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 first-line therapy.
Occult fungal infection should be considered in any patient with chemotherapy-induced neutropenia and fever 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 do 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.
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. 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 organisms. Many textbooks about infectious diseases provide excellent in-depth reviews of antibiotic characteristics and are recommended for additional information. ,
Bacterial infections in the intensive care unit
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), coagulase-negative 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. 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 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 α-toxin-mediated injury to pneumocytes. In adolescents with cystic fibrosis, coinfection and colonization with S. aureus and Pseudomonas aeruginosa confers more rapid decline in lung function —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), trimethoprim-sulfamethoxazole (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. In children with STSS or necrotizing fasciitis, clindamycin is often used in conjunction with a β-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. S. pyogenes is uniformly susceptible to β-lactam antimicrobial agents (penicillins and cephalosporins); susceptibility testing is needed only for non–β-lactam agents, such as erythromycin, clindamycin, or a macrolide, to which S. pyogenes can be resistant. 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). 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 5 years has been reduced by as much as 74% in population studies. 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 third-generation cephalosporin (ceftriaxone) should be used. S. pneumoniae has developed increasing resistance to β-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 β-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. 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 2 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.
Gram-negative organisms include Enterobacteriaceae , a large family of enteric gram-negative, facultatively anaerobic, rod-shaped bacteria that include extended-spectrum β-lactamase producing 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 gram-negative 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 plasmid-derived AmpC β-lactamases or the production of plasmid-mediated extended-spectrum β-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. 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 6 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 2 to 5 years. In one longitudinal report, 25% of hospitalized children with pertussis required time in the ICU and infants younger than 2 months were at highest risk for needing ICU treatment. In one ICU cohort, elevated white blood cell count was associated with the need for mechanical ventilation, pulmonary hypertension, and mortality. 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.
Anaerobic infections encountered in the PICU are commonly associated with organisms colonizing the oropharynx or intestinal tract. These infections are associated with mastoiditis, retropharyngeal 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. 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 β-lactam agent, is recommended for patients with invasive infection caused by Fusobacterium spp. Antimicrobial resistance has increased worldwide in anaerobic bacteria; local susceptibility testing and periodic surveillance is indicated for all clinically significant anaerobic isolates.
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. , 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.
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 (β-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. , 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 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.
|Acinetobacter spp. a||++||++||+++||+++||+++||++||++||++++||+||+|
|Methicillin-susceptible Staphylococcus spp. ( S. aureus or coagulase-negative staphylococci)||0||+++++||+++++||+++++||++++||++|
|Methicillin-resistant Staphylococcus spp.||0||0||0||+++++||++++||+|
|Enterococcus faecium a||++||0||0||++++||++++||0|
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 risk-benefit 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 do 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.
β-Lactam antibiotics are a diverse group of antibiotics. The β-lactam 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 β-lactam structure is thought to interfere with bacterial cell wall synthesis and repair by preventing transpeptidation and transglycosylation of the pentapeptide precursors. 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 β-lactam agents. Long-term high-dose use of all β-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 β-lactamase inhibitor, tazobactam. Piperacillin has enhanced activity against gram-negative organisms, including P. aeruginosa , with reasonable gram-positive coverage, including Enterococcus spp .
β-lactam antimicrobial plus β-lactamase inhibitor combination
Ampicillin, amoxicillin, and piperacillin have been combined with a β-lactamase inhibitor that allows for enhanced gram-negative activity when compared with the β-lactam alone. The first β-lactam drug effectively binds to the target site in the bacteria and results in the death of the organism. The β-lactamase inhibitor has poor intrinsic activity as an antibiotic but may irreversibly bind to and neutralize the β-lactamase enzyme that the organism has produced. The combination adds to the spectrum of the original antibiotic when the mechanism of resistance is a β-lactamase 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 β-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.
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 β-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 gram-negative activity. The second-generation cephalosporins (cefuroxime, cefoxitin, cefotetan) have increased intrinsic activity against gram-negative 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 β-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 β-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 β-lactamase degradation. The fifth-generation cephalosporin, ceftaroline, is the first β-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. ,
Newer combination cephalosporin/β-lactamase inhibitors are currently FDA approved for adults for infections with multidrug-resistant 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 and AmpC β-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.
Three carbapenems—imipenem, meropenem, and ertapenem—are currently FDA approved in pediatric patients older than 3 years of age for the treatment of complicated skin and skin structure infections (SSIs), complicated intraabdominal infections, and meningitis. The carbapenem’s β-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 gram-negative, 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 ESBL-producing gram-negative organisms or those harboring a chromosomally mediated AmpC β-lactamase, such as Enterobacter spp.
With respect to toxicity, the carbapenems are well tolerated, although imipenem displays interference with CNS γ-aminobutyric acid inhibition, increasing the risk for seizure activity in children. Meropenem is the preferred carbapenem for children at risk for seizures or with CNS infections and inflammation.
Aztreonam, the only monobactam currently available for clinical use in the United States, has a unique chemical structure in its β-lactam ring that enhances activity and stability to β-lactamases. It displays aerobic, gram-negative activity, including activity against many strains of P. aeruginosa . It has very little gram-positive activity.
Aminoglycoside antibiotics are bactericidal in a concentration-dependent 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 gram-negative organisms that are 10 times higher than those documented under ideal laboratory conditions. Aminoglycoside-induced nephrotoxicity has been described, even in noncritically ill children, and is associated with poorer outcomes.
The previously held notion that an aminoglycoside should be combined with a β-lactam to slow the development of resistance has been challenged in light of data suggesting that this combination may confer no survival benefit. , Empiric addition of gram-negative coverage with an aminoglycoside may have the strongest positive effect on outcomes in neutropenic populations. A potential survival benefit associated with empiric combination therapy appears greatest for high-risk patients 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. 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.
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 . , 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 gram-positive organisms, including MRSA. Their role in the management of children remains unsettled.
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, even in the absence of overt infection. 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
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 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.
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 1 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 gram-negative 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.
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 β-lactam–resistant strains of S. pneumoniae and S. aureus (MRSA) has led to increased use of clindamycin in children. 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.
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, coagulase-negative 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.
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 β-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.
With antibiotic resistance increasing dramatically in gram-negative pathogens, colistin has returned to clinical use and now represents a therapy of last resort for organisms resistant to all other available antibiotic therapy. 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. , In addition, aerosolized colistin has been used as an adjunctive or monotherapy for gram-negative pulmonary infections. Clinically significant bronchospasm may occur.
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.
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; immune-mediated thrombocytopenia; and with intravenous use, lactic acidosis.
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.
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 gram-positive 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. The primary toxicity seen is a dose-dependent, 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. , 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. 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 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.
Antibiotic resistance is increasing in gram-negative bacteria. Outbreaks by enteric gram-negative bacilli that carry chromosomal AmpC β-lactamases (present in Enterobacter , Serratia , and Citrobacter ) are increasing. The glucose nonfermenting gram-negative 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. Extended- or continuous-infusion dosing strategies with β-lactams such as Zosyn, cefepime, or meropenem for treatment of susceptible Pseudomonas strains in critically ill patients may optimize bactericidal exposure and have been associated with improved outcomes.
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 β-lactamase-producing and carbapenemase-resistant gram-negative bacteria. There is a growing amount of data regarding dosing and safety in pediatric populations. Several other newer agents are in clinical trials in adults for treatment of carbapenemase-resistant infections, including (1) meropenem/vaborbactam (a carbapenem/β-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. Indeed, Candida spp. are the third most common cause of hospital-acquired bloodstream infection in the United States, following coagulase-negative staphylococci and enterococci. 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.
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. 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. 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 3 days.
There are many Candida spp., each with their own unique pathogenicity and susceptibilities. C. albicans and C. parapsilosis remain the most common pathogens identified, although the incidence of infection due to other species (e.g., C. glabrata , C. tropicalis , C. krusei , and more) is rising. Blood culture remains the gold standard for the diagnosis of invasive candidiasis, although its sensitivity will vary depending on the extent of infection and particular Candida spp. Most Candida spp. are azole susceptible ( eTable 107.3 ), but there are certain subgroups that may have azole resistance, notably C. glabrata , C. krusei , and C. auris. In suspected candidiasis, an echinocandin (i.e., caspofungin) should be initiated empirically.