Impact of pneumococcal conjugate vaccine on resistance is unclear

MIAMI BEACH Fla. – The pneumococcal conjugate vaccine (PCV7, Prevnar, Wyeth) protects against the seven serotypes that cause the most invasive disease in U.S. children and are the strains most likely to be resistant to antibiotics. Although it has been available to the public for two years, it is still too soon to change treatment regimens based on receipt of vaccine, Sheldon L. Kaplan, MD, said here.

“Resistance among pneumococci for antibiotics from penicillin to cephalosporins can be multifactorial,” Kaplan explained at Miami Children’s Hospital’s 38th Annual Pediatric Postgraduate Course.

Experts do not know how the conjugate vaccine is going to impact resistance. “There is the hope that it will decrease antibiotic resistance as the prevalence of these serotypes decline,” said Kaplan, chief of infectious diseases at Texas Children’s Hospital and professor and vice-chair for clinical affairs, department of pediatrics at Baylor College of Medicine in Houston.

Resistance data

Data from 1999 showed that more than 25% of the U.S. isolates that caused invasive disease were non-susceptible to penicillin and of that group, almost half were fully resistant to penicillin. Approximately 15% to 18% of isolates were non-susceptible to the second- and third-generation cephalosporins and about 30% were non-susceptible to trimethoprim-sulfamethoxazole (TMP-SMX).

“I think our resistant rates now are probably closer to 35% to 40% of pneumococcus to penicillins, perhaps, half of that to the third-generation cephalosporins,” he said. “It varies depending on what area of the country you come from; the Southeast seems to have the highest rates of resistance among the states in the United States.”

The National Clinical Laboratory standard breakpoints for antibiotics have changed. The minimum inhibitory concentration (MIC) breakpoint for amoxicillin has been doubled.

“We have clinical data to show that what we thought might be a resistant isolate, really isn’t. You can reach serum levels that are exceedingly resistant and the patient’s clinical outcome is perfectly acceptable,” said Kaplan, a member of the editorial advisory board of Infectious Diseases in Children.

Kaplan called the breakpoints a moving target and said that as clinical outcomes information becomes available it changes the breakpoints designated in the laboratory.

“This allows us to treat more patients with penicillin instead of a third-generation cephalosporin. I think as clinicians, if you get a report from the laboratory that’s got this big ‘R’ on it marked resistant, even though a patient may be getting better, you feel uncomfortable continuing this antibiotic, and there are certainly medico-legal ramifications. So, as we get these clinical outcomes data, these levels are changing,” he said.

Another change that has occurred is that the breakpoints are being designated based on the site of infection. “So if you have a patient with pneumococcal meningitis, an MIC of 0.5 µg/ml or less is considered susceptible, 1 is considered intermediate and 2 or greater is considered resistant. These are based upon the fact that there were a number of kids with pneumococcal meningitis who were failing treatment with cefotaxime or ceftriaxone, and the MICs to the organism were 2 or greater,” he said. However, these same drugs can be used successfully to treat bacteremia or pneumonia.

Therefore, an organism that causes a disease that does not affect the central nervous system (CNS) is considered a susceptible isolate if it has an MIC of 1 or less; intermediate is 2 and resistant is 4 or greater. “A clinician must understand what the site of infection is to properly interpret the findings. The laboratory might not know that this positive blood culture is from a kid who might have meningitis. They may be reporting two different interpretive values for you,” he explained.

Multiple resistance

An isolate that is non-susceptible to penicillin is likely to be resistant to other antibiotics, he said.

Still, a Korean study demonstrated that penicillin or ampicillin worked in non-CNS pneumococcal infections, primarily pneumonia, even if the child was infected with a penicillin-intermediate or -resistant isolate with an MIC of 2 µg/ml or greater. Another study done in South America supported this finding.

“We had a multicenter group that looked at our isolates causing pneumococcal pneumonia in kids who received just a ß-lactam, even though the MIC to their organism was 1 µg/ml or greater for ceftriaxone — and essentially all 14 kids who had pneumococcal pneumonia with a ceftriaxone non-susceptible isolate did quite well with a ß-lactam antibiotic, although some did receive clindamycin as well.”

“And this makes sense because the serum levels of ceftriaxone [Rocephin, Roche], cefotaxime [Claforan, Aventis] or cefuroxime [Zinacef, GlaxoSmithKline] are quite high. They reach 100 to 150 µg/ml and that will exceed an MIC of 4,” Kaplan said.

“For at least now, we feel comfortable that we can treat a pneumococcal pneumonia even with ceftriaxone or cefotaxime with MICs of 4 µg/ml. Whether you need to use these drugs is still an issue, and I would encourage the use of more ampicillin.”

The pneumococcal surveillance group has reported more complicated pneumococcal pneumonias in the past six to seven years, which has not been associated with pneumococcal resistance. “What is really interesting, among our complicated pneumonias, serotypes 1 and 3 are major players here. If you combine these serotypes they account for about one-third of our complicated pneumonias,” he said.

They are not covered by PCV7, so the vaccine probably will not change them. The CDC has been following invasive pneumococcal disease in children in 12 locations. In 2001, there was about a 70% decrease in invasive isolates for those younger than 12 months old; there was a 67% decline in those 12 to 24 months, but not much change in older children, which makes sense since the younger children are the targets of the vaccine.

“We have to keep an eye on this. In our eight-center study, we’ve seen about a 60% decline in invasive isolates, and I can tell you we’ve seen no change yet in resistant isolates. Resistance was still going up a year after the vaccine was licensed,” he said.

It is too early for the receipt of the vaccine to change medical practice for young children. Kaplan said receipt of PVC7 should not affect whether one orders a lumbar puncture or the selection of antimicrobial agents.

“If you know a child has had three doses or even four doses of pneumococcal conjugate vaccine, it has not wiped out pneumococcal disease, so I don’t think it should change your approach,” Kaplan said.

For Your Information:

• Kaplan SL. Antibiotic-resistant pneumoniae. Presented at the 38th Annual Pediatrics Postgraduate Course “Perspectives in Pediatrics.” Jan. 24-30. Miami Beach, Fla.