1. Discuss the types of infection caused by MRSA.

2. Describe the differences between mild, moderate, and severe MRSA infections and their clinical implications.

3. Empirically manage MRSA infections.

4. Diagnose and manage UTI.

5. Determine which patients are the best candidates for vesicoureteric reflux prophylaxis.

MRSA: From the Patient to the Laboratory and Back Again
Stephen C. Eppes, MD, Professor of Pediatrics, Jefferson Medical College, and Chief, Division of Infectious Diseases, Thomas Jefferson University Hospitals, Alfred I. duPont Hospital for Children, Wilmington, DE

Background: Staphylococcus aureus (S aureus) carried by 10% to 36% of healthy children; usually colonizes nares and skin; infection occurs when organism penetrates skin or mucous membranes, resulting in skin or soft tissue infection; bacteremia occurs when organism penetrates nasal or oropharyngeal mucosa, allowing hematogenous dissemination; most common cause of soft tissue, bone, and joint infections

Patterns of disease

Invasion with tissue destruction: usually skin infection, but if organism invades bloodstream (bacteremia), may lead to osteomyelitis or pneumonia

Furuncles (boils): most common manifestation of staphylococcal infection; carbuncles—severe or coalescing boils leading to deeper infection in subcutaneous fat; cellulitis—disseminated infection in soft tissue

Pneumonia: often causes severe, destructive, necrotizing form of pneumonia; radiography reveals pneumatoceles (damaged lung tissue with extra-alveolar air)

Toxin-mediated: scalded skin syndrome (caused by exfoliative toxin; Nicolsky’s sign [upper layer of epidermis exfoliates easily when rubbed]; toxic shock syndrome, with mucocutaneous systemic manifestations, followed by peeling of palms and soles; staphylococcal food poisoning

Laboratory findings: Gram stain shows characteristic grape-like clusters; agar plate shows golden colonies surrounded by zone of beta hemolysis

Virulence factors: disease-causing enzymes and toxins produced by organism; catalase test—involves use of hydrogen peroxide; distinguishes between staphylococcal and streptococcal organisms; coagulase test— distinguishes coagulase-negative staphylococci from more virulent S aureus

Resistance testing: most laboratories now use Kirby-Bauer method; E test—variant of Kirby-Bauer method; impregnate paper strip with gradient of antibiotic concentrations to determine minimum inhibitory concentration

Methicillin-resistant S aureus (MRSA): first emerged in 1970s; vancomycin used instead; by late 1990s, became less susceptible to vancomycin, with vancomycin-resistant S aureus appearing early in 21st century (still uncommon); hospital resistance rates >60%; compared to non-MRSA strains, MRSA infections associated with significantly higher morbidity and mortality; community-acquired MRSA (CA-MRSA) infection—first reported between 1997 and 1999 in children and adults lacking traditional MRSA risk factors; today accounts for 70% to 75% of all S aureus infections in some communities; most common strain USA300

CA-MRSA risk factors: crowding; skin-skin contact; being in military, prison, or daycare; participation in competitive sports; epidemiology—intrahousehold spread and recurrences among family members and individuals common; like hospital-acquired MRSA (HA-MRSA), resistant to ß-lactam antibiotics

Prevalence of CA-MRSA: speaker estimates that approximately 10% of children in many communities now carry MRSA (usually CA-MRSA); HA-MRSA still responsible for most MRSA-associated deaths; CA-MRSA most common cause of all skin and soft tissue infections

MRSA genetics: staphylococcal “chromosomal cassette” has mec genes 1,2,3 (associated with HA resistance due to excessive antibiotic exposure); also has mec genes 4,5 (associated with CA resistance); Panton-Valentine leukocidin (PVL) gene—encodes for leukocidin, which damages leukocytes and impairs their ability to fight S aureus; associated with increased virulence, invasive infections, necrotizing pneumonia, staphylococcal sepsis, and other severe infections; almost all CA-MRSA associated with PVL gene, USA300 strain

Management: know local prevalence; examine hospital’s antibiogram; culture aggressively; understand susceptibility testing; manage according to level of severity; draining pus key (permits culturing, is therapeutic, sometimes curative); ensure appropriate follow-up

Assess clinical severity: mild—patient afebrile, with no underlying problems; outpatient management usually sufficient; moderate—fever, and skin or soft tissue infection; may require hospitalization; severe—septic or toxic shock; complicated pneumonia; limb-threatening infection; pelvic syndrome; necrotizing fasciitis; Waterhouse- Friderichsen syndrome

Identify site of infection: skin and soft tissue most common; more significant organ and tissue involvement, sepsis, and toxic shock increase risk for bad outcome, and therefore necessitate more aggressive management

Assess patient: high-risk groups include immunocompromised patients, diabetics, and neonates

Management of cutaneous abscess: infections >5 cm require hospitalization; incision and drainage usually curative; ß-lactam antibiotics (eg, cephalosporins, penicillins) contraindicated in communities in which CA-MRSA prevalence >10%; mild illness—oral linezolid and vancomycin recommended; more serious illness— vancomycin; linezolid; clindamycin and daptomycin also good choices

Linezolid: first of new class of drugs (oxazolidinones); inhibits protein synthesis; spectrum almost exclusively gram-positive; main use against resistant gram-positive organisms; oral bioavailability 100%; side effects manageable; 10-day course for typical adult costs approximately $1500; insurance company may require letter of medical necessity for approval

Daptomycin: lipopeptide antibiotic; may have most rapid microbicidal action against gram-positive organisms; only available intravenously; toxic to skeletal muscle (patient may complain of muscle ache; creatine phosphokinase levels may rise)

Clindamycin: good activity against CA-MRSA; however, resistance inducible in some strains; make sure laboratory performs “D test” to ascertain whether organism susceptible (positive result indicates resistance)

Empiric treatment: skin and soft tissue—trimethoprim-sulfamethoxazole (TMP-SMZ; drawbacks include no proven track record against deep invasive infection; 4% risk for hypersensitivity reaction); clindamycin (bad taste drawback; some children refuse to take); doxycycline (use restricted to patients >8 yr of age); osteomyelitis— clindamycin; vancomycin for D test-positive strains; pneumonia—clindamycin or vancomycin plus cephalosporin; sepsis and toxic shock—vancomycin still covers almost 100% of MRSA

MRSA eradication: in review of 6 studies involving 384 people, no antibiotic successful; intensive regimen combining chlorhexidine, mupirocin, rifampin, and doxycycline effective in adults; other studies show success in colonized health care providers

Real-life cases: 14-yr-old girl with boils on legs, axillae, and otherwise healthy—bathe with chlorhexidine and dilute bleach (1 tablespoon/gallon); intranasal mupirocin; change razors frequently; wipe household surfaces with 10% bleach solution; alcohol-based hand cleaners; 3-yr-old child with 1-cm boil on buttock, 4 cm of surrounding erythema, and afebrile—incision and drainage; 7-yr-old boy with pain in right knee, femoral tenderness, temperature of 102o F, and erythrocyte sedimentation rate of 70 mm/H —patient has osteomyelitis; vancomycin, clindamycin, and linezolid best antibiotic choices; teenage girl with 2-day history of fever, vomiting, and diarrhea; has rash resembling sunburn; near syncope—toxic shock syndrome; treat with vancomycin and clindamycin

UTI and Genitourinary Reflux
Julia S. Barthold, MD, Associate Professor, Division of Urology, Alfred I. duPont Hospital for Children, Wilmington

Background: urinary tract infections (UTIs) occur in 3% to 5% of girls; during first year after birth, more common in boys; prevalence increases in girls near time of toilet training; risk higher in uncircumcised than circumcised boys; symptoms in young children nonspecific; dipstick analysis highly suggestive of UTI if positive for leukocytes and nitrites; urinalysis and culture necessary for definitive diagnosis

Physical examination: look for abdominal findings; ask about voiding habits; consider occult spinal disease as possible underlying factor

Pathogenesis: critical factors organism virulence and host susceptibility; fimbriae of gram-negative organisms adhere to periurethral area, foreskin, leading cystitis, pyelonephritis

Risk factors: urinary tract anomalies; bladder abnormalities; family history of recurrent UTI; sexual intercourse (teenagers)

Factors that do not increase risk: bubble baths; improper wiping; labial adhesions; do not circumcise solely to lower risk for UTI

Diagnosis: formal urinalysis unnecessary if dipstick results negative

Urine collection: if child toilet-trained, separate labia, clean front to back, and catch midstream sample in cup; if child not voiding, catheterization gold standard

Bacterial etiology: Escherichia coli most common cause; boys may contract gram-positive infection (Enterococcus most common); Pseudomonas and fungal infections possible in people with urinary tract anomalies or history of antibiotic use

Treatment: ideally, achieves high urinary concentration, with little effect on other flora, and low risk for resistance; narrow spectrum preferred

Factors that influence choice of therapy: whether child febrile; whether infection complicated or uncomplicated; route of administration (oral or parenteral; may depend on age); other confounding factors (treatment for asymptomatic bacteriuria contraindicated for children on clean intermittent catheterization)

Uncomplicated UTI: amoxicillin (Augmentin; resistance rates high); TMP-SMZ (eg, Bactrim; also associated with high resistance rates; broader spectrum agent may be better choice); nitrofurantoin (Macrodantin; usually reserved for prophylaxis); cephalosporins; quinolones

Complicated UTI: older child, non-toxic—oral antibiotics; infant or toxic—determine whether hospitalization required

Length of treatment: 3 to 5 days sufficient for milder cases, longer for pyelonephritis; efficacy and scarring not affected by mode of administration (base on clinical criteria)

Elimination dysfunction: signs and symptoms include infrequent voiding, frequent (but ineffective) defecation, and overactive bladder with frequency, urgency, and incontinence; true dysfunctional voiding rare; voiding and stooling diaries recommended

Treatment: clean out patients who pass soft stool less frequently than every other day; change to fluids and fiber; rare use of intermittent catheterization

Imaging: ultrasonography (US) usually not helpful in early stage of illness; assess kidneys first with dimercaptosuccinic acid (DMSA) or renal cortical scan; if positive, follow up with vesicoureterogram (VCUG) or US; DMSA scan findings seen in ≈50% of young children with afebrile UTI; ≈50% of those will have scarring; wait ≥6 mo after resolution of infection before performing DMSA scan to get accurate picture of scarring; obstructive uropathy rare, but vesicoureteric reflux (VUR) common among infants and toddlers; increases risk for scarring and pyelonephritis; UTIs often recur

Relationship between VUR and UTI: standard conceptual model holds that VUR renders patient more prone to severe UTI, renal scarring, and long-term complications; actual risk unclear; prophylactic use of antibiotics thought to prevent recurrent UTI; surgery for VUR thought to reduce risk for pyelonephritis and scarring; however, these assumptions hard to prove

Evidence-based conclusions: VUR predisposes to pyelonephritis, but does not cause UTI; correcting VUR decreases risk for pyelonephritis, but not risk for cystitis; US not a sensitive detector of renal scarring; risk for hypertension correlates with degree of scarring and grade of reflux; some patients develop new scars after single infection; primary renal abnormalities associated with reflux without UTI, and scarring, especially in male infants; open questions—prophylaxis may not prevent UTI or scarring; antireflux surgery may not prevent scarring; early treatment of pyelonephritis may not reduce risk for scarring; conclusion—scarring risk most likely related to genetic susceptibility, infecting organism, and degree of reflux

Management: speaker first uses fluoroscopic VCUG with cyclic filling; sedation usually offered, especially if patient a toddler (nitrous oxide also an option, especially for older children); US also performed, although value questionable; most cases of VUR mild to moderate; may resolve without treatment over time, but may take years; prophylaxis currently used before VCUG to decrease slight risk for UTI related to catheterization

Factors supporting use of VUR prophylaxis: young age (ie, not yet toilet-trained); high-grade reflux; history of febrile or recurrent infections; known renal scarring; unresolved or untreated voiding problems; frequent or recurrent UTI, even without VUR; trimethoprim treatment of first choice; other options include TMP-SMZ and nitrofurantoin; alternate between TMP-SMZ and nitrofurantoin for breakthrough infections

Surgery: limit to cases of severe VUR, scarring, or noncompliance

Dextranomer plus hyaluronic acid (Deflux): injected into lower ureter; elevates ureter, helps prevent reflux; less invasive (but also less effective or reliable) than open surgery, with 10% risk for recurrence

After toilet-training: stop prophylaxis, but monitor closely

Recommendations: document febrile UTIs in infants; utilize VCUG or DMSA scan to determine risk; follow high-risk individuals