as second line agents for otitis and sinusitis and for pathogen specific infections.37 Advantages of New Macrolides Retain spectrum of activity of erythromycin Increased spectrum against H. influenzae and nontuberculous mycobacteria Improved pharmacokinetics Decreased gastrointestinal side effects The advantages are that they retain the spectrum of erythromycin, they increase the spectrum against these things, they have improved pharmacokinetics, but really the main advantage of clarithromycin and azithromycin is in their dosing and their improvement in altered side effects. So that b.i.d. or once a day dosing is preferable to four times a day dosing, and the decrease in side effects is really the major advantage.38 Disadvantages New Macrolides Broader spectrum of activity Does not broaden spectrum for erythromycin resistant pneumococcus High cost Adverse effect of clarithromycin headache, neurologic changes The disadvantage is that they have a broader spectrum of activity. It does not really broaden the spectrum for erythromycin resistant pneumococcus. So, if your pneumococcus is resistant to erythromycin, it is equally resistant to clarithromycin and azithromycin. The relative cost is higher, and azithromycin is extraordinarily expensive, but because it's been used for half of the time for five days rather than the usual 10 day course, it is pretty equivalent to clarithromycin, but it is about 10 or 12 times higher in cost than erythromycin. The uncommon effects of clarithromycin such as headache and neurologic changes are uncommon but can occur.39 Clindamycin Activity Clinical Uses PCN susceptible S. aureus Anaerobes Toxoplasma No H. influenzae or M. catarrhalis Penicillin allergic Resistant pneumococci Intraabdominal infections Toxoplasmosis Clindamycin. Clindamycin is a drug that we had not used previously as much as we are using now, but now with resistant infections, we are seeing new uses for clindamycin. It has activity against penicillin susceptible organisms, Staph aureus, anaerobes, Toxoplasma. It doesn't have activity against Hemophilus or Moraxella catarrhalis. Especially in bite wounds, it doesn't cover Eikenella, so that it cannot be used as a single agent in this. That is why we use amoxicillin-clavulanate or the combination ones for bite wounds. The clinical uses of clindamycin are in the penicillin allergic, in the resistant pneumococcal infection, intra-abdominal infections, not alone but with other Gram-negative rod agents, and then in patients with toxoplasmosis.40 Adverse Effects of Clindamycin Clostridium difficile colitis Hepatotoxicity Stevens-Johnson syndrome Eosinophilia Clindamycin adverse effects are C. difficile colitis. It definitely has been associated with colitis, but I am not really sure that it is more associated than any of the other antibiotics. Amoxicillin is the one that is used the most, and amoxicillin is the antibiotic that is most associated with C. difficile by the sheer numbers of its usage. Clindamycin can cause hepatotoxicity. It can cause Stevens-Johnson, and it may cause eosinophilia. Overall, it is used a lot and it is a safe alternative.41 Quinolones Nalidixic Acid Ciprofloxacin Norfloxacin Quinolones have been increasingly used in pediatrics, and although they are not approved for use in pediatrics, we do have an increasing experience with the quinolones and may choose them as alternatives in some patients for specific reasons. 42 Quinolones Spectrum of Activity Gram positives +/-S. pneumoniae +/-S. aureus Gram negatives Pseudomonas aeruginosa Other Chlamydia, Mycoplasma, Mycobacterium, Bartonella, Plasmodium They are not wonderful for pneumococcus or for Staph aureus, these are not drugs for resistant pneumococcal infections or for Staph aureus infections. But they are good for Gram negatives, particularly Pseudomonas. That is one of the areas of major use is as an outpatient drug for pseudomonal infection. Other uses include Bartonella henslae which is the agent of cat scratch disease. 43 Potential Uses of Quinolones Pulmonary infections in cystic fibrosis Complicated urinary tract infections Chronic suppurative otitis media Complicated osteomyelitis Resistant nosocomial infections Prophylaxis for N. meningitidis Gastrointestinal infections The potential uses for the quinolones. We have lots of experiennc in the cystic fibrosis patients, with very little adverse effects that we can attribute to the quinolones. Complicated urinary tract infections caused by Gram-negative rods that are resistant to other drugs. For chronic suppurative otitis media when Pseudomonas may be one of the pathogens. Complicaate osteomyelitis such as that associated with decubital ulcers with Gram-negative rods and where resistant Pseudomonna may be a problem. Resistant infections. There are theoreticca risks of growth problems with quinolones. It is also used for gastrointestinal infections such as Salmonella. 44 Adverse Effects of Quinolones Diarrhea Arthralgias and tendon rupture Increased liver enzymes Possible effect human cartilage growth Adverse effects. Quinolones do cause diarrhea. It has been reported to cause arthralgias and there was recently a report of an Achilles tendon rupture associated with quinolone use, particularly ciprofloxacin. But the question of the effect on human cartilage growth is becoming more and more of a question. This is definitely seen in animals, but in cystic fibrosis patients where we use large quantities of ciprofloxacin, in doing MRIs of their joints there is really no detectable damage to the cartilage. So I think we are getting more and more comfortable with quinolones. Obviously not as a first choice. But their potential uses in pediatrics are going to be becoming more and more prevalent. 45 Sulfonamides Agent Activity Clinical Uses TMP/sulfamethoxaz ole (Bactrim, Septra) PCN susceptible, except Gp A strep and anaerobes GNR-Salmonella, Shigella H. influenzaee Pneumocystis Second-line therapy for otitis media and sinusitis Bacterial enteritis Pneumocystis Erythro/sulfamethox azole Pediazole) Erythromycin suscepttibl H. influenzae M. catarrhalis Second-line therapy for otitis media and sinusitis Sulfonamides. TMP/sulfa does not have activity against group A strep. It has no anaerobic activity at all. The Gram-negative rods, that it is very good for are Salmonella, shigella, Hemophilus influenza. It is the drug of choice for Pneumocystis carinii pneumonia infections. Its clinical uses are as a second line agent for otitis and sinusitis. For bacterial enteritis and for Pneumocystis. Erythro/sulfa (Pediazole) takes the activity of all the erythromycin and increases activity for Hemophilus and Moraxella. It is a second line agent for otitis and sinusitis.46 Adverse Effects of Sulfonamides Gastrointestinal disturbances Skin rashes -more common in HIV infected patients Erythema multiforme and Stevens-Johnson syndrome Adverse effects of the sulfonamides. Skin rashes are very prominent and are more common in HIV patients than in non-HIV infected patients. Erythema multiforme and Stevens-Johnson syndrome seem to have a higher association with sulfonamides than with other antibiotics, although it can occur with other antibiotics. But there seems to be somewhat of a higher association with sulfonamides and Stevens-Johnson.47 Vancomycin Activity Clinical Uses PCN susceptible MRSA S. epidermidis Enterococcus sp C. difficile pathogen specific infection of medical devices Vancomycin. The activity of vancomycin is that it is penicillin susceptible. It includes methicillin resistant Staph aureus and is really the best drug for methicillin resistant Staph aureus infections. It is the drug that we use when Staph epidermidis infection is thought of, such as in patients with indwelling devices and indwelling venous catheters. Enterococcus is usually susceptible, although now we know that enterococcus has the ability to develop vancomycin resistance, and this is an increasing problem that is going to becoming even more of a problem in pediatric institutions. Then we use the oral preparatiio for C. difficile. Really the clinical uses are for infection of medical devices and truly pathogen specific when you have MRSA or if you have a susceptible Enterococcus. The routine use of vancomycin for C. difficile colitis is not recommended because we do not want to encourage Enterococcus resistance. Metronidazole should be used instead.48 Adverse Effects of Vancomycin Ototoxicity -in patients with renal disease or concurrent aminoglycosides Red man syndrome Hypotension associated with infusion The infusion of the intravenous vancomycin can cause a red man syndrome that is not an allergy. It responds very nicely to decreasing the rate of infusion or stopping it for a little bit and starting up again at a lower rate. It also responds nicely to antihistamines. There have been patients with hypotension associated with the infusion, which readily gets better with stopping it.49 Aminoglycosides Agents Activity Clinical Uses Gentamicin Netilmicin GNR GNR infections Amikacin Resistant GNR Hospital GNR Tobramycin P. aeruginosa Aminoglycosides. Their activity is for Gram-negative rods and Gram-negative rods only. It is a little bit better for resistant Gram-negative rods, so some are no longer using gentamicin but have switched to amikacin because they have a problem with a particular Gram-negative rod that may be resistant. Tobramycin is specific for Pseudomonas aeruginosa. They are used for Gram-negative rod infections, and apart from urinary tract infections, should not be used as the sole agent. 50 Adverse Effects of Aminoglycosides Nephrotoxicity Ototoxicity Reversible neuromuscular blockade Need to monitor levels Adverse effects. They have nephrotoxicity and ototoxicity. It can cause neuromuscular blockade, which is an important factor in patients with botulism because this small neuromuscular blockade becomes clinically significant in those patients, and it may precipitate respiratory arrest in that patient. There is new information that once daily dosing of aminoglycosides may be as effective as the three times a day dosing, with less side effects. More pediatric information is coming forward with that.51 Tetracyclines Agents Activity Clinical Uses Tetracycline Doxycycline Chlamydia Mycoplasma RickettsiiaEhrlichia Borrelia Brucella, Francisella Propionobacteria Eikenella Pathogen specific Not for Gp A Strep Tetracyclines are really pathogen specific. It includes very broad pathogens that are kind of unusual. It really is not for group A streptococcus.52 Adverse Effects of Tetracycline Gastrointestinal disturbances Deposition of drug in bones and teeth Contraindicated in children <8 years Photosensitivity Hepatotoxicity -especially with IV tetracycline Bacterial overgrowth They are not used often in pediatric patients because they are contraindicated because they deposit in bones and teeth and stain the teeth. Remember if you are using it for patients for acne, tell them that it causes photosensitivity so that they can get ready when they get out into the sun. 53 Chloramphenicol Activity Clinical Uses Penicillin susceptible H. influenzae Anaerobes Salmonella Shigella Rickettsia Rocky mountain spotted fevve in children less than 8 years old Chloramphenicol is something that has a very good spectrum activity, but it is not used very much because we have very good alternatives. But remember one of the main clinical uses is for Rocky Mountain Spotted fever in that patient that is less than eight years of age. There have been failures when it has been used for resistant pneumococcus despite its good in vitro activity. So it is not recommended. 54 Adverse Effects of Chloramphenicol Idiosyncratic aplastic anemia Bone marrow suppression Gray baby syndrome Hepatotoxicity Need to monitor levels Adverse effects include bone marrow suppression and aplastic anemia; these have precluded its use in pediatrics. 55 Rifampin Activity Clinical Uses S. aureus Streptococci N. meningitidis H. influenzae Mycobacterium Synergy device infection Mycobacterial infection Prophylaxis for H. influenzae and N. meningitides Rifabutin has better activity for MAI than rifampin Rifampin. We use it a lot as synergistic for microbacterial infections and prophylaxis. It really should not be used to treat infections alone because organisms become rapidly resistant to rifampin.56 Rifamycins -Adverse Effects Hepatotoxicity especially with other drugs or pre-existing liver disease Changes color of all body secretions to orange It does change the color of all body secretions. It makes them a bright orange. That is how you know the patient is getting rifampin but you have to warn the patient about this. 57 Metronidazole Activity Clinical Uses Anaerobes G. vaginalis Entamoeba Trichomonas Giardia Anaerobic infections C. difficile Pathogen specific Metronidazole is good for anaerobes, and that includes all of these organisms as well as Giardia. Its clinical uses are anaerobic infections, C. difficile, and pathogen specific infectioons 58 Adverse Effects of Metronidazole Neurotoxicity Peripheral neuropathy Gastrointestinal disturbances Metallic taste Mutagenic and carcinogenic in lab animals A peripheral neuropathy and neurotoxicity can occur, which is more frequent in adults. I has a metallic taste. We use it quite frequently for anaerobes and for C. difficile colitis. 59 References 1. Jacobs RF, Schutze GE, Young RA, et al. Antimicrobial Agents In: Principles and Practice of Pediatric Infectious Diseases. Eds: Long SS, Pickering LK, Prober CG New York, Churchill Livingstone 1997 2. Spect WT, Blumer I (eds). The Pediatric Clinics of North America: Symposium of Anti-Infective Therapy. Philadelphhia WB Saunders Co, 1983 3. Smith AL (ed). Antibiotic Update. Pediatric Annals 1993; 22.' 155-200