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Update


INFECTIOUS DISEASE

How to respond to a CMV diagnosis in pregnancy; worries over methicillin-resistant S. aureus infection in and out of pregnancy; more on HPV vaccination

June 2007 · Vol. 19, No. 06

IN THIS ARTICLE

Four studies caught my eye this past year. The first describes the use of systematic methodology to confirm the diagnosis of primary cytomegalovirus (CMV) infection in pregnancy and lower the rate of unnecessary pregnancy termination. Investigators were able to reclassify approximately 70% of women who had been diagnosed with CMV infection and reduce the number of pregnancy terminations by 73%.

Two other studies help define the emerging problem of community-acquired methicillin-resistant Staphylococcus aureus (MRSA) infection, when to look for it, and how to treat it. In the first, researchers isolated S. aureus from the wounds of 320 patients with community-acquired infection and tested the samples for methicillin resistance, finding a prevalence of 59%. In the second study, investigators analyzed culture specimens from pregnant women for the presence of group B streptococci and S. aureus colonization. They found colonization with group B streptococci to be significantly associated with S. aureus colonization, with a prevalence odds ratio of 2.1.

The fourth study concerns the human papillomavirus (HPV) vaccine. Women given an HPV-16 L1 virus-like particle vaccine and followed for 4 years remained 100% free of cervical intraepithelial neoplasia (CIN) grades 2 and 3, unlike women who received placebo.

I believe these 4 studies represent the most significant developments of the past year in the field of infectious disease.

Don’t rush a diagnosis of CMV infection in pregnancy

Guerra B, Simonazzi G, Banfi A, et al. Impact of diagnostic and confirmatory tests and prenatal counseling on the rate of pregnancy termination among women with positive cytomegalovirus immunoglobulin M antibody titers. Am J Obstet Gynecol. 2007;196:221.e1–6.

CMV infection is a common and important perinatal pathogen. Each year in the United States, approximately 1% of gravidas acquire primary infection. Of these, about 40% transmit infection to the fetus. The rate of transmission is highest when maternal infection occurs in the third trimester, but the risk of serious fetal injury is greatest when maternal infection occurs in the first trimester. Ten percent to 20% of congenitally infected infants are acutely symptomatic at birth. Approximately 20% of these newborns die; most survivors have serious long-term complications. In contrast, CMV infection that recurs during pregnancy poses only minimal risk to the baby.1

Many women choose to have their pregnancy terminated when they learn they have a primary CMV infection.

Details of the study

This retrospective study was designed to determine whether a systematic diagnostic algorithm reduces the rate of unnecessary abortion in women who have apparent acute CMV infection during pregnancy. Guerra and colleagues evaluated 1,857 consecutive patients in practices in Italy who had a positive anti-CMV immunoglobulin M (IgM) antibody assay in the first or second trimester and were referred to a tertiary care facility for further diagnostic testing. Universal screening for CMV is now common among practitioners in Italy, and virtually all of these patients were completely asymptomatic.

At the tertiary facility, investigators tested again for CMV-specific IgM, as well as IgG, by enzyme immunoassay. They also tested for IgM by immunoblot and determined the avidity of anti-CMV IgG. Women who had IgG of low or moderate avidity with confirmed IgM, and those who clearly seroconverted to IgG were assumed to have a primary infection.

Women who were positive for IgM with high-avidity IgG were assumed to have nonprimary infection. Women who were seronegative for both antibodies were classified as uninfected. Those who were IgM-negative with high-avidity IgG were classified as previously infected. Women with an acute infection were then counseled by a specialist and offered amniocentesis and targeted ultrasonography.

Only 11.9% of women with primary infection chose abortion

Of the 1,857 women in this study, 445 were classified as having primary infection (group 1); 53 (11.9%) women elected to terminate their pregnancy. At autopsy, 38 of the 53 fetuses were found to be infected. In the other 15 cases, the pregnancy was terminated in the first trimester, and postmortem examination was not performed.

In the 1,205 women found to have nonprimary infection or previous infection (group 2), only 5 (0.4%) had the pregnancy terminated in the first trimester, and no postmortem examinations were performed. The difference in the observed rates of abortion between groups 1 and 2 was highly significant (P<.001).

Given their observations in group 1, the authors estimated that, on the basis of the initial screening tests at the referring institutions, approximately 196 (11.9%) of all patients in groups 1 and 2 would have elected abortion. By using confirmatory tests combined with counseling by a specialist, the authors were able to reduce the number of abortions from 196 to 53, a 73% decrease.

Always confirm an initial diagnosis

Given the ominous prognosis for congenital CMV infection and the major psychological implications and sobering finality of abortion, it is imperative that clinicians confirm the diagnosis of primary CMV infection. Because most cases of CMV infection in immunocompetent adults are asymptomatic, the diagnosis is typically confirmed by serology. Unfortunately, the serologic tests for CMV are not as straight-forward and reliable as tests for other viral infections such as rubella. Commercially available tests for anti-CMV IgM often have false-positive and false-negative results. In addition, IgM antibody may be detected as long as 9 months after a primary infection and may subsequently re-appear during reactivation of a latent infection or reinfection.2,3


Be selective, on the basis of risk factors and clinical manifestations, when screening pregnant women for cytomegalovirus infection.

Routine screening is not necessary

The authors’ findings vividly illustrate the potential errors that can occur when a large number of asymptomatic patients are routinely screened for CMV. Because of these pitfalls, I do not recommend routine screening. Rather, screening should be selective, directed at women who:

  • have clinical manifestations of CMV infection
  • are immunosuppressed
  • have small children in daycare or work in daycare themselves or
  • have documented exposure to someone with CMV infection.

If the initial immunoassay for CMV IgM is positive, a confirmatory immunoblot test for IgM should be performed, as well as avidity testing for IgG.

If primary infection is confirmed, the patient should undergo targeted ultrasonography and amniocentesis to assess for manifestations of congenital infection and to detect CMV in amniotic fluid by culture or polymerase chain reaction (PCR) testing. If the sonogram shows signs of fetal injury, or the PCR test is positive, the woman should be counseled about the options, which include experimental immunotherapy with hyperimmune anti-CMV globulin4 and pregnancy termination.

The study by Guerra and colleagues is a welcome addition to the obstetric literature. By using a systematic diagnostic algorithm that included an enzyme-linked immunosorbent assay and an immunoblot assay for IgM antibody and avidity testing for IgG antibody, the authors were able to reclassify approximately 70% of patients as either uninfected or previously infected. As a result, they reduced the number of pregnancy terminations by 73%, an objective end-point that clearly has great social, economic, and medical impact.

Most community S. aureus infections are methicillin-resistant

Moran GJ, Krishnadasan A, Gorwitz RJ, et al. Methicillin-resistant S. aureus infections among patients in the emergency department. N Engl J Med. 2006;355:666–674.

Moran and colleagues reviewed the records of 422 adults with acute purulent and soft-tissue infections who were evaluated in 11 university-affiliated emergency departments in August 2004. Wounds were routinely cultured. When S. aureus was isolated, the organisms were tested for antimicrobial susceptibility to identify those that were methicillin-resistant. The PCR test was used to identify genes for staphylococcal enterotoxins A through E and H, toxic shock syndrome toxin, and Panton–Valentin leukocidin. The same methodology was used to identify the gene complex staphylococcal cassette chromosome mec (SCCmec). This complex contains the mecA gene that confers methicillin resistance.

Of the 422 patients, 320 (76%) had S. aureus isolated from their wound. The prevalence of methicillin resistance was 59%. Ninety-seven percent of MRSA isolates were pulsed-field type USA 300. SCCmec type IV and the Panton–Valentin leukocidin gene were detected in 98% of MRSA isolates. Other toxin genes were rare.

Only 2 drugs were 100% effective

Among MRSA isolates, 100% were susceptible to rifampin and trimethoprim-sulfamethoxazole (TMP-SMX), 95% were susceptible to clindamycin, and 92% were sensitive to tetracycline. Only 60% were sensitive to fluoroquinolones, and only 6% were sensitive to erythromycin. Only 43% of patients received initial empiric therapy with antibiotics to which their organisms were sensitive.

Reason to worry

S. aureus is an important pathogen in obstetric patients. It is the causative organism of toxic shock syndrome and the dominant pathogen in patients with puerperal mastitis, as well as one of the key causes of postoperative wound infection. When penicillin was developed in 1941, all strains of S. aureus were sensitive to the drug. Within a few short years, however, most hospital-acquired strains became resistant.

Methicillin was introduced in 1961 to treat these resistant staphylococcal species. Unfortunately, by the mid-1960s, methicillin-resistant S. aureus (MRSA) infections began to appear. By the 1990s, MRSA infections were common in hospitalized patients, particularly in intensive care units. Hospital-acquired MRSA isolates are often sensitive to only a few select antibiotics such as vancomycin, linezolid, and quinupristin/dalfopristin.5

In the late 1990s and early 2000s, MRSA began to appear in community-acquired infections in both adults and children. Most of these isolates have been implicated in skin and soft-tissue infections, but some have been responsible for invasive infection, bacteremia, and even death.6 Compared with hospital-acquired MRSA, these community isolates are more likely to be sensitive to commonly used antibiotics.

Always culture an infected wound

Knowledge of these sensitivity patterns is of great importance. Regrettably, as noted by Moran and associates, more than half of the patients (57%) were initially treated with antibiotics to which their infecting organism was resistant.

The clinical implications are clear:

  • We must be aware that many community-acquired soft-tissue infections will be caused by drug-resistant staphylococci.
  • Because antibiotic resistance is so prevalent, a culture of the infected wound should be obtained routinely so that antimicrobial therapy can be modified if the patient fails to respond to initial treatment.
  • Antibiotic therapy alone is rarely sufficient for abscesses in the soft tissue and skin; adequate surgical drainage is essential.
  • Fundamental infection-control measures, such as careful handwashing, adequate skin preparation prior to surgery, and local wound care, are of greater importance than ever.


Most cases of community-acquired MRSA have been isolated from skin and soft tissue; surgical drainage is necessary when infection advances to abscess in those sites.

In gravidas with group B strep, look for S. aureus

Chen KT, Huard RC, Della-Latta P, Saiman L. Prevalence of methicillin-sensitive and methicillin-resistant Staphylococcus aureus in pregnant women. Obstet Gynecol. 2006;108:482–487.

To assess the prevalence of methicillin-sensitive and community-acquired methicillin-resistant S. aureus colonization in pregnant women, Chen and colleagues evaluated de-identified culture specimens that had originally been submitted to the microbiology laboratory for identification of group B streptococcal infection. As opposed to hospital-associated MRSA isolates, community-associated methicillin-resistant strains were defined as those possessing the type IV or V staphylococcal chromosomal cassette mec element and lacking a multi-drug-resistant phenotype.

Of the 2,963 culture specimens in the prospective surveillance study, 743 (25%) were positive for group B streptococci, and 507 (17%) were positive for S. aureus. Group B streptococcal colonization was significantly associated with S. aureus colonization; the prevalence odds ratio was 2.1. Fourteen of the 507 S. aureus isolates were methicillin-resistant (2.8%; 95% confidence interval [CI] 1.4–4.2%). Thirteen of the 14 strains (93%) were community-acquired.

S. aureus may cause sepsis, wound infection, bacteremia, and other ills

The unique feature of this study is the observation that vaginal colonization with group B streptococci was significantly associated with colonization with S. aureus—one of the possible causative pathogens in chorioamnionitis, endometritis, wound infection, bacteremia, puerperal mastitis, and toxic shock syndrome. The organism also may cause serious neonatal infection, particularly sepsis.

Continued...
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