Familiarity with susceptibility patterns a must when choosing antibiotics for common infections

“Know your bugs, know your drugs,” Sarah S. Long, MD, said during a speech at the 22nd Annual Infectious Diseases in Children Symposium held in New York City.

Although antibiotics have yielded huge benefits for patients since their introduction into medical practice, inappropriate use of these agents has led to antimicrobial resistance among many bacteria. It is a vicious cycle in which antibiotics are prescribed to eradicate the bacteria, but some bacteria remain and transfer their mutations in the community, which complicates diagnosis and treatment options.

Due to the link between antibiotic prescribing and development of antibiotic resistance, extensive efforts, including the CDC’s “Get Smart” campaign, have focused on reducing antibiotic prescribing for conditions in which antibiotics are not usually indicated.

Long, chief in the section of infectious diseases at St. Christopher’s Hospital for Children in Philadelphia, and several other speakers at the IDCNY Symposium offered advice and reviewed the latest literature on managing some of these infections, including urinary tract infections, acute otitis media, bacterial sinusitis and community-associated methicillin-resistant Staphylococcus aureus.

Larry K. Pickering, MD, of the CDC, said increases in resistant infections mandate knowledge of prevention and treatment options. One example he used was gonorrhea. Fluoroquinolone resistance has become such a problem with gonorrhea treatment that as of 2009, it is no longer recommended in the Red Book.

UTIs

One area of antibiotic overuse that has been criticized of late includes antibiotic prophylaxis use for children with UTIs. The issue took center stage in early November as investigators with the PRIVENT (Prevention of recurrent urinary tract infection in children with vesicoureteric reflex and normal renal tracts) trial published a study that concluded that long-term, low-dose trimethoprim-sulfamethoxazole moderately decreased UTIs in predisposed children.

Long said antibiotic prophylaxis guidelines may change when results from the RIVUR (Randomized intervention for children with vesicoureteral reflux) study, a randomized, placebo-controlled clinical trial involving 600 patients, become available.

This NIDDK-sponsored trial, which Infectious Diseases in Children Editorial Board Member Alejandro Hoberman, MD, is involved with, is currently in the recruiting stage and will explore whether children with vesicoureteral reflux need to be treated with antimicrobial prophylaxis, and whether treatment prevents recurring UTIs and renal scarring.

In an interview with Infectious Diseases in Children, Hoberman said the results of the PRIVENT trial showed that a “one-size-fits-all approach” for children with this condition might not be appropriate. The trial showed an overall reduction of about 6 percentage points in the absolute risk of symptomatic and febrile UTIs; time-to-event-analysis showed that the benefit was not sustained and about 14 children would need to be treated to prevent one infection. However, there are still probably subgroups of children who have a higher risk of recurrent UTIs and renal scarring.“None of us are ready to discount the efficacy of antimicrobial prophylaxis in those subgroups of children that are predisposed,” Hoberman said. “Perhaps just earlier diagnosis and treatment of UTIs, and management of the dysfunctional elimination frequently associated will make the biggest difference in preventing recurrent UTIs and renal scarring.”

Honing in on those children who would benefit most from prophylaxis would go a long way to reduce overuse of antimicrobials, Hoberman added.

For those children who do not have recurrent infections, Long said she recommends treating girls and uncircumcised boys younger than 12 months who are experiencing UTI symptoms, including suprapubic tenderness, persistent fever (longer than 24 hours), increasing temperature and who are moderately ill appearing. She cited data from a study conducted by Shaikh and colleagues that showed UTI rates increased from 3% to 17% among children younger than 2 years with these risk factors.

Long said she prefers a stepwise approach to treatment for febrile patients without focused signs or symptoms who do not have risk factors, as suggested in a separate study by Shaikh et al, whose results were published in Journal of the American Medical Association.

Long said third-generation cephalosporins are about 97% effective against Escherichia coli and gram negatives.

Janet Casey, MD, who also spoke at the meeting and is a clinical associate professor of pediatrics at the University of Rochester in New York, said testing options for UTI are important, and a dipstick chemical screening that looks at proteinuria, hematuria and pyuria should facilitate diagnosis. If all tests are normal, the likelihood of UTI is low, and if any one test is positive, further evaluation should be performed.

AOM management

Another area where proper diagnosis is key to guiding antibiotic choices is in AOM treatment, according to Casey.

“Factors that influence clinical outcome for AOM, sinusitis and tonsillopharyngitis can be broken down into three main categories: proper diagnosis, pharmacokinetic and pharmacodynamic properties of antibiotics, and choice of the right antimicrobial agent, dose and course of therapy,” Casey said.

Diagnosing AOM can be difficult. Many published AOM trials and meta-analyses have been criticized for poor methodology of diagnostic criteria of AOM for study patient inclusion.

The AAP guideline, “Diagnosis and Management of Acute Otitis Media,” recommends pneumatic otoscopy, tympanometry or acoustic reflectometry to aid in the diagnosis of AOM (vs. visualization alone) while still allowing some uncertainty in providing an accurate diagnosis. However, in a survey by Vernacchio and colleagues published in 2006, more than 60% of surveyed physicians used pneumatic otoscopy either never or in fewer than 50% of children, and 12% reported never using any of these diagnostic measures in the survey described above.

The diagnosis of AOM in a child who likely has otitis media with effusion contributes to the unnecessary use of antibiotics, Casey said.

In an interview with Infectious Diseases in Children, Editorial Board Member Michael Pichichero, MD, said the confusion between AOM and otitis media with effusion occurs because of an “inability to adequately visualize the tympanic membrane, often due to cerumen in the way.” He added that over-reliance on symptoms, desire to please parents who seem to be interested in securing an antibiotic and lack of time to fully assess the patient and explain that an antibiotic is not needed are other reasons for overuse of antibiotics for AOM.

About 30 million courses of antibiotics continue to be prescribed in the United States each year to treat AOM, despite decreases in disease incidence since the introduction of seven-valent pneumococcal conjugate vaccine (Prevnar, Wyeth) in 2000.

Replacement serotypes such as nonvaccine pneumococcal strains and antibiotic-resistant organisms, including Haemophilus influenzae and Morexella catarrhalis, continue to cause AOM. Guidelines from AAP, published in Pediatrics, currently recommend antibiotic treatment for definite AOM cases in children younger than 2 years and severe cases in children older than 2 years.

“Those who receive treatment get better faster,” Long said, adding that antibiotics can reduce the duration, persistence and recurrence of AOM, as well as a patient’s risk for suppurative otitis media and intracranial mastoiditis.

But treatment effects are often modest — Long said there is about a 95% symptom-resolution rate among those administered antibiotics vs. 80% among those administered placebo seven to 14 days after treatment. (For more on AOM treatment, see the Point/Counter on watchful waiting).

Current antibiotic choices include amoxicillin (90 kg/day) or ceftriaxone daily intramuscularly for patients with AOM caused by penicillin-resistant streptococcal pneumonia, according to Long, as macrolides and TMP-SMX are often ineffective. If a physician chooses ceftriaxone, three daily doses are necessary due to higher minimum inhibitory concentrations.

If H. influenzae or M. catarrhalis are suspected pathogens, Long recommended treating with amoxicillin clavulanate or cephalosporins. Amoxicillin clavulanate ES (Augmentin ES-600, GlaxoSmithKline; 90 kg/day) or a single dose of ceftriaxone plus amoxicillin (90 kg/day) are options if pneumococcus is suspected in addition to H. influenzae and M. catarrhalis.

“I don’t mean to encourage you to use amoxicillin clavulanate as the first-line therapy,” Long said, adding that the therapy is only warranted when there are “frequent relapses and problematic cases.”

Options for patients with penicillin allergies are limited and include azithromycin, clarithromycin or clindamycin plus sulfisoxazole. Patients with nontype 1 penicillin allergies can be treated with cefdinir, cefuroxime, cefpodoxime and ceftriaxone, Long said. “There is no cephalosporin that is as good as ampicillin for pneumococcal disease, so it’s a bit of a trade off.”

Pichichero said it is important to keep the antibiotic course as short as possible when treating patients for AOM.

“Slowly, the CDC and AAP are coming around to accepting the data that most ear and even sinus infections can be treated successfully with just five days of antibiotic,” Pichichero said. “Traditional 10-day therapy is infrequently given to the end, usually stopped at five days, anyway, and provides families with leftover antibiotic indiscriminately used at a later time when it has lost potency and has a greater potential to select for resistant bacteria.”

Managing sinusitis

Determining whether sinusitis is bacterial is often difficult and influences whether an antibiotic will be an effective treatment, according to Long.

“If you’re making this diagnosis in about 10% of the children that you’re seeing for acute respiratory illness, that’s about the right ballpark,” she said.

Patients with persistent infection (nasal discharge or daytime cough without improvement after 10 days) or severe infection (high fever and purulent nasal discharge for three consecutive days) are most likely to have a bacterial pathogen, Long said, citing previously published data in Pediatrics from a study conducted by Wald and colleagues in which 75% of patients who met these criteria had positive cultures.

“If purulent nasal discharge lasts more than 10 days, physicians may presume that a diagnosis of sinusitis can be made, and they should initiate treatment with antibiotics. This diagnosis is not 100% accurate in all cases, but it is endorsed by the AAP,” Casey said.

Recently, worsening symptoms — such as a new fever after a previously resolved fever, or increases in nasal discharge and cough after six days — have also been deemed markers for initiating antibiotic therapy.

Although results of past clinical trials conducted to explore the benefit of antibiotics have had conflicting results, results of a trial indicated that amoxicillin-clavulanate (90 kg/ day) was effective in treating patients 10 years or younger who had culture-confirmed bacterial sinusitis (n=135), with a 50% cure rate among patients administered the drug vs. 14% of patients administered placebo.

MRSA

As MRSA has spread from the hospital setting into the community, recurrent soft skin infections are among the most commonly encountered pediatric manifestations, and Long said a multifaceted management strategy may be the best option.

“Everyone with recurrences deserves at least one course of antibiotics to which the organism is susceptible,” Long said. Clindamycin, linezolid, doxycycline and TMP-SMX are among available options.

Because MRSA can colonize multiple sites on the body and is not just limited to the nasopharynx, decolonization can be complicated and is often unsuccessful. “You can attempt decolonization in extraordinary circumstances, but first tell the family that it’s not going to work in two out of three cases,” Long said.

If decolonization is attempted, Long suggested the following regimen:

• Active antibiotics — 14 days.
• Rifampin — seven days.
• Mupirocin — 14 days.
• Empty and thoroughly clean bathrooms; use separate towels and wash clothes.
• Patient should shower or bathe daily using chlorhexidine or bleach baths (one-half cup in one-quarter tub) once daily for 14 days, then twice weekly for 12 months.

“This is a tough nut to crack,” Long said. Only 26% of patients assigned to this regimen remained colonized vs. 58% of patients in a placebo group, results from a 2007 study indicated.

No matter what the infection, Long said physicians must respect the growing problem of antibiotic resistance.

“Use antibiotics only to shorten the course of infection or to prevent complications. Don’t use little doses, and don’t give an antibiotic if it’s not a bacterial infection,” she said. “Give a good dose at the high end of what’s acceptable. Give the right duration, and then stop.” – by Nicole Blazek

Would a watchful waiting approach reduce antibiotic use for AOM?

For more information:

• AAP. Pediatrics. 2004;113:1451-1465.
• Casey J. Office lab testing.
• Long SS. Antibiotics for common infections in outpatients.
• Pickering L. What’s new with the Red Book? All presented at: The 22nd Annual Infectious Diseases in Children Symposium; Nov. 21-22, 2009; New York.
• Shaikh N. JAMA. 2007;298:2895-2904.
• Shaikh N. Pediatr Infect Dis J. 2008;27:302-308.
• Simor AE. Clin Infect Dis. 2007;44:178-185.
• Wald ER. Pediatrics. 2009;124:9-15.