The β-lactam antimicrobials include the penicillins, cephems, carabepenems, monobactams (step 1, Figure 39-2), and many β-lactamase inhibitors (step 3, Figure 39-2). They are characterized by a four-membered β-lactam ring. Otherwise they are structurally distinct, with differences in their ability to bind their target, the penicillin binding proteins (PBPs, also called transpeptidases). Bacteria have a large variety and number of PBPs, so the spectrum of β-lactam activity is related to the binding affinity to the key PBPs in a given bacterial isolate. Binding of PBPs by β-lactams prevents cross-linking of the peptidoglycan layer of the cell wall, resulting in bacterial death. These drugs are considered bactericidal, with killing related to time over the MIC. Bacteria protect themselves from β-lactams mainly by (1) producing β-lactamases that hydrolyze the β-lactam ring, (2) altering the PBP to change the β-lactam-PBP binding affinity, or (3) creating changes in porins or efflux pumps to effectively decrease the intracellular concentration of drug. There are many different types of β-lactamases that vary from very narrow penicillinases (such as that produced routinely by S aureus), to more sophisticated and broad types produced by gram-negatives, of which there are hundreds. Amongst these are the inducible β-lactamases (IBL) that become clinically apparent only after β-lactam use. IBLs are common in organisms such as Serratia, Pseudomonas, Proteus, Citrobacter ferundii, Enterobacter, and Aeromonas. There are also the extended spectrum β-lactamases (ESBLs), which are primarily produced by Klebsiella spp. and E coli. These are of particular concern because the plasmids (see Fig. 39–2) encoding them are transmissible between organisms and often harbor other types of resistance. Of increasing concern are the plasmids encoding carbapenem resistance, since they often contain other types of resistance mutations and have the potential to become untreatable with current drugs.
Although allergy to β-lactam antimicrobials is reported commonly by parents, this history is not highly predictive of an allergic reaction. A history of anaphylactic-type reactions warrants caution or avoidance of cephalosporins and penicillins until evaluated by an allergist. As patients labelled with a penicillin allergy may receive inferior treatment strategies their whole lives, confirming the details of the history is important, with referral for allergy testing if the history is consistent with a concerning reaction.
Penicillins and Aminopenicillins
Penicillins, amoxicillin, and ampicillin are the drugs of choice to treat infections with group A streptococcus (including acute pharyngitis), group B streptococcus, most pneumococci, most enterococci, syphilis, N meningitides, leptospira, rat-bite fever, actinomycosis, many oral anaerobes, and most Clostridium and Bacillus species. They are also used for prophylaxis in rheumatic fever or for patients with asplenia. Amoxicillin/ampicillin is considered first line for community acquired pneumonia, otitis media, and oral treatment of Lyme disease in children less than 8 years. They penetrate all tissues relatively well, and amoxicillin offers moderate bioavailability, notably much better than all of the oral cephalosporins (though comparable to cephalexin). More time above the MIC is achieved with higher, more frequent dosing; for example, amoxicillin dosed 90 mg/kg divided three times daily for S pneumoniae (with MIC of 1-2 mcg/mL) will achieve 7–8 hours of time over the MIC, while if divided only two times a day will exceed the MIC for only 5–6 hours.
The common β-lactamase inhibitors (sulbactam, clavulanic acid and tazobactam, but not avibactam) are themselves β-lactams in structure, but do not have antibacterial activity. Instead, they act as “decoys,” binding bacterial β-lactamases so that their companion drug is free to bind the target PBP. They are available in combination with penicillins and aminopenicillins in amoxicillin-clavulanic acid (oral) and ampicillin-sulbactam (IV), offering expanded activity to methicillin susceptible S aureus (MSSA), Moraxella catarrhalis, Klebsiella spp., and β-lactamase producing gram-negatives (such as some Haemophilus influenza, E coli) and anaerobes (such as Bacteroides fragilis, and Fusobacteria spp.). This makes them useful for treating mixed infections, for example dog bites or tonsillar and parapharyngeal abscesses, orbital cellulitis, step-down therapy for ruptured appendicitis, and refractory sinusitis and otitis media. Notably, they offer no advantage in the treatment of S. pneumoniae or other streptococci, as these do not produce β-lactamases. Piperacillin-tazobactam similarly expands coverage, including possible coverage for P aeruginosa. This drug has a niche in complex abdominal infections and hospital-associated pneumonia, but should be used sparingly due to its broad spectrum and risk of AKI. Piperacillin-tazobactam is particularly nephrotoxic, especially when used with other nephrotoxic drugs such as vancomycin. While the penetration of the penicillins and aminopenicillins is good into most spaces, the penetration of the β-lactamase inhibitors is poorly understood. β-Lactam with β-lactamase inhibitor combinations are notorious for causing diarrhea, particularly amoxicillin-clavulanic acid, where care in choosing the right formulation to appropriately dose the clavulanic acid component is important.
The penicillinase-resistant penicillins were essentially developed as anti-MSSA antibiotics, to combat the narrow-spectrum β-lactamase (penicillinase) produced by nearly all MSSA. These drugs, which include nafcillin, oxacillin, methicillin, and dicloxacillin, offer structural protection to the β-lactam structure so that it is unavailable to penicillinases. They are associated with renal toxicity, which is not uncommon with long-term use. Also common are drug fever, rashes, and neutropenia. Oxacillin and methicillin are renally excreted, whereas nafcillin is excreted through the biliary tract. Nafcillin is a venous irritant, making it difficult to maintain peripheral intravenous access; it also causes severe damage with extravasation, so it is best used with large or central lines. Because of their expense and side effect profiles, these drugs have largely been supplanted by cefazolin (IV) and cephalexin (oral), but the IV forms retain a niche in the treatment of endocarditis and CNS infections caused by MSSA. Dicloxacillin is used as step-down therapy when appropriate, and for outpatient treatment of SSTI in adults. Other notable uses include Kingella kingae and some other gram-positive organisms (eg, group A streptococcus and Proprionobacterium acnes).
Cephems are the largest group of antibiotics. They are often categorized in “generations,” which is not a chemical relationship, but rather similarity in antimicrobial spectra based on binding to various PBPs. All the resistance mechanisms mentioned above for β-lactams also apply to cephalosporins. Gram-negative organisms have an ever-expanding variety of β-lactamases, the most problematic of which in routine practice are the inducible and extended spectrum β-lactamases (IBLs and ESBLs).
The first-generation cephalosporins include cefazolin (IV) and cephalexin (oral), which are mainly used to treat infections with MSSA or as empiric therapy for urinary tract infections. In particular, they are highly effective treatment for skin/soft tissue infections (SSTI), as they also have activity against group A streptococci, and in initial and oral step-down treatment of musculoskeletal infections in children. Because of its high concentration in urine, cephalexin is considered first line for urinary tract infections, and oftentimes achieves adequate killing in organisms deemed “resistant.”
The second-generation cephalosporins include cefuroxime (IV) and cefprozil and cefuroxime (oral). These have somewhat reduced, but acceptable, activity against gram-positive cocci, and greater activity against some gram-negative rods compared with first-generation cephalosporins, but not as much as third. They are active against H influenzae and M catarrhalis, including strains that produce β-lactamases capable of inactivating ampicillin. Cefoxitin is also considered a second-generation cephalosporin, and adds anaerobic activity, making it useful in the treatment of non-perforated appendicitis or pediatric cholangitis; its half-life is very short and resistance is increasing, so it should be reserved for nonserious infections.
Third-generation cephalosporins have substantially less activity against some gram-positive cocci, such as S aureus, though notably they retain good activity against S pneumoniae and group A streptococcus; however, they have increased activity against aerobic gram-negative bacteria, and generally have good CNS penetration. Cefotaxime and ceftriaxone are examples of intravenous drugs, whereas cefpodoxime and cefdinir are oral options. Ceftazidime provides similar coverage (with decreased S pneumoniae coverage), but provides some activity against P aeruginosa, though resistance may be induced quickly.
Cefepime is considered a fourth-generation cephem. It retains considerable activity against MSSA while also being active against P aeruginosa and some other IBL producers, such as Enterobacter spp. It is a zwitterion and as such efficiently penetrates the gram-negative outer cell membrane. Notably it is hydrolyzed by ESBLs, so confers no advantage against these pathogens.
Ceftaroline is the only fifth-generation cephem, and it is the only one able to treat MRSA through binding of the altered PBP (encoded by mecA); it does not have activity against P aeruginosa. Ceftaroline was recently approved in children. None of the cephems have activity against enterococci.
There are now two cephems combined with β-lactamase inhibitors used in adults, ceftazidime-avibactam and ceftolozane-tazobactam. These both have activity against P aeruginosa, and variable coverage against many other resistant gram-negatives. Neither is approved in pediatrics.
The oral cephems, except cephalexin, have very poor serum levels and often do not achieve adequate time over the MIC for sufficient killing. In general, they are poorly absorbed, highly protein bound, often are given at too prolonged an interval, and generally should not be widely used. For organisms susceptible to amoxicillin, they are pharmacokinetically inferior and should be used only to treat those with allergy, or when the organism is resistant to penicillins. In general, longer time above the MIC is achieved in the middle ear and urine compared to other locations.
Aztreonam is the only monobactam antimicrobial agent approved in the United States. Although not approved for use in children younger than age 9 months, there is considerable pediatric experience with aztreonamin neonates and premature infants. Aztreonam is active against aerobic gram-negative rods, including P aeruginosa. Aztreonam has activity against H influenzae and M catarrhalis, including those that are β-lactamase producers. Most patients with allergy to penicillin or cephalosporins are not allergic to aztreonam. An exception is the child with a prior reaction to ceftazidime, since this drug and aztreonam share a common side chain.
Aztreonam delivered by aerosolization using a proprietary nebulization system is approved for therapy of P aeruginosa infection in patients with cystic fibrosis. Safety and efficacy have not been established in children younger than 7 years. Therapy is delivered three times daily for 28 days with a goal to improve respiratory function.
Meropenem, ertapenem, doripenem, and imipenem comprise the carbapenems, which are very broad antimicrobials that are effective against gram-negative aerobes, most anaerobes, and many gram-positive organisms. They have some activity against MSSA (but not MRSA), S pneumoniae, E fecalis (but not E faecium), and various other gram-positives. Except for ertapenem, they treat most multi-drug resistant gram-negatives, including P aeruginosa and those with IBLs and ESBLs. Imipenem-cilastatin is a combination that contains cilastatin, which inhibits the metabolism of imipenem in the kidneys resulting in high serum and urine levels. An increased frequency of seizures is encountered when central nervous system infections are treated with carbapenems, particularly imipenem. Because carbapenems are active against so many species of bacteria, there is a strong temptation to use them as single-drug empiric therapy. Units that use carbapenems heavily encounter resistance in many different species of gram-negative rods that can develop in a single patient within days due to bacteria developing a porin/efflux mechanism. Carbapenem use should therefore be reserved for patients with confirmed (or at high risk for) resistant infection. β-Lactamases capable of attacking the carbapenems now exist and are spreading worldwide; organisms harboring these plasmids often have many resistance mechanisms, and are susceptible to few (if any) remaining treatment options.
Glycopeptides include vancomycin, telavancin, oritavancin, and dalbavancin (step 2, Figure 39–2). They are characterized by their large molecular size, which will not penetrate the outer cell membrane of gram-negative organisms. Like the β-lactams, they also are active on the cell wall, inhibiting peptidoglycan synthesis by preventing cross-linking at the terminal amino acids (D-alanine). It is debated if their efficacy is most related to time over the MIC or AUC over MIC, but in either case, they are considered cidal. Bacteria protect themselves mainly through (1) changing the terminal amino acid to D-lactate so that vancomycin cannot bind, or (2) thickening the cell wall (vancomycin-intermediate and resistant S aureus) such that the glycopeptide present is not sufficient to bind enough targets to prevent cross-linking. In terms of side effects, they have notable nephrotoxicity and are a common cause of drug-related AKI. Red-man syndrome (flushing and itching with infusion) does not represent a true allergic response and can be mitigated with slower infusions (over 1 hour) and premedication with diphenhydramine or hydrocortisone. All the glycopeptides have similar spectra of activity, including MRSA, coagulase negative staphylococci, ampicillin-resistant enterococci, and resistant S pneumoniae. Orally, vancomycin is not systemically absorbed but effectively kills C difficile, though at this time it is reserved for severe or refractory cases. The glycopeptides differ in dosing strategies, with telavancin dosed once daily, and both dalbavancin and oritavancin dosed once-weekly. These three drugs are not FDA-approved for use in children.
The empiric use of vancomycin has increased tremendously over the last decade. Thus, vancomycin-resistant enterococci (VRE) is now problematic, particularly in inpatient units, intensive care units, and oncology wards. Vancomycin-intermediate and vancomycin-resistant S aureus now exist, which is of concern because of the inherent virulence of many S aureus strains. Vancomycin use should be monitored carefully in hospitals and intensive care units. Vancomycin should not be used empirically when an infection is mild or when other antimicrobial agents are likely to be effective, and should be stopped promptly if infection is caused by organisms susceptible to other antimicrobials. Attention to obtaining cultures prior to vancomycin initiation is required, as susceptibility to oral alternatives is not predictable.
Vancomycin’s efficacy requires a sufficient trough (15–20 mcg/mL for CNS, endocarditis, and bone infections, 10–15 mcg/mL for other infections); this can be difficult to achieve in some pediatric ages, thus monitoring and dose adjustment are necessary. Continuous infusion can be used if sufficient levels are not achievable with Q6 hour dosing. The trough concentrations are usually drawn before the fourth dose, but should be drawn sooner if the patient is at risk of AKI; a high trough can both indicate and cause renal injury. Serum creatinine should be checked in all patients administered vancomycin to monitor for AKI and adjust dosing if needed. Vancomycin peak levels are no longer routinely monitored because the increased purity of the formulations has resulted in less ototoxicity. For patients receiving antimicrobials for weeks to months, weekly clinical assessment and laboratory assessment of urine, creatinine, and complete blood count will facilitate detection of toxicity.
Daptomycin is unique in that it is a lipopeptide that inserts into the lipid-rich cell inner membrane of gram-positive bacteria (step 4, Figure 39–2). This results in depolarization and cell death. It is unclear if this bactericidal mechanism is related to the time that intracellular levels exceed the MIC or whether AUC over MIC is most important. Microbes protect themselves by changing the charge of their cell membranes, such that daptomycin cannot insert. Since daptomycin cannot penetrate the gram-negative outer cell membrane (envelope), it is only active against gram-positive organisms and has a clinical niche against MRSA and vancomycin-resistant E faecium. Daptomycin may insert itself into lipid layers of human cells, particularly muscle, causing creatinine phosphokinase (CPK) elevation. Rhabdomyolysis has been reported and monitoring of CPK in children is recommended. Because it is a lipid, surfactant in lung will envelop the drug rendering it inactive for lung infections.
Sulfonamides—the oldest class of antimicrobials—are usually used in a fixed combination with trimethoprim (TMP-SMX) to inhibit two steps in the folate synthesis pathway (which then inhibits DNA biosynthesis, step 8, Figure 39–2) for greater efficacy (step 5, Figure 39–2). AUC over MIC confers efficacy. TMP-SMX is generally considered static. Resistance is usually related to alterations in the targets or decreased drug concentrations due to efflux or decreased entry. TMP-SMX is particularly associated with Stevens-Johnson syndrome, though this is rare. It also may cause hematologic abnormalities that can be severe. It should not be used in patients with G6PD deficiency. TMP-SMX is most often used clinically to treat MRSA SSTIs, urinary tract infections, and susceptible strains of Haemophilus spp., Shigella spp., or Salmonella spp. TMP-SMX is a mainstay in prophylaxis and treatment of Pneumocystis jiroveci infection, and in treatment of Nocardia spp., brucellosis, and Stenotrophomonas maltophilia. As an intravenous formulation, it requires large volume infusion over 2 hours every 6 hours, so is rarely given via this route. Pathogens with significant resistance include group A streptococcus, S pneumoniae, and various gram-negatives.
Metronidazole is a pro-drug that is only converted to its active form by anaerobic, amoebic, and protozoal organisms (step 6, Figure 39–2). Once converted, it is debated if these intermediates bind DNA, RNA or essential proteins leading to cell death. Effective killing is related to the AUC over MIC, and it is considered bactericidal. It has PAE and a long half-life, so could be dosed less frequently than the current recommendation of three to four times daily. In pediatric appendicitis, it often is dosed once daily. Resistance mechanisms are not well investigated, but likely relate to lack of conversion to active drug. It is most active against gram-negative and positive rods, such as Bacteroides, Fusobacterium, Clostridium, Prevotella, and Porphyromonas. Gram-positive anaerobic cocci such as Peptococcus and Peptostreptococcus are often more susceptible to penicillin or to clindamycin. Metronidazole is the drug of choice for bacterial vaginosis and for C difficile enterocolitis. It is active against many parasites, including Giardia lamblia and Entamoeba histolytica. Metronidazole is highly bioavailable, and has excellent penetration including CNS.
The macrolide antimicrobials in common use include erythromycin, azithromycin and clarithromycin (step 6, Figure 39–2). They block RNA translation and assembly of the 50S ribosomal subunit, and thus inhibit protein synthesis. Efficacy is related to AUC over MIC. Macrolides are considered static. Microbes protect themselves by altering the macrolide binding site with methylation, or through efflux of the drug. Because of ease of dosing and tolerability, azithromycin is the most commonly prescribed macrolide, and in fact, is one of the most commonly prescribed antimicrobials in the United States. This likely indicates overuse, given its rarity as first-line agent in national treatment guidelines and frequent resistance. Gastrointestinal side effects are common with the macrolides, particularly with erythromycin, which is controversially used as a pro-motility agent. They are associated with pyloric stenosis in infants, again mostly erythromycin. They all prolong the QTc interval, a consideration in at-risk patients; azithromycin has an FDA warning discouraging use for this reason.
Azithromycin has a large volume of distribution, where it has a prolonged half-life; although it is dosed for 5 days, intracellular drug is present approximately 10 days. Azithromycin is used to treat Campylobacter, Shigella, and Salmonella infections, including typhoid fever resistant to ampicillin and TMP-SMX, and is thus used for presumed bacterial traveler’s diarrhea. All macrolides are active against many bacteria that are resistant to cell wall–active antimicrobials, and are the drugs of choice for Bordetella pertussis, Legionella pneumophila, C pneumoniae, M pneumoniae, and C trachomatis infections. Azithomycin and clarithromycin also have activity against some mycobacteria. Resistance among other common pathogens, such as S pneumoniae, group A streptococcus, S aureus, and Haemophilus spp. limit azithromycin’s efficacy for otitis media, sinusitis, and community-acquired pneumonia (except for Mycoplasma).
Clindamycin targets protein synthesis through inhibiting peptidyl tranferase at the 50S ribosomal subunit (step 6, Figure 39–2). Its efficacy is related to the AUC over MIC, and it is considered bacteriostatic. Resistance is mediated by methylation of the binding site; this mechanism may be detected only after induction with erythromycin (using a D-test), or may be constitutive. Efflux of drug is another mechanism of resistance. Clindamycin is highly bioavailable, and penetrates most spaces very well except spinal fluid and urine, so it should not be used for infection in those spaces. It concentrates in joint fluid. It does have brain penetration (though not good CSF), so can be used for diseases such as CNS toxoplasmosis. It is active against many anaerobes and gram-positive organisms, including S pneumoniae, S pyogenes and MRSA, though resistance is becoming more prevalent. It is not active against enterococci. Because of its unique spectrum, it is often used to treat mixed aerobic gram-positive and anaerobic infections, such as sinusitis, dental, oral and neck abscesses, pelvic inflammatory disease, and deep infections from pressure ulcers. Because it inhibits protein (and thus toxin production), it is often used to treat serious toxin-mediated diseases such as toxic shock syndrome. It also may be active against non-replicating bacteria that may be present in undrained abscesses. Clindamycin is associated with the occurrence of C difficile–related pseudomembranous colitis in adults, but this relationship is uncommon in children, although diarrhea is a frequent side effect. Though clindamycin is an old drug, it is particularly expensive, and has palatability issues in liquid formulations.
Linezolid is the first oxazolidinone in use (step 6, Figure 39–2). Its target is the 50s-ribosomal RNA subunit to prevent initiation of protein synthesis. Because of this mechanism, cross-resistance with other classes of antimicrobials is uncommon. A mutation of the binding site on the ribosomal subunit has made resistance increasingly common. Efficacy is related to AUC over MIC, and linezolid is considered bacteriostatic. Linezolid has broad gram-positive activity, including some anaerobes, but it should be reserved for MRSA, VRE, or treatment of gram-positive infections in those who cannot receive nephrotoxic drugs. It has very limited gram-negative activity. Linezolid comes in an IV formulation, but is highly bioavailable and is usually used orally. Linezolid is safe and well tolerated in children, but neutropenia and thrombocytopenia are not infrequent. A complete blood count should be monitored in patients at increased risk for these problems and in patients receiving therapy for 2 weeks or longer. Linezolid is an inhibitor of monoamine oxidase (MAO) and should not be used in patients taking MAO inhibitors, or in patients taking phenylpropanolamine or pseudoephedrine.
Tetracyclines, including doxycycline, minocycline, and tigecycline, interact with tRNA at the 30S ribosomal subunit to prevent protein synthesis (step 6, Figure 39–2). To protect itself, the microbe may develop proteins that protect the tRNA target, or efflux pumps to decrease drug concentrations. Efficacy is related to AUC over MIC, and these drugs are considered static. Tetracyclines are effective against a broad range of bacteria, but are most commonly used against B pertussis, many species of Rickettsia, Chlamydia, and Mycoplasma. Doxycycline is a drug of choice for eradication of C trachomatis in pelvic inflammatory disease and nongonococcal urethritis. Doxycycline is often preferred over the others because it is better tolerated than tetracycline, twice-daily administration is convenient, and it can be taken with food. Notable side effects of the tetracyclines are staining of permanent teeth, so they are generally not given to children younger than age 8 years if an alternative exists. However, a single course of a tetracycline does not pose a significant risk of tooth staining. Increased photosensitivity is a notable side effect, and minocycline (commonly used for acne) has a particular association with DRESS syndrome. Doxycycline is used for therapy of Q fever and rickettsial infections (Rocky Mountain spotted fever, ehrlichiosis, anaplasmosis, rickettsialpox) and endemic and murine typhus. Doxycycline can also be used as an alternative to macrolides for M pneumoniae and C pneumoniae infections, and for treatment of psittacosis, brucellosis, P multocida infection, and relapsing fever.
Tigecycline is a glycylcycline (an analogue of tetracycline) that is active against many gram-negative aerobes, anaerobes, and gram-positive cocci including MRSA and enterococci. Tigecycline is not active against P aeruginosa, but is useful against VRE and resistant gram-negatives other than P aeruginosa. In trials of bacteremia it is inferior to other agents if the organism is susceptible to the comparator. It is approved for children over 8 years.
The aminoglycosides include gentamicin, tobramycin, amikacin, and streptomycin (step 6, Figure 39–2). They bind to ribosomal RNA in the 30S subunit to inhibit protein synthesis. A high peak above MIC is required for efficacy. Because microbes will not replicate for a long time post aminoglycoside exposure (post-antibiotic effect), aminoglycosides can be dosed once daily. However, once daily dosing is still controversial in pediatrics due to faster clearance in children. Variation in dosing strategies exists due to lack of consensus. While efficacy is associated with an adequate peak (8 times MIC), toxicity is associated with a high trough. The most common toxicity is renal followed by ototoxicity. Bacteria gain resistance either through bacterial modification of the aminoglycoside such that it cannot bind its target, or through changes in drug entry due to alterations in porin channels. Aminoglycosides are active against gram-negative bacteria. When used together with β-lactams and vancomycin against some gram-positives, aminoglycosides may enter past the damaged cell wall and have a synergistic effect. Synergy is described for Group B streptococci, enterococci, staphylococci, and Listeria monocytogenes, and is accomplished with a low dose of drug. All aminoglycosides are active against pseudomonas, but especially tobramycin. Amikacin is less susceptible to microbial modification, so organisms resistant to other aminoglycosides may remain susceptible to amikacin. Addition of an aminoglycoside to another active agent, such as a β-lactam, for gram-negative infections is now generally considered to add more toxicity than benefit. However, this remains appropriate for empiric therapy in patients at risk for resistant gram-negative resistant while awaiting speciation and susceptibilities. Tobramycin and amikacin both have inhaled forms, and though relative penetration to alveoli is not clear, they are both used in patients with cystic fibrosis. Streptomycin is still used for tuberculosis in endemic areas of the world, but ototoxicity otherwise limits its usefulness. As a group, the aminoglycosides do not penetrate CSF particularly well, thus treatment with a third-generation cephalosporin is preferred. They also are not active in acidic environments, rendering them less active in abscesses and bone.
Because of their renal and ototoxicity, creatinine measurement and therapeutic drug level monitoring is necessary. Drug levels are usually checked between the third and fourth dose, but sooner in children at high risk for renal impairment. Efficacy of gentamicin and tobramycin are correlated with peaks of at least 8–12 mcg/mL for Q8 hour dosing or 20–30 mcg/mL for once daily dosing. The goal is for trough levels to be less than 2 mcg/mL to mitigate toxicity. For amikacin, desired peak for Q8 hour dosing is 20–35 mcg/mL, and a trough less than 10 mcg/mL. In children expected to receive long-term therapy, drug levels and creatinine should be checked weekly and hearing screening should be considered, especially for those with elevated trough levels.
Rifamycins include rifampin, rifabutin, rifaximin, and rifamycin B (step 7, Figure 39–2). They are RNA polymerase inhibitors, and thus the only antimicrobials that block transcription. They are active against a wide variety of organisms, including many mycobacteria. Resistance develops quickly (usually via a mutation in RNA polymerase) so they are rarely used alone. Rifampin is used as prophylaxis against disease in those exposed to various agents, for example H influenzae, N meningititis, and M tuberculosis. It is also used as combination therapy to penetrate bacterial biofilms for patients with prosthetic material in place. Rifampin and rifabutin are used to treat tuberculosis; rifabutin is often preferred in patients co-infected with HIV as rifampin decreases levels of some HIV medications. Most rifamycins, rifampin in particular, induce P450 enzymes, lowering the concentrations of many other drugs, including birth control, opiates, immune-suppressive agents, HIV medications, and some anesthetics, and thus their possible benefit must be weighed against the dangers of lowering levels of these other drugs. These drugs penetrate many spaces, and will turn body fluids such as tears, urine, and feces orange. This is an important and troubling side effect to warn patients about, and those with contact lenses should be counseled to wear glasses while on therapy to prevent staining. Oral preparations of rifamycins are highly bioavailable. Rifaximin, because it is non-absorbable avoids drug interactions or side effects, and can be used for the treatment and prevention of traveler’s diarrhea in people over 12 years, though this will predispose to the acquisition of drug-resistant organisms.
Fluoroquinolones include norfloxacin, ofloxacin, ciprofloxacin, levofloxacin, moxifloxacin (though dosing is not established in children), and gatifloxacin drops (step 8, Figure 39–2). They target bacterial topoisomerases, inhibiting DNA replication and repair. Efficacy is based on the AUC over MIC. Fluoroquinolones are bactericidal. Levofloxacin and ciprofloxacin are active against P aeruginosa. In addition to gram-negative activity, levofloxacin has activity against some strains of MRSA, S pneumoniae, and Enterococcus fecalis (not E faecium). They are also active against many atypical pathogens, such as mycoplasma, chlamydophila, and legionella. Ofloxacin and levofloxacin are used for treatment of some cases of M tuberculosis and some atypical mycobacterial infections. Due to activity against N meningititis and Yersinia pestis, ciprofloxacin is considered for prophylaxis of exposed persons. Fluoroquinolones are often active against N gonorrhea (though increasing resistance described), and C trachomatis. They often are active against the common causes of traveler’s diarrhea, though increasing resistance has removed them as first-line agents in many geographic areas. Bacteria protect themselves by altering the targeted topoisomerases to prevent binding, and through efflux of drug. This class of drugs is highly associated with bacterial resistance and secondary C difficile infection. When these organisms acquire mutations that encode resistance, often they are accompanied by genes encoding resistance to other classes of antimicrobials. They also select for hypervirulent, hyper spreading strains of C difficile that endanger not only the patient receiving the fluoroquinolone, but other patients on the same unit to whom the strain may spread. When an outbreak of C difficile infection is present in a hospital setting, stopping use of these drugs is an appropriate intervention. They are also associated with tendon rupture in adults, leading to an FDA warning to limit use, and with arthropathy in children. These drugs are highly bioavailable, and generally should be used orally. One caveat is that they are inactivated by divalent cations, so they cannot be given with multivitamins, dairy containing products, or infant formulas, making them difficult to administer to infants and children. The liquid formulation of ciprofloxacin adheres to plastic and cannot be given via G-tube. Ciprofloxacin comes in otic and ophthalmic formulations. Given the induction of resistant organism and C difficile acquisition, and dietary limitations, fluoroquinolones should be used sparingly in pediatrics. They do have a place in the treatment of organisms resistant to other classes of drugs.