eT A B LE 10 7 1 A n ti b io ti c A ct iv it y fo r G ra m N eg at iv e Pa th o g en s (0 t o 1 1 1 1 1 ) Or ga ni sm Ti ca rc ill in Cl av ul an at e Pi pe ra ci lli n Ta zo ba ct am Ce fta zi di m e[.]
111 111 Enterobacter spp Pseudomonas aeruginosa 11 111 1111 1111 PiperacillinTazobactam 111 1111 1111 1111 1111 Ceftazidime 111 1111 1111 1111 1111 Ceftriaxone 111 111 11 1111 1111 Cefepime Susceptibility data are averaged,44–46,48,49,97 with local hospital data potentially much different than these values a Colistin may be effective in vitro against organisms resistant to all available agents, with limited data on efficacy and significant toxicities.21 Stenotrophomonas 11 1111 Klebsiella spp Acinetobacter spp 1111 Escherichia coli a TicarcillinClavulanate Organism eTABLE Antibiotic Activity for Gram-Negative Pathogens (0 to 11111) 107.1 11 1111 111 1111 1111 Tobramycin 11 111 1111 1111 1111 Ciprofloxacin 1111 1111 11111 11111 11111 Meropenem 1111 0 11 TrimethoprimSulfamethoxazole 11 0 0 Doxycycline 1266.e1 1266.e2 eTABLE 107.2 Antibiotic Activity for Gram-Positive Pathogens (0 to 11111) Organism Ampicillin Oxacillin Cefazolin Vancomycin Linezolid Clindamycin Methicillin-susceptible Staphylococcus spp (S aureus or coagulase-negative staphylococci) 11111 11111 11111 1111 11 Methicillin-resistant Staphylococcus spp 0 11111 1111 Enterococcus faecalis 1111 0 1111 1111 Enterococcus faecium 11 0 1111 1111 Streptococcus pneumoniae 111 111 111 111 111 111 a Susceptibility data are averaged,40,44,50,97 with local hospital data potentially much different than these values For vancomycin-susceptible strains a S O O O N N S O Cephem Penam O O O N O N O Oxacephem O Carbacepham N N Carbacephem S O N Cepham Oxacepham O S N Penem O O Clavam O N Carbapenam N N Clavem O N Carbapenem • eFig 107.1 Structures of b-lactam antibiotics CHAPTER 107 Bacterial and Fungal Infections and AmpC b-lactamase–producing gram-negative organisms Dosing and safety data are becoming increasingly more plentiful in children and in clinical scenarios involving multidrug-resistant organisms with few treatment options.29 Carbapenems Three carbapenems—imipenem, meropenem, and ertapenem— are currently FDA approved in pediatric patients older than years of age for the treatment of complicated skin and skin structure infections (SSIs), complicated intraabdominal infections, and meningitis The carbapenem’s b-lactam ring structure differs slightly from the penicillins and cephalosporins to enhance activity and stability (see Fig 107.1) Carbapenems are each similar in their broad antimicrobial spectrum of activity, which includes gramnegative, gram-positive, and anaerobic organisms Carbapenems are generally reserved for nosocomial infections or those due to organisms for which there are few alternatives, such as ESBLproducing gram-negative organisms or those harboring a chromosomally mediated AmpC b-lactamase, such as Enterobacter spp With respect to toxicity, the carbapenems are well tolerated, although imipenem displays interference with CNS g-aminobutyric acid inhibition, increasing the risk for seizure activity in children.30 Meropenem is the preferred carbapenem for children at risk for seizures or with CNS infections and inflammation Monobactams Aztreonam, the only monobactam currently available for clinical use in the United States, has a unique chemical structure in its b-lactam ring that enhances activity and stability to b-lactamases It displays aerobic, gram-negative activity, including activity against many strains of P aeruginosa It has very little grampositive activity Aminoglycosides Aminoglycoside antibiotics are bactericidal in a concentrationdependent fashion against a wide range of aerobic pathogens These agents inhibit protein synthesis by irreversibly binding to the 30S ribosomal subunit The gram-negative spectrum of activity is extensive, including enteric bacilli (E coli, Klebsiella, Enterobacter, Serratia), P aeruginosa, and many gram-negative bacilli These antibiotics have no clinically relevant anaerobic activity The most widely available parenteral aminoglycoside agents are gentamicin, tobramycin, and amikacin These agents are not used as primary therapy for CNS infections owing to poor penetration into the spinal fluid and thus the high risk for systemic toxicity at levels required for CNS penetration Caution should be exercised in the use of these agents in undrained abscess infections, including intraabdominal infections The acidic and anaerobic conditions present in abscesses produce MICs against aerobic gramnegative organisms that are 10 times higher than those documented under ideal laboratory conditions.31 Aminoglycoside-induced nephrotoxicity has been described, even in noncritically ill children, and is associated with poorer outcomes.32 The previously held notion that an aminoglycoside should be combined with a b-lactam to slow the development of resistance has been challenged in light of data suggesting that this combination may confer no survival benefit.33,34 Empiric addition of gram-negative coverage with an aminoglycoside may have the strongest positive effect on outcomes in neutropenic populations.35 A potential survival benefit associated with empiric combination therapy appears greatest for high-risk patients 1267 with a history of previous colonization or infection with multidrug-resistant gram-negative (MDRGN) bacteria, those who have received broad-spectrum antibiotic therapy within 30 days, those undergoing a prolonged hospitalization, or those in a community with a high prevalence of MDRGN bacteria.34 The addition of gentamicin may shorten time to bacterial clearance but may have limited impact on bacteremic relapse and increase the risk of developing acute kidney injury.22 Glycopeptides Vancomycin is currently the only available glycopeptide available for clinical use in the United States Vancomycin is primarily active against aerobic and anaerobic gram-positive organisms Vancomycin is bactericidal against virtually all strains of staphylococci and against most strains of streptococci, although it is bacteriostatic against the enterococci Resistance to vancomycin is noted to occur in strains of Enterococcus faecium (vancomycin-resistant enterococcus [VRE]) and has also been described in S aureus.36,37 This class of antibiotic is cell wall active, as are the penicillins, but has a different mechanism of action in prevention of pentapeptide cross-linking in the formation of cell wall peptidoglycan The tissue distribution of vancomycin is extensive, with elimination of unmetabolized antibiotic by the kidney Dosage adjustment is required in renal insufficiency Penetration into the CSF is not well studied and may be erratic The toxicities of vancomycin are primarily nephrotoxicity and ototoxicity As with the aminoglycosides, close attention to serum antibiotic concentrations will mitigate clinically significant toxicity The new generation lipoglycopeptides—dalbavancin, telavancin, and oritavancin—are FDA approved in adults for the treatment of complicated skin or SSIs caused by susceptible grampositive organisms, including MRSA Their role in the management of children remains unsettled Macrolides Erythromycin and the related macrolides clarithromycin and azithromycin may be required in the PICU for children with severe pertussis or atypical pneumonia, or in children with extensive drug allergy precluding the use of standard antiinfective agents The macrolides bind to the 50S ribosomal subunit of susceptible bacteria, inhibiting protein synthesis In general, both clarithromycin and azithromycin are better tolerated than erythromycin and achieve high intracellular concentrations, with demonstrated efficacy against intracellular pathogens All of the macrolides demonstrate activity against atypical bacteria, including Mycoplasma pneumoniae, Chlamydia, Legionella, and Bordetella pertussis In addition, azithromycin has potential efficacy as a modulator of airway hyper-responsiveness,38 even in the absence of overt infection.39 Therefore, azithromycin may have a role for children in the ICU with community-acquired pneumonia and exacerbation of underlying chronic lung disease, cystic fibrosis, or asthma Macrolides are metabolized by cytochrome P450 enzymes, which cause potential drug-drug interactions Fluoroquinolones This class of broad-spectrum agents has been extremely successful in adults over the past 20 years Because of concerns regarding cartilage toxicity in weight-bearing joints of experimental animals, however, pediatric studies have been limited The mechanism of 1268 S E C T I O N X I Pediatric Critical Care: Immunity and Infection action of quinolones involves inhibition of DNA synthesis by interference with two bacterial enzymes The activity of each specific quinolone and the rapidity of the development of resistance to the specific quinolone depend on the relative activity of the quinolone against these enzymes.40 Ciprofloxacin, the first of the agents approved for use in adults, shows a high level of activity against fluoroquinolone-sensitive P aeruginosa and many enteric bacilli causing both nosocomial (E coli, Klebsiella, Enterobacter) and gastrointestinal infections (Salmonella, Shigella, Campylobacter, Yersinia, and Aeromonas) Although resistance to ciprofloxacin in P aeruginosa and other bacilli has been increasing, susceptibility in pediatric inpatient units has remained reasonable Ciprofloxacin is FDA approved in children older than year for the treatment of complicated urinary tract infections, pyelonephritis, and postexposure treatment of inhalational anthrax Subsequent chemical modifications of fluoroquinolones have resulted in a set of agents with good to excellent activity against gram-positive cocci, including group A streptococcus, S pneumoniae, and S aureus These agents—levofloxacin and moxifloxacin—are effective in both gram-positive and gramnegative infections Although case reports of possible cartilage toxicity exist, no documented case unequivocally caused by fluoroquinolones in children has been published in any prospective study.41 Miscellaneous Clindamycin A member of the lincosamide family, clindamycin inhibits the growth of bacteria by binding to the 50S subunit of the ribosome and is bacteriostatic or bacteriocidal dependent on dose and tissue compartment Clindamycin is active against gram-positive organisms and many anaerobes Activity against b-lactam–resistant strains of S pneumoniae and S aureus (MRSA) has led to increased use of clindamycin in children.42 Clindamycin may be used for treatment of MRSA skin infections and pneumonia However, it is not recommended as the sole agent for critically ill patients with MRSA infections given its potential bacteriostatic (as opposed to bactericidal) mechanism of action.43 Linezolid Linezolid is the first in a class of new antibiotics, the oxazolidinones These antibiotics are protein synthesis inhibitors that interfere with mRNA binding at the 30S ribosome subunit Linezolid is a bacteriostatic agent useful in the treatment of infections caused by gram-positive organisms, including MRSA, coagulasenegative staphylococci, and VRE Linezolid has been studied and has received FDA approval for use in children, including neonates Linezolid is approved for the treatment of community- and hospital-acquired pneumonia, complicated and uncomplicated skin and soft-tissue infections, and bacteremia caused by vancomycin-resistant organisms A concern that appears to have little clinical relevance in healthy children treated under controlled conditions is the drug’s nonselective, reversible inhibition of monoamine oxidase Nevertheless, this drug interaction profile has a potential impact on the patient in the PICU who is receiving adrenergic or serotonergic drugs Linezolid has been reported to be associated with hematologic side effects and, rarely, with optic neuritis and peripheral neuropathy.44 Metronidazole A nitroimidazole derivative, metronidazole is an effective antibiotic for parasitic and anaerobic bacterial infections The primary use of metronidazole in the PICU includes infections caused by b-lactamase–positive strains of B fragilis (intraabdominal infections) and those caused by C difficile (pseudomembranous colitis) Resistance to metronidazole has not been a clinical problem despite significant clinical use The distribution of the drug in tissues such as those in the CNS is extensive It has been a standard component of therapy for anaerobic deep-tissue space infections and has been used in the treatment of anaerobic brain abscesses Colistin With antibiotic resistance increasing dramatically in gramnegative pathogens, colistin has returned to clinical use and now represents a therapy of last resort for organisms resistant to all other available antibiotic therapy.45 Colistin (colistimethate), or polymyxin E, has broad-spectrum bactericidal activity against gram-negative organisms by acting as a cationic detergent, destroying the bacterial cytoplasmic membrane Colistin has no activity against gram-positive organisms or against B fragilis The chief toxicities of this agent include nephrotoxicity, peripheral neuropathy, confusion, coma, and seizures The drug is renally eliminated; thus, dosage adjustment is required with renal insufficiency Limited data in pediatric burn and critical care patients suggests that colistin is effective and safe for multidrug-resistant gram-negative infections.46,47 In addition, aerosolized colistin has been used as an adjunctive or monotherapy for gram-negative pulmonary infections Clinically significant bronchospasm may occur Doxycycline Doxycycline is part of the tetracycline class of antibiotics It is considered bacteriostatic, and its mechanism of action is to inhibit protein synthesis by reversibly binding to bacterial 30S ribosomal subunits Doxycycline has a broad spectrum of activity, particularly against atypical bacterial infections due to rickettsia, chlamydia, brucellosis, Lyme disease, and mycoplasma It also has activity against community-acquired MRSA and S maltophilia While most tetracyclines are not acceptable for use in children owing to risk of permanent tooth discoloration, doxycycline can safely be administered for short durations (#21 days) regardless of age.48 Trimethoprim-Sulfamethoxazole TMP-SMX is a combination antibiotic that works by blocking folic acid synthesis in susceptible bacteria Pediatric dosing is based on the trimethoprim component It is used widely in critically ill pediatric populations, particularly as part of Pneumocystis jirovecii prophylaxis regimens in patients with malignancies, patients with congenital or acquired immunodeficiencies, and those who have undergone stem cell or organ transplantation Treatment with TMP-SMX in pediatric critical illness is most commonly used for active treatment of Pneumocystis pneumonia (PCP) and is the first-line agent recommended for S maltophilia infections The drug interactions and side effect profile are not insignificant It should be used with caution in patients on spironolactone because of risk for hyperkalemia Important side effects of TMX-SMX include skin sensitivity, such as Stevens-Johnson syndrome; hematologic abnormalities, such as aplastic anemia; hemolysis in glucose-6-phosphate dehydrogenase deficiency; immunemediated thrombocytopenia; and with intravenous use, lactic acidosis CHAPTER 107 Bacterial and Fungal Infections Tigecycline Tigecycline is a glycylcycline, is considered a bacteriostatic agent, and has broad-spectrum antibacterial activity against gram-positive and gram-negative aerobes and anaerobes, including MRSA and MDRGN bacteria Tigecycline is approved for use in adult patients with complicated skin infections and SSIs, complicated intraabdominal infections, and community-acquired pneumonia While safety and efficacy have not been established in children, information gathered from published and unpublished trials, databases, and compassionate use in children has been published to help guide appropriate use of tigecycline in children with serious multidrug-resistant infections.49 Daptomycin Daptomycin belongs to a more recent class of antibiotics, the lipopeptides Daptomycin disrupts the cell membrane and is rapidly bactericidal It has a broad range of activity against grampositive bacteria, including methicillin-, vancomycin-, and linezolid-resistant organisms It should not be used to treat pulmonary infections because surfactant inhibits its activity Daptomycin is currently approved for use in adults with complicated skin infections and SSIs as well as right-sided endocarditis and staphylococcal bacteremia A recent review of daptomycin therapy in invasive gram-positive infections in children showed that it was effective and well tolerated.12 The primary toxicity seen is a dosedependent, reversible myopathy that can be monitored by elevation in serum creatinine phosphokinase Antibiotic Resistance and Treatment of Multidrug-Resistant Pathogens Antibiotic Resistance Mechanisms In the ICU, antibiotic use is extensive, resulting in selective pressure for antibiotic-resistant pathogens The basic mechanisms of resistance can be divided into two broad categories.50,51 The first is by accumulation of genes coding for resistance; the protein products of these antimicrobial resistance genes (AMRs) may alter the antibiotic structure or may alter the antibiotic’s target site within the pathogen via changes in the cell wall or antibiotic binding sites The second resistance mechanism occurs by extrusion of the antibiotic from within the organism by efflux pumps Although community-acquired pathogens most often express only one mechanism of resistance, nosocomial pathogens may express both of these mechanisms simultaneously The result is a high degree of antibiotic resistance Genes encoding antibiotic resistance may be shared between organisms within a species or between species Antibiotic-resistant mutants normally exist at low frequencies in any given population of bacteria Antibiotic exposure is often the selection pressure allowing these otherwise silent mutants to achieve significant numbers, leading to treatment failure The clinical expression of antibiotic resistance may involve several different mechanisms operating simultaneously within a pathogen Treatment of Multidrug-Resistent Pathogens Community-acquired MRSA is increasingly a significant pathogen in children.52 MRSA develops resistance via the mecA gene; detection of this gene predicts failure of treatment with oxacillin Vancomycin remains the mainstay of treatment for serious MRSA infections Few pediatric clinical trials have investigated superiority 1269 of alternative antibiotics to vancomycin A pediatric study compared vancomycin to linezolid for the treatment of nosocomial pneumonia, bacteremia, or skin and soft-tissue infections and found that the cure rates were similar.53 Antibiotic resistance is increasing in gram-negative bacteria Outbreaks by enteric gram-negative bacilli that carry chromosomal AmpC b-lactamases (present in Enterobacter, Serratia, and Citrobacter) are increasing.54 The glucose nonfermenting gramnegative bacteria, including Stenotrophomonas and Acinetobacter spp., may also cause antibiotic-resistant organism infections, particularly in the immunocompromised child Treatment for patients potentially infected with these organisms should be guided by local resistance patterns and antibiograms Extendedor continuous-infusion dosing strategies with b-lactams such as Zosyn, cefepime, or meropenem for treatment of susceptible Pseudomonas strains in critically ill patients may optimize bactericidal exposure55 and have been associated with improved outcomes.56 Colistin is an option for multidrug-resistant gram-negative infections New combination cephalosporin agents may be considered in multidrug-resistant infections, including ceftolozane/tazobactam, which targets carbapenem-resistant P aeruginosa, and ceftazidime/ avibactam, with activity against ESBL- and AmpC b-lactamaseproducing and carbapenemase-resistant gram-negative bacteria There is a growing amount of data regarding dosing and safety in pediatric populations.29 Several other newer agents are in clinical trials in adults for treatment of carbapenemase-resistant infections, including (1) meropenem/vaborbactam (a carbapenem/ b-lactamase inhibitor combination agent); (2) eravacycline (similar to tigecycline but overcomes efflux resistance); and (3) plazomicin (a new aminoglycoside less affected by the most common aminoglycoside-resistance mechanism) Pediatric dosing and utility of these agents remain unknown at this time Fungal Infections and Antifungal Agents Invasive fungal infections are increasingly recognized as a significant risk among immunocompromised and critically ill children.57 Indeed, Candida spp are the third most common cause of hospital-acquired bloodstream infection in the United States, following coagulase-negative staphylococci and enterococci.58 As they are also associated with excessive morbidity and mortality, a basic understanding of the epidemiology, diagnosis, and management of invasive fungal infections is essential Candida Candidemia is associated with a high rate of morbidity and mortality among children in the PICU The 30-day mortality rate for children in the PICU with candidemia may be as high as 37% to 44% A multivariate analysis of children with invasive candidemia at a large tertiary children’s hospital found that admission to the PICU at the time of diagnosis and the presence of an arterial catheter were the only two independent risk factors for death.59 General risk factors for the development of a Candida central line–associated bloodstream infection (CLABSI) among pediatric patients include intestinal failure, presence of a gastrostomy tube, and receipt of total parenteral nutrition or blood transfusions.60 Factors specifically associated with the development of candidemia for children in the PICU include presence of a central venous catheter or ECMO cannulae, peritoneal dialysis, a diagnosis of malignancy and/or hematopoietic stem cell transplantation, and receipt of broad-spectrum antibacterial agents for longer than days.59 ... Cefazolin Vancomycin Linezolid Clindamycin Methicillin-susceptible Staphylococcus spp (S aureus or coagulase-negative staphylococci) 11111 11111 11111 1111 11 Methicillin-resistant Staphylococcus spp... antibiotic’s target site within the pathogen via changes in the cell wall or antibiotic binding sites The second resistance mechanism occurs by extrusion of the antibiotic from within the organism by... multidrug-resistant gram-negative (MDRGN) bacteria, those who have received broad-spectrum antibiotic therapy within 30 days, those undergoing a prolonged hospitalization, or those in a community with a high