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), 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 bacteria

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

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.

β-lactam antibiotics

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.

Structures of β-lactam antibiotics.

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 .

Aminoglycosides

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.

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 . ^, 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.

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, 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

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 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.

Miscellaneous

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.

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. 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.

eTABLE 107.3

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