Updates
Booster Vaccination for Pertussis Recommended
By Carol A. Kemper, MD, FACP, Clinical Associate Professor of Medicine, Stanford University, Division of Infectious Diseases; Santa Clara Valley Medical Center, Section Editor, Updates Section Editor, HIV, is Associate Editor for Infectious Disease Alert
New York Times, June 30, 2005, page A13.
The Advisory Committee on Immunization Practices (ACIP) has recommended that the new acellular pertussis vaccine be routinely administered to all 11 and 12-year-olds as part of routine preventative care. In addition, teens ages 13 to 18 who missed the booster or who received the older tetanus-diphtheria vaccine, should receive the new vaccine. Previously, no whooping cough vaccine was licensed for use in individuals past the age of 7 years, but pertussis epidemiology is changing with, as immunity wanes, a clear increase in teens and adults. While older individuals tend to have milder disease, they often serve as the source of infection for young children.
Two new pertussis vaccines have just received approval by the United States FDA, including Boostrix® from GlaxoSmithKline, which was licensed in May for use in children ages 10 to 18 years of age (See IDA June 2005), and Adacel® from Sanofi Pasteur, which was licensed in June 2005 for use in individuals aged 11 to 64. The adolescent/adult formulations of these vaccines contain a lower dose of pertussis antigens with tetanus and reduced diphtheria toxoids. The ACIP elected to defer recommendations for booster pertussis vaccination of adults to a later date. Although the Centers for Disease Control and Prevention almost always accept the recommendations of the ACIP, final changes in guidelines for vaccination will be published in an upcoming MMWR.
New TB Drug Enters Clinical Trials
Peninsula Daily News. June 15, 2005.
Human trials of a new antituberculosis drug called PA-184 have begun in 53 healthy volunteers in Lincoln, Nebraska. This is the first antituberculosis agent with a novel mechanism of action to have been developed in more than 30 years, despite the fact that it is estimated that one-third of the world’s population is latently infected with TB and it kills over 2,000,000 people annually.
PA-184 is the leading candidate in a group of small compounds containing a nitroimidazopyran nucleus that inhibit protein synthesis and cell wall lipids, following activation by a mechanism dependent on MTb F420 cofactor. While the spectrum of activity of PA-184 is limited primarily to M. tuberculosis complex, it has proven potent both in vitro and in animal models. In addition, unlike other anti-tuberculosis drugs, PA-184 has activity against both replicating and static M. tuberculosis. PA-184 demonstrates no cross-resistance with other anti-tuberculosis agents.
Against a broad range of MTb isolates, PA-184 was highly active against all isolates with an MIC < 1 mcg/mL, including multi-drug resistant isolates. In a murine model, the activity of PA-184 was similar to moxifloxacin (100 mg/kg) and isoniazid (25 mg/kg), administered as single agents, and it was slightly more active than rifampin (20 mg/kg) (Lanaerts AJ, et al AAC 2005; 49(6):2294-301; Tyagi S, et al AAC 2005, 49(6):2289-93). When combined with isoniazid, it prevented the selection of INH-resistant mutants. In addition, PA-184 continued to demonstrate potent bactericidal activity through a 2-month continuation phase of treatment against organisms that had persisted despite combination 3-drug therapy. These data suggest that the addition of PA-184 to existing regimens may prevent the emergence of drug resistance during treatment, and may allow for shorter durations of total therapy.
This newer class of drugs is being investigated through a unique public-private partnership led by a not-for-profit consortium called the Global Alliance for TB Drug Development, US government agencies, and 2 pharmaceutical companies. PA-184 was originally developed by Chiron Corporation in Emeryville, California, and was sold to the Global Alliance in 2002 for a modest fee, for eventual global distribution for free in Third World countries. Chiron retains the rights for commercial distribution in the United States and the rest of the developed world.
Bartonella quintana: An Ancient Disease?
Drancourt M, et al. J Infect Dis. 2005; 191:607-611.
For those fans of Crime Scene Investigation (CSI) on television, you probably already know that examination of dental pump by molecular mechanisms is similar to examination of a blood sample. These investigators in Didier Raoult’s Rickettsial Disease Laboratory in Marseille, France, continue to hunt down intriguing evidence for various rickettsial and Bartonella spp.
B. quintana is now known to be the causative agent of trench fever, which killed thousands of soldiers in World War I. In modern times, it is known to infect about 10-15% of homeless people with body lice in North America and Europe, in whom it causes a variety of problems, including lymphadenitis, bacteremia, and culture-negative endocarditis. It is transmitted only by the body louse, Pediculus humanus corporis.
Surmising that ectoparasitism was common in ancient peoples, Drancourt and colleagues examined 12 teeth from 6 human remains dug up from archaeological sites in Peyraoutes and Roaix, both located in southeastern France, for evidence of Bartonella quintana. Carbon dating estimated the age of the teeth to be between 2230 B.C. to 1950 B.C. Extraction and amplification of DNA demonstrated that one tooth from Peyraoutes contained a genetic fragment identical to that of B. quintana. The amplicon had 97% homology with the modern B. quintana groEL gene and 92% homology with the analogous gene in the modern B. henselae CAL-1 strain. The ancient sequence contained 2 mutations not present in modern B. quintana.
These findings indicate that human beings—at least those who were clothes and were thus vulnerable to body lice—were exposed to B. quintana more than 4000 years ago, indicating that trench fever is actually an ancient disease. A similar investigation recently found evidence of B. henselae DNA in the dental pulp of a 13th-16th century cat.
Directed Salvage Regimens for HIV
Torti C, et al. Clin Infect Dis. 2005;40: 1828-1836.
The more widespread availability of HIV resistance testing, either through genotype or phenotype resistance testing, as well as the availability of assays for measuring drug blood concentrations, have been widely hailed as necessary for optimal management of HIV therapy. However, few studies, this among them, have been able to conclusively demonstrate the benefit of these newer technologies in outcome treatment.
Torti and colleagues at the Institute for Infectious and Tropical Diseases in Brescia, Italy, assessed a management strategy approach to the selection of HIV salvage therapy called the Resistance and Dosage Adapted Regimens (RADAR) Study. A total of 265 patients were randomized to switch their current failing HIV treatment based on the results of either an interpreted genotype resistance testing or an interpreted virtual phenotype resistance testing. In addition, participants were further randomized to interval therapeutic drug monitoring (TDM) or no TDM. Blood levels of the most potent agent in their regimen, either a protease inhibitor (PI) or a non-nucleoside reverse transcriptor (NNRTI), were measured at weeks 1, 4, 12, and 24 of the study. The primary end point was evidence of a virologic benefit at week 24, defined as an HIV RNA < 400 copies/mL.
Based on the entry resistance testing results, 230 patients were assigned a new regimen, 112 of whom were also randomized to the TDM arm. The baseline characteristics of these patients were similar between groups (mean CD4 counts ranged from 350-410 and viral loads were 3.8 log10 copies/mL for each of the groups). Independent predictors of a beneficial virologic outcome were a limited history of PI use, the use of a ritonavir-boosted PI in the new regimen, and higher Ctrough values for either PIs and NNRTIs. A negative predictor was poor adherence; of those whose mean Ctrough values in the lowest 25th quartile, 64% had poor adherence.
No statistically significant difference in 24-week outcomes was observed in patients randomized to either the genotype vs virtual phenotype arms, or in those randomized to TDM vs. no TDM. There was a trend towards a possible benefit of TDM at week 4 (57% virologic response for controls vs 64% virologic response for TDM) and week 12 (64% controls vs 74% TDM); however, these differences were not statistically significant.
Interestingly, although recommendations based on the results of TDM frequently advocated increased drug dosing, many physicians and patients chose to instead increase drug exposure by attempting to improve adherence—obviously not very successfully. Many patients simply refused to increase their drug dosing, despite the recommendations. In addition, the use of boosted PI-containing regimens was so successful that it may have minimized the value of resistance testing to drug selection. This study once again demonstrates that if a significant percentage of HIV+ patients have problems with adherence to antiretroviral therapies, the benefits of sophisticated monitoring techniques and resistance assays at improving outcomes are lost.
The Advisory Committee on Immunization Practices (ACIP) has recommended that the new acellular pertussis vaccine be routinely administered to all 11 and 12-year-olds as part of routine preventative care.You have reached your article limit for the month. Subscribe now to access this article plus other member-only content.
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