e4 Key words rheumatologic, autoimmune, autoinflammatory, lupus, macrophage activation syndrome, pulmonary renal syndrome, cytokine storm Abstract Pediatric rheumatology encompasses an array of hetero[.]
e4 Abstract: Pediatric rheumatology encompasses an array of heterogeneous autoimmune and autoinflammatory disorders Suspicion for rheumatic disease should be high when children present with persistent fevers of unknown origin, arthritis, multiorgan involvement, or unexplained high inflammatory markers Diagnosis of rheumatologic disease is challenging, as few clinical features are pathognomonic and few diagnostic tests are confirmatory Infectious and oncologic processes may mimic rheumatic diseases and must be excluded A child may present to intensive care owing to life-threatening manifestations of an undiagnosed rheumatologic disease or with severe complications of a known disorder Intensive care unit providers require an understanding of the clinical presentation, diagnosis, and therapeutic management of rheumatologic diseases in order to provide early effective recognition and management of these complex patients Key words: rheumatologic, autoimmune, autoinflammatory, lupus, macrophage activation syndrome, pulmonary renal syndrome, cytokine storm 107 Bacterial and Fungal Infections DE BORAH E FRANZON, EMILY R LEVY, AND MATT S ZINTER • • • Emergence of resistant organisms is increasing in critically ill patients, requiring clinicians to use alternative drug and dosing strategies and to become familiar with institutional-specific resistance profiles Infectious metastatic foci of disease in patients with persistent bacteremia should be considered, which would warrant further workup, such as abdomen, chest, bone/joint, or brain imaging, echocardiography, and ophthalmologic examination Invasive candidiasis results in mortality rates as high as 44% Guidelines suggest echinocandins (e.g., caspofungin) as firstline therapy Occult fungal infection should be considered in any patient with chemotherapy-induced neutropenia and fever Due to the high severity of illness of children in the pediatric intensive care unit (PICU), it is important to treat confirmed and suspected infections aggressively to obtain the best clinical and microbiological outcomes Timely antibiotic administration is essential—delays may adversely impact outcomes In addition to selecting appropriate antimicrobial therapy in critically ill pediatric patients, the importance of source control and decontamination at the site of infection remains paramount, whether for the central nervous system (CNS), blood, urine, skin, abdominal cavity, bone, or pleural space Obtaining cultures from suspected sources is the gold standard in diagnostic evaluation Broad-range molecular diagnostics and biomarkers may also play a role in identifying and managing infections in the PICU The importance of timely broad-spectrum empiric antimicrobials must be balanced with their potential to promote antibiotic resistance Since antibiotic resistance may lead to increased morbidity and mortality as well as increased healthcare costs, deescalation of antibiotics based on microbiological and susceptibility data as well as clinical improvement is imperative.1 This chapter discusses the most clinically important gram-positive, gram-negative, and fungal organisms encountered in critically ill children and reviews major classes of antibiotics and antifungals, including those currently under investigation by the US Food and Drug Administration (FDA), for use in children Mechanisms of resistance are presented, as are strategies designed to meet the challenge of treating and preventing the development of resistant • • • PEARLS persisting more than 96 hours despite empiric antibiotic therapy Broad-range polymerase chain reaction diagnostic panels offer quick and comprehensive diagnoses Additional “shotgun” sequencing-based diagnostics are increasingly available for nasal swabs, bronchial lavage and pleural fluid, stool, blood, and cerebrospinal fluid They can be used when available if there is clinical suspicion for a particular infection but currently not replace cultures Antimicrobial stewardship programs that implement strategies to reduce unnecessary antimicrobial use can be cost-saving and help address resistance in the intensive care unit setting organisms Many textbooks about infectious diseases provide excellent in-depth reviews of antibiotic characteristics and are recommended for additional information.2,3 Bacterial Infections in the Intensive Care Unit Gram-Positive Bacteria Common gram-positive infections encountered in critically ill children include Streptococcus pyogenes (group A strep), Streptococcus pneumonia (pneumococcus), methicillin-sensitive (MSSA) and methicillin-resistant Staphylococcus aureus (MRSA), coagulasenegative staphylococcus (CoNS), enterococcus, and occasionally other streptococcal species, such those in the viridans group (e.g., S mitus) The following sections highlight key features of serious infection, treatment, or resistance for the important gram-positive bacteria that may be encountered in the PICU Invasive infection with S aureus is a serious condition that carries significant morbidity and mortality.4 With each day of S aureus bacteremia, there is potential for worse outcomes, often secondary to metastatic foci of disease, such as septic emboli in the lungs, brain, viscera, and extremities; septic thrombophlebitis; infective endocarditis; pneumonia; epidural abscesses; osteomyelitis, and septic arthritis Careful and frequent physical examinations for stigmata of disease and comprehensive imaging may be essential to fully evaluate for source and complications S aureus 1263 1264 S E C T I O N X I Pediatric Critical Care: Immunity and Infection secretes exoproducts such as S aureus staphylococcal protein A (SpA), which influences host inflammatory response leading to serious conditions such as toxic shock syndrome S aureus as a pulmonary coinfection, particularly in children with influenza virus, carries significant mortality risk, in part due to a-toxin-mediated injury to pneumocytes.5 In adolescents with cystic fibrosis, coinfection and colonization with S aureus and Pseudomonas aeruginosa confers more rapid decline in lung function6— appropriate treatment of flares is imperative Antibiotic selection for suspected or confirmed S aureus infection depends on methicillin sensitivity and includes penicillins, first-generation cephalosporins (for MSSA) and glycopeptides (vancomycin), trimethoprimsulfamethoxazole (TMP-SMX), clindamycin, daptomycin, and linezolid (for MRSA) Infectious presentations caused by group A streptococcus (GAS) in children are commonly pharyngitis and cellulitis but can be invasive and life threatening, including bacteremia, endocarditis, osteomyelitis, strep toxic shock syndrome (STSS), and necrotizing fasciitis Invasive GAS infections are more common in infants than older children and when present can progress rapidly to overwhelming sepsis Necrotizing fasciitis often involves an extremity following minor trauma and presents as pain out of proportion to examination If suspected, it should prompt urgent surgical evaluation and debridement of deep tissue with Gram stain and cultures; waiting for imaging could delay diagnosis The more than 240 serotypes of GAS are distinguished by their M proteins The M protein of the GAS serotype causing STSS produces exotoxins acting as superantigens that stimulate production of tumor necrosis factor and other inflammatory mediators that cause capillary leak and other physiologic changes, leading to hypotension and multiorgan damage STSS can occur at any age in patients with a focus (i.e., skin, bone, joint) and in bacteremia without a focus STSS is diagnosed using clinical and laboratory findings, including hypotension, rash, acute kidney injury, coagulopathy, hepatic dysfunction, and isolation of GAS in culture of sterile or nonsterile sources.7 In children with STSS or necrotizing fasciitis, clindamycin is often used in conjunction with a b-lactam agent (penicillin or cephalosporin) to stop streptococcus toxin production as quickly as possible The data suggest improved outcomes in patients treated with the combination.8 S pyogenes is uniformly susceptible to b-lactam antimicrobial agents (penicillins and cephalosporins); susceptibility testing is needed only for non–b-lactam agents, such as erythromycin, clindamycin, or a macrolide, to which S pyogenes can be resistant.9 Postinfectious complications of GAS pharyngitis include acute rheumatic fever causing symptomatic carditis, acute glomerulonephritis resulting in acute renal failure, and pediatric autoimmune neuropsychiatric disorders associated with streptococcal infection (PANDAS).10 Each of these can be serious and may require management in the ICU S pneumonia is a gram-positive diplococcus composed of more than 90 serotypes Pneumococcal infections in the PICU can range from community-acquired pneumonia with empyema and parapneumonic effusions resulting in acute respiratory failure to meningitis, mastoiditis, pericarditis, peritonitis, septic arthritis, bacteremia, and sepsis Since worldwide adoption of pneumococcal conjugate vaccine (PCV), invasive pneumococcal disease in children younger than years has been reduced by as much as 74% in population studies.11 Select patient populations encountered in the PICU are at increased risk for invasive pneumococcal disease: those with asplenia or altered splenic function (sickle cell disease), diabetes mellitus, chronic kidney disease, chronic liver disease, and patients with altered complement or innate immunity For suspected invasive pneumococcal infections, a thirdgeneration cephalosporin (ceftriaxone) should be used S pneumoniae has developed increasing resistance to b-lactam antibiotics, macrolides, and TMP-SMX; thus, without susceptibilities, one should cover broadly For children with life-threatening pneumococcal infections, particularly meningitis, the addition of vancomycin to either ceftriaxone or cefotaxime has been the standard of care until susceptibility data are available and therapy can be narrowed if appropriate Other options for therapy of non-CNS infections caused by resistant strains include a newer-generation fluoroquinolone or linezolid CoNS, S epidermidis most commonly, is a gram-positive coccus in clusters, a common commensal organism, and a frequent source of catheter-associated bloodstream infection More than 90% of CoNS strains are methicillin resistant and b-lactam resistant In suspected or confirmed CoNS infections—particularly in patients with central venous catheters and indwelling foreign bodies, including cerebrospinal fluid (CSF) shunts, peritoneal catheters, spinal instrumentation, baclofen pumps, pacemakers, or prosthetic joints—intravenous vancomycin is the treatment of choice Duration of treatment is often 10 to 14 days unless the device is removed, in which case a 5- to 7-day course may be sufficient Enterococcus faecalis and E faecium are gram-positive cocci in pairs that are universally resistant to cephalosporins and often resistant to aminoglycosides and vancomycin Enterococci are associated with bacteremia, device-associated infections, intraabdominal abscesses, and urinary tract infections in those with abnormal genitourinary anatomy If susceptibilities allow, ampicillin is the treatment of choice However, empirically, vancomycin is typically used in children The majority of E faecalis strains are ampicillin-susceptible, but E faecium strains may be multidrug resistant In the setting of vancomycin resistance, linezolid is a mainstay of treatment; however, resistance to linezolid has been reported Daptomycin and tigecycline both have excellent activity against vancomycin-resistant enterococcus (VRE), although there is limited pediatric experience to date The incidence of VRE infections is increasing, particularly in neonatal ICUs, in oncology wards, and in patients with gastrointestinal disease A review of pediatric patients with multidrug-resistant gram-positive infection showed that the addition of daptomycin to the treatment regimen resulted in clinical improvement in the majority of patients, and in six of seven patients with persistent bacteremia, it resulted in bacteriologic cure.12 Brief mention of the viridans streptococci, bacteria that colonize the oropharynx, is warranted, as they are the most common cause of bacterial endocarditis in children Those at great risk are children with congenital heart disease Viridans group streptococci also cause bacteremia in neutropenic cancer patients in the first weeks after hematopoietic stem cell transplantation due to high co-incidence of mucositis with neutropenia Viridans group streptococci may also be a pathogen causing central line-associated bacteremia Most Viridans group streptococci are susceptible to penicillin American Heart Association guidelines recommend treatment regimens for endocarditis.13 Gram-Negative Bacteria Gram-negative organisms include Enterobacteriaceae, a large family of enteric gram-negative, facultatively anaerobic, rod-shaped bacteria that include extended-spectrum b-lactamase producing CHAPTER 107 Bacterial and Fungal Infections Escherichia coli, Klebsiella, Enterobacter, Proteus, Serratia, and multidrug–resistant Pseudomonas, Stenotrophomonas, and Acinetobacter Reservoirs for gram-negative bacilli can be present within the healthcare environment, and infections can occur through transmission from hospital personnel as well as from contaminated environmental surfaces such as sinks, countertops, and respiratory therapy equipment Children with defects in the integrity of skin or mucosa, neutropenia, metabolic syndromes, abnormalities of gastrointestinal or genitourinary tracts, recent invasive or surgical procedures, and with indwelling vascular catheters are at risk for gram-negative bacterial infections Frequent use of broad-spectrum antimicrobial agents in the PICU may enable selection and proliferation of strains of gramnegative bacilli that are resistant to multiple antimicrobial agents and can present a treatment challenge Multiple mechanisms of resistance in gram-negative bacilli can be present simultaneously While combination penicillins, cephalosporins, aminoglycosides, and monobactams are often the mainstay of therapy for enteric gram-negative infection, antimicrobial resistance resulting from either the production of chromosomally encoded or plasmidderived AmpC b-lactamases or the production of plasmid-mediated extended-spectrum b-lactamases (ESBLs) occurs in E coli, Klebsiella spp., and Enterobacter spp Pseudomonas aeruginosa, Acinetobacter baumannii, and Stenotrophomonas spp are strictly aerobic, nonfermenting gram-negative bacteria that cause a variety of local and systemic infections in both immunocompetent and immunocompromised patients These can be hospital-acquired pathogens causing opportunistic infections, such as ventilator-associated pneumonia Other infections caused by these organisms include skin and soft-tissue infections, osteomyelitis, and bacteremia P aeruginosa has been a long-standing nosocomial problem in neonatal ICUs and PICUs.8 Among the gram-negative bacilli, Acinetobacter spp and P aeruginosa have the largest number and variety of resistance mechanisms, presenting numerous treatment challenges in ICU patients Bordetella pertussis, a fastidious gram-negative coccobacillus organism that is difficult to isolate in nasopharyngeal cultures, can cause serious illness in children Unimmunized or underimmunized infants less than months of age are at greatest risk for life-threatening complications from B pertussis infection, including apnea, pneumonia, pulmonary hypertension, and, rarely, encephalopathy Despite widespread vaccination, pertussis outbreaks occur every to years In one longitudinal report, 25% of hospitalized children with pertussis required time in the ICU and infants younger than months were at highest risk for needing ICU treatment.14 In one ICU cohort, elevated white blood cell count was associated with the need for mechanical ventilation, pulmonary hypertension, and mortality.15 Azithromycin remains the preferred therapy for B pertussis due to a short treatment regimen, daily dosing, and well-tolerated side effect profile Leukoreduction therapy (exchange transfusion, leukapheresis, or both) is sometimes considered in certain clinical situations when children present with extremely high leukocytosis that may result in the development of pulmonary hypertension secondary to leukocyte aggregation in the pulmonary microvasculature.15 Anaerobic Infections Anaerobic infections encountered in the PICU are commonly associated with organisms colonizing the oropharynx or intestinal tract These infections are associated with mastoiditis, retropharyngeal 1265 abscesses, meningitis, epidural abscesses, subdural empyemas, pneumonia, and abdominal infections, such as neutropenic colitis, peritonitis, or abscesses Bacteria recovered from culture may include anaerobic, non–spore-forming, gram-negative bacilli, such as Bacteroides, Prevotella, and Fusobacterium spp.; spore-forming gram-positive cocci, such as Clostridium; and non–spore-forming bacilli, such as Actinomyces and Propionibacterium A clinically important anaerobic infection encountered in critically ill patients is internal jugular vein thrombophlebitis— Lemierre disease—most commonly caused by Fusobacterium necrophorum The classic syndrome, more common in adolescents, may start with fever and sore throat followed by severe neck pain and may include unilateral neck swelling, trismus, and dysphagia Lemierre disease causes a sepsis syndrome associated with internal jugular vein thrombophlebitis and may manifest as multiple-organ dysfunction with disseminated intravascular coagulation, pleural empyema, pyogenic arthritis, or osteomyelitis Persistent headache or focal neurologic signs may indicate the presence of cerebral venous sinus thrombosis, meningitis, or brain abscess In addition to having a high index of suspicion for this disease, obtaining timely imaging of the head, neck, and chest; urgent surgical intervention with debridement and culture; and initiation of appropriate antimicrobials are all important aspects of successful management.16 Most anaerobes, including Fusobacterium species, are generally susceptible to metronidazole, clindamycin, carbapenems, and third-generation cephalosporins Combination therapy with metronidazole or clindamycin, in addition to a b-lactam agent, is recommended for patients with invasive infection caused by Fusobacterium spp.17 Antimicrobial resistance has increased worldwide in anaerobic bacteria; local susceptibility testing and periodic surveillance is indicated for all clinically significant anaerobic isolates.18 General Considerations for Antibiotic Therapy Tissue penetration and dosing of antimicrobials are critical considerations when selecting an antibiotic regimen in the PICU Additionally, side effect profiles in specific disease states encountered in critically ill children—such cytopenias, kidney injury, and liver dysfunction—may impact antimicrobial selection Pharmacokinetic (PK) and pharmacodynamic (PD) characteristics of different classes of antibiotics help determine the dosing regimen required for microbiological and clinical cure.19,20 Mechanical support methods, such as continuous renal replacement therapy (CRRT) and extracorporeal membrane oxygenation (ECMO), may alter the volume of distribution and necessitate dosing adjustment.21 It is imperative to achieve appropriate concentrations of the antibiotic in relationship to the organism’s minimum inhibitory concentration (MIC) Based on PK/PD characteristics, antibiotics can be classified as concentration-dependent (fluoroquinolones, aminoglycosides), time-dependent (b-lactams), or both concentration- and time-dependent antibiotics (glycopeptides) These parameters are important to consider, since the inappropriate dosing of antibiotics may facilitate the development of antibiotic resistance and increase the odds of morbidity and mortality.8,22–24 Close attention to drug levels is critical to ensure efficacy while limiting drug-related toxicity After an infection is suspected on the basis of the clinical, laboratory, and imaging characteristics of the child, appropriate 1266 S E C T I O N X I Pediatric Critical Care: Immunity and Infection cultures from suspected or likely sources should be obtained Broad-spectrum antibiotics should be administered empirically, according to the local susceptibility patterns Data suggest that using appropriate antimicrobials without delay decreases morbidity and mortality, the overall costs of treating the infection, and the emergence of resistance The relative activity of antimicrobial agents against gram-negative (eTable 107.1) and gram-positive pathogens (eTable 107.2) is provided, although clinicians should consult their local antibiogram When culture results and sensitivities are available, antibiotic choice can be tailored to a narrower spectrum for completion of therapy If a child has a multidrug-resistant infection, the riskbenefit analysis may well favor the use of an antibiotic with an otherwise poorly tolerated safety profile if no other alternative exists In some critically ill children, combination antibiotic therapy may be warranted to augment the antibiotic killing capacity, increase tissue penetration, or prevent antibiotic resistance These include, but are not limited to, select cases of pseudomonal infection in neutropenia, MRSA endocarditis, and severe enterococcus infections On the basis of the overall clinical assessment, supported by laboratory and imaging data and the response to empiric therapy, the physician needs to decide whether to continue therapy for a complete treatment course or to stop the antibiotics if data not support an infection as the cause of the child’s clinical state Optimal duration of antibiotic therapy for infections in the PICU is poorly defined However, in specific situations, shorter duration of antibiotic use may provide comparable clearance of infection while also providing a reduction in length of ICU stay, antibiotic resistance, and the emergence of secondary infections Monitoring serum inflammatory markers—such as C-reactive protein, white blood count, and procalcitonin—may allow optimization of both the antibiotic regimen and duration of treatment.25 Antibiotic Classes b-Lactam Antibiotics b-Lactam antibiotics are a diverse group of antibiotics The blactam ring that characterizes these compounds is usually attached to a ring structure that defines the class of antibiotic agents as penicillins, cephalosporins, carbapenems, or monobactams (eFig 107.1) The b-lactam structure is thought to interfere with bacterial cell wall synthesis and repair by preventing transpeptidation and transglycosylation of the pentapeptide precursors.26 The target transpeptidase enzymes, also known as penicillin-binding proteins (PBPs), are vital for the maintenance of cell wall integrity The PBPs carried by different bacterial species have different structures, leading to differences in the binding affinity for various b-lactam agents Long-term high-dose use of all b-lactam agents may be associated with reversible neutropenia Penicillins can be divided into groups that are based largely on spectrum of activity and chemistry The natural penicillins, penicillin G and penicillin V, are active against a number of aerobic and anaerobic bacteria but are primarily used for the treatment of streptococcal (group A and group B streptococci) and spirochete infections, such as syphilis The aminopenicillins, ampicillin and amoxicillin, have expanded activity against gram-negative organisms The penicillinase-resistant penicillins, oxacillin and nafcillin, are highly effective for the treatment of infections due to MSSA Piperacillin is the only extended-spectrum penicillin currently available in the United States and only in fixed combination with the b-lactamase inhibitor, tazobactam Piperacillin has enhanced activity against gram-negative organisms, including P aeruginosa, with reasonable gram-positive coverage, including Enterococcus spp b-Lactam Antimicrobial Plus b-Lactamase Inhibitor Combination Ampicillin, amoxicillin, and piperacillin have been combined with a b-lactamase inhibitor that allows for enhanced gramnegative activity when compared with the b-lactam alone The first b-lactam drug effectively binds to the target site in the bacteria and results in the death of the organism The b-lactamase inhibitor has poor intrinsic activity as an antibiotic but may irreversibly bind to and neutralize the b-lactamase enzyme that the organism has produced The combination adds to the spectrum of the original antibiotic when the mechanism of resistance is a blactamase enzyme The addition of sulbactam to ampicillin (Unasyn) and clavulanate to amoxicillin (Augmentin) expands the spectrum of activity to include Haemophilus influenzae, Bacteroides fragilis, and many b-lactamase producing gram-negative organisms Similarly, the addition of tazobactam to piperacillin (Zosyn) results in enhanced anaerobic and gram-negative activity Of note, tazobactam has poor blood-brain barrier penetration; thus Zosyn does not work well for suspected CNS infections Cephalosporins The cephalosporins fall roughly into five “generations” that can be distinguished on the basis of activity against gram-negative pathogens and their stability to a number of the gram-negative b-lactamases First-generation cephalosporins (cephalexin, cefazolin) are generally most active against some gram-positive pathogens such as group A streptococci and MSSA, with more limited gramnegative activity The second-generation cephalosporins (cefuroxime, cefoxitin, cefotetan) have increased intrinsic activity against gramnegative organisms, including E coli and Klebsiella, decreased activity against MSSA compared with the first-generation cephalosporins, but are sufficient to achieve clinical success in most situations The third-generation cephalosporins (cefotaxime and ceftriaxone) have enhanced stability against the most prevalent b-lactamases of H influenzae, E coli, and Klebsiella and enhanced activity against many of the Enterobacteriaceae but are not stable in the presence of the inducible chromosomal b-lactamases (e.g., AmpC) of Enterobacter, Serratia, or Citrobacter Ceftazidime, another third-generation cephalosporin, has greater intrinsic activity against P aeruginosa than previous cephalosporins Cefepime, a fourth-generation cephalosporin, has the best overall activity against both gram-negative and gram-positive pathogens, with activity against P aeruginosa equivalent to ceftazidime and activity against MSSA equivalent to second-generation cephalosporins It is also the most stable to b-lactamase degradation The fifthgeneration cephalosporin, ceftaroline, is the first b-lactam antibiotic with activity against MRSA Aerobic gram-negative bacilli are generally susceptible, with the exception of P aeruginosa The in vitro pattern of susceptibility of gram-negative bacilli is similar to ceftriaxone While approved for adults, it has recently been shown to be safe and efficacious in children with community-acquired pneumonia and skin and soft-tissue infection.27,28 Newer combination cephalosporin/b-lactamase inhibitors are currently FDA approved for adults for infections with multidrugresistant organisms, including ESBL-producing gram-negative bacteria These agents include ceftolozane/tazobactam, which targets carbapenem-resistant P aeruginosa, and ceftazidime/ avibactam, which offers activity against both ESBL-producing ... Streptococcus pyogenes (group A strep), Streptococcus pneumonia (pneumococcus), methicillin-sensitive (MSSA) and methicillin-resistant Staphylococcus aureus (MRSA), coagulasenegative staphylococcus... based on microbiological and susceptibility data as well as clinical improvement is imperative.1 This chapter discusses the most clinically important gram-positive, gram-negative, and fungal organisms... flares is imperative Antibiotic selection for suspected or confirmed S aureus infection depends on methicillin sensitivity and includes penicillins, first-generation cephalosporins (for MSSA) and glycopeptides