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Limited options left to treat N. gonorrhoeae
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In August, the CDC issued new treatment guidelines for Neisseria gonorrhoeae, based on evidence that resistance to cefixime, an oral cephalosporin, was emerging. Patients who test positive for gonorrhea are now to be treated with a combination of drugs: ceftriaxone, an injectable cephalosporin, and either azithromycin or doxycycline.
After ceftriaxone, however, there are no highly effective and well-studied options for this infection, which was once able to be treated with just an oral drug. Because resistance to ceftriaxone is almost inevitable, based on the history of N. gonorrhoeae, there is a call by public health officials worldwide to scale-up research for new treatment options for this common STD.
“There have been increasing reports of resistance to oral cephalosporins, which were the mainstay of treatment for several years,” Robert Kirkcaldy, MD, MPH, medical epidemiologist in CDC’s Division of STD Prevention, told Infectious Disease News. “We have seen this bug do this before so it’s not entirely unexpected, but it’s still alarming because we have so few drugs available. Our prevention and control efforts really rely on effective treatments for gonorrhea.”
Kimberly Workowski, MD, said the percentage of isolates with elevated MICs for oral cephalosporins is increasing in the US.
Photo courtesy of Workowski K
The CDC estimates that more than 700,000 people in the United States develop new gonorrhea infections each year. In 2010, data from the Gonococcal Isolate Surveillance Program (GISP) showed that 27.2% of the isolates collected were resistant to penicillin, tetracycline and ciprofloxacin.
Infectious Disease News discussed the emergence of drug-resistant N. gonorrhoeae with several experts to find out how this emerging resistance is going to affect patients and what must be done to make sure that gonorrhea remains a treatable disease.
History of resistance
Gonorrhea treatment resistance has a long history, dating back to when antibiotics were first used to treat gonorrhea. According to Khalil Ghanem, MD, PhD, associate professor of medicine at Johns Hopkins University School of Medicine and director of HIV, STD and TB Clinical Services for Baltimore City Health Department, the first antimicrobial used to treat gonorrhea was a sulfa drug, to which gonorrhea developed resistance very quickly.
When penicillin came along, it was introduced on a large scale for gonorrhea treatment in the late 1940s. Within a few years, a penicillin-resistant strain of gonorrhea was evident. However, penicillin was the treatment of choice for several decades, Ghanem said. To overcome the resistance, which was slowly developing, penicillin was prescribed in higher doses. However, by the early 1980s, penicillin could no longer be used to treat gonorrhea.
“At that point, we had fluoroquinolones available, so we could still give a pill and treat the gonorrhea,” Ghanem said in an interview. “Within a few years, the first strain of fluoroquinolone-resistant gonorrhea had manifested, and by 2007, the CDC changed the treatment recommendations for gonorrhea from oral fluoroquinolones to oral cephalosporins.”
According to Ghanem, the first case of cephalosporin-resistant gonorrhea was detected as early as 1982, but because fluoroquinolones were the mainstay of treatment, it wasn’t a problem at the time. Now, after being the CDC-recommended treatment for 5 years, resistance to cephalosporins has emerged throughout the world. Injectable cephalosporins are the last remaining drugs, which are reliably effective at treating gonorrhea, but resistance has been documented.
Patterns of resistance
Resistance to antimicrobials is determined by monitoring changes in the minimum inhibitory concentrations of an antimicrobial. According to Kimberly Workowski, MD, professor of medicine at Emory University, the percentage of isolates with elevated MICs for oral cephalosporins has been increasing slowly in the United States, from 0.7% in 2009 to 13% in 2011.
“The increases in MICs for cephalosporins may seem small, but on a bigger scale, it is likely to increase in the future,” Workowski said in an interview. “Because this increase was first in Southeast Asia, CDC recommended combination therapy with ceftriaxone and either azithromycin or doxycycline.”
Khalil Ghanem
Patterns of resistance are detected through GISP, a CDC national sentinel surveillance system, which was established in 1986. GISP is a collaborative project between sentinel sites STD clinics selected throughout the country, five regional laboratories. Each month, N. gonorrhea isolates are collected from the first 25 men who present with gonorrhea to STD clinics throughout the country. The laboratories perform antimicrobial susceptibility testing on the isolates and determine the MICs.
In the United States, there has been no resistance observed to ceftriaxone. But there have been reports of clinical failure to the drug in Japan, according to Susan Philip, MD, MPH, director of STD prevention and control services at the San Francisco Department of Public Health.
“We know from historical trends that resistance to different classes of antibiotics is typically identified initially in Japan and then in other Pacific countries,” Philip said in an interview. “In the United States, drug resistance is usually first identified in Hawaii and then on the West coast, so here in San Francisco, we’re especially concerned. It’s worrisome because there are no other classes of drugs left to treat N. gonorrhoeae after cephalosporins and we already have seen resistance to the oral cephalosporins.”
Drug-resistant N. gonorrhoeae is most prevalent on the West Coast and also among men who have sex with men. Ghanem said that the MICs tend to be higher in both of these populations and that the same phenomenon happened when fluoroquinolone-resistance emerged.
Patient concerns
The current treatment recommendation is 250 mg ceftriaxone given intramuscularly, combined with either a 1-g single oral dose of azithromycin or a 100-mg dose of doxycycline given twice-daily for 7 days. According to the CDC, azithromycin is the preferred second agent because of the convenience and compliance advantage with single-dose therapy and because of the higher prevalence of resistance to tetracyclines. Those with an allergy to cephalosporins should receive a 2-g single dose of azithromycin and return within 7 days for a test of cure.
“The test of cure should be considered for patients who receive any treatment other than the combination treatment of ceftriaxone plus azithromycin or doxycycline,” Ghanem said. “Having to bring a patient back for this test is a huge strain on public health clinics, so everyone tries to use the recommended first-line treatment to prevent this.”
The recommendation for an injectable drug as first-line therapy poses problems for expedited partner therapy (EPT), a practice in which physicians treating patients with gonorrhea or chlamydia can also provide the patient with prescriptions for treatment for their sexual partners, without them coming in for exams.
Not all states allow EPT. But for those that do, the preferred regimen is cefixime in combination with azithromycin, Kirkcaldy said. However, because these patients are not receiving the optimal therapy, they are urged to present to a physician’s office for a test of cure after completing treatment.
“Under the current treatment guidelines, every effort should be made to ensure that a patient’s sex partners from the past 60 days are evaluated and treated with the recommended regimen,” Kirkcaldy said. “However, that may not always be possible, so providers can still consider the oral regimen for EPT for heterosexual partners who cannot be linked to evaluation and treatment in a timely manner.”
From a public health standpoint, EPT is recommended, Philip said. But with the treatment guidelines, there is concern about whether this practice should continue, since continued use of the oral therapy may contribute to the development of additional resistance, she said.
Use of culture
Of the approximately 320,000 new gonorrhea infections that occur in the United States yearly, only about 5% of them are evaluated as part of the GISP network. Patients that are part of this network have specimens that are cultured and tested for antimicrobial susceptibility.
In regular practice, however, patients do not provide cultures for this testing.
“One of the quandaries we have is that over the years, we’ve moved away from culture as the diagnostic method and onto nucleic acid amplification tests,” Philip said. “They are excellent tests that are much more sensitive than culture. But we do not yet have the ability to do antimicrobial susceptibility testing on those specimens. Culture use is waning, except for those patients in GIST.”
Patients with a positive gonorrhea test by nucleic acid amplification test are treated with ceftriaxone and need no further evaluation. If patients are treated with any other regimen, they should return in 7 days for a test-of-cure. But if a patient’s symptoms do not resolve, and there is concern about treatment failure, the physician should notify the local health department and obtain a culture, Philip said.
However, it is not that simple, Workowski said, since most physicians and regional laboratories no longer have the capability to perform culture in their offices. Even for those that use off-site laboratories, these specimens cannot be transported easily.
“If someone fails the recommended treatment, you should perform culture at the relevant site and perform susceptibility testing,” Workowski said. “But when providers don’t have the capacity to perform culture, they need to identify labs that have retained the ability to do culture.”
There is research under way to establish molecular methods to detect resistance that do not require culture, Workowski said. There are limited data on the specific mutations that are associated with resistance, however, there may be different mutations that can be associated with resistance.
Prevention and control
Besides to surveillance programs, providers also must be about prevention and screening recommendations.
According to Workowski, effective antimicrobial treatment is the foundation of a gonorrhea prevention program. Surveillance programs for antimicrobial resistance are crucial to make sure that treatment remains effective.
In study results published in the Annals of Internal Medicine, Workowski said there must be international collaboration to monitor resistance, and geographic information systems must be expanded to monitor infections. In addition, risk factors for antimicrobial resistance must be evaluated.
Primary screening the populations at highest risk for infection is another component of gonorrhea control. The US Preventive Services Task Force recommends that all sexually active women at increased risk be screened. In addition, CDC recommends MSM to be screened for gonorrhea and other STDs. Secondary screening, by retesting patients 3 to 4 months after treatment and evaluating and treating partners is also a critical component to gonorrhea prevention and control.
Robert Kirkcaldy
“Many patients that are asymptomatic and need to be aware of their risk,” Workowski said. “Providers should be aware of the screening criteria, and make sure that partners of patients with gonorrhea are evaluated and treated.”
After ceftriaxone
For now, ceftriaxone with azithromycin is an effective combination treatment for gonorrhea. Yet, with the development of resistance to oral cephalosporins, and a history of resistance developing to every other available antimicrobial class, the hunt for new treatment options is a top priority.
“From a business model perspective, this is a challenging thing to do because the economics of antimicrobial development are not always favorable to developing new ones,” Kirkcaldy said. “That said, there are several drug companies that are still committed to it and investing in it. We need to continue to highlight this emerging threat of antimicrobial resistance and continue to encourage drug companies to invest in this critical area.”
Within the Prescription Drug User Fee Act, which was renewed by Congress in 2012, the Generating Antibiotic Incentives Now (GAIN) Act incentivizes pharmaceutical companies to research and develop new antimicrobial drugs for the treatment of infectious diseases.
At this time, it is not clear what other treatment options physicians can turn to. According to Ghanem, there are some treatments available, but they are not simple. For example, gentamicin has shown some efficacy against gonorrhea, he said, but it is an injectable agent that is associated with kidney toxicity and ototoxicity. Another option is carbapenams, but with a single dose ranging from $40 to $60, compared with the less than $5 for a dose ceftriaxone, this option would pose a huge burden on public health clinics, Ghanem said.
“When we lose cephalosporins, there are other options available, but none of those options are ideal,” Ghanem said. “When we lose cephalosporins, which will only be in a matter of time, we will be in a difficult situation.”
According to Kirkcaldy, there is a study being funded by the National Institutes of Allergy and Infectious Diseases that recently completed enrollment, in which combinations of antibiotics currently available in the United States are being evaluated. In addition, there is a phase 2 study of a new drug ongoing, but, if the results are favorable, larger, phase 3 studies will still need to be conducted.
“We are calling on our researchers and pharmaceutical companies to jumpstart research to identify new drugs or evaluate currently existing drugs,” Kirkcaldy said. “Before the crisis emerges, now is the time to prevent untreatable gonorrhea from becoming a reality.” — by Emily Shafer
References:
CDC. MMWR. 2012;61:590-594.
Workowski K. Ann Intern Med. 2008;148:606-613
For more information:
Robert Kirkcaldy, MD, MPH, can be reached at cdcinfo@cdc.gov.
Susan Philip, MD, can be reached at: STD Prevention and Control Services, San Francisco Department of Public Health, 1360 Mission Street, Suite 401, San Francisco CA, 94103. Email: susan.philip@sfdph.org
Kimberly Workowski, MD, can be reached at: Division of Infectious Diseases, Emory
University, 550 Peachtree St., Suite 7000, Atlanta, GA, 30308. Email: kworkow@emory.edu
Disclosure: Ghanem, Kirkcaldy, Philip and Workowski report no relevant financial disclosures.
Perspective
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Robert Nicholas, PhD
One of the big issues in gonorrhea worldwide is monitoring resistance. Many clinical labs are moving away from doing MIC testing because it is expensive and so and are doing a lot of PCR testing because it is cheap and fast. The problem is that the latter approach does not give any indication of resistance trends. In the United States, gonorrhea resistance is monitored through GISP, in which they perform MIC testing on a certain percentage of isolates from patients in larger cities. But in areas that are resource-poor, where gonorrhea rates are actually fairly high, monitoring is poor and thus antibiotic treatment may not be optimal, which can promote the emergence and spread of resistant strains. We’re trying to identify all of the mutations that are involved in resistance. This knowledge can eventually be used for gene sequencing and PCR to detect these mutations, which will allow better tracking and epidemiology of resistant strains.
My research focuses on beta-lactam resistance, which includes penicillin and cephalosporins. For many years, penicillin was the drug of choice for gonorrhea, but resistance made it obsolete. Ceftriaxone is now the only drug recommended to treat gonorrhea in the United States. My research started with studying penicillin resistance and is now focused on cephalosporin resistance. The biggest issue that we have now is the emergence of ceftriaxone-resistant strains that have appeared, not in the United States, but in Japan, France and Spain. Cephalosporin resistance has built upon the foundation developed by penicillin-resistant strains: these strains have the mutations that are associated with resistance to penicillin, but they acquire a new version of one of the penicillin-resistance determinants, penA. This new penA allele is very different from the penA alleles associated with penicillin resistance. Combined with other determinants found in penicillin-resistant isolates, this new penA allele makes the strain untreatable with ceftriaxone.
Chromosomally-mediated beta-lactam resistance in gonorrhea occurs through mutations in five different loci: penA, mtrR, penB, ponA and a fifth one, which we know very little about. These endogenous genes all contain mutations that give rise to resistance. penA encodes a penicillin-binding protein involved in cell wall synthesis during cell division in gonococci. Penicillin and ceftriaxone bind irreversibly to this protein and inactivate it. The penA alleles associated with penicillin and ceftriaxone resistance have acquired mutations that are major contributors to resistance. The mtrR determinant is usually a mutation within the promoter region for the MtrCDE efflux pump. This is a protein that pumps out hydrophobic compounds and antibiotics from both within the cell and the periplasm. The mtrR mutation causes a 10-fold increase in the expression of the efflux pump, which confers a significant increase in resistance not only to penicillin, cephalosporins and macrolides, but also to many other drugs used to treat gonococcal infections. penB is a mutation in the outer membrane porin that decreases the diffusion of antibiotic into the cell. ponA is a penicillin-resistance determinant that is involved in penicillin resistance, but doesn’t seem to be much involved in ceftriaxone-resistance. Lastly, the fifth determinant, which we don’t yet know much about, causes a five-fold increase in resistance to penicillin, ceftriaxone and other bactericidal antibiotics. These genes work in concert: Alone, they generally have small (two- to six-fold) effects on resistance, but all together, they can increase resistance from 400-fold up to 3,000-fold. Although penA and ponA are specific for beta-lactam resistance, mtrR and penB are involved in resistance to a wide range of antibiotics, including beta-lactams, and provide a non-specific barrier to any new antibiotics that might be used to treat gonorrhea.
penA is the focus of the resistance story right now. In the early 2000s, strains from Japan began to emerge that were much more resistant to oral cephalosporins than previous strains. These strains had most of the resistance determinants discussed above, but the major difference is that they harbored penA genes that were highly mosaic, meaning they contained DNA from several Neisseria species. If you look at the protein encoded by a mosaic penA allele from a cephalosporin-resistant strain, it might have up to 70 mutations compared to a wild-type strain, although not all of those mutations contribute to resistance. My group is working to identify the amino acids that, when mutated, are responsible for increasing resistance. So far, we have published the structure of the protein encoded by penA and we’ve been able to identify a set of mutations that are responsible for about 80% of the resistance conferred by resistant alleles. The mutations have very subtle effects on the proteins, since these mutations must remodel the active site of the protein to exclude the substrate analogs without causing a loss of its normal activity, but these changes are very effective at increasing resistance. In one of the new cephalosporin-resistant strains, if you take its penA gene and put it into a wildtype strain, you will see up to a 300-fold increase in MIC for ceftriaxone, just with this one gene. If you combine that with mtrR, penB, ponA and the fifth factor, you get a 3,000-fold increase in the MIC of ceftriaxone. We’re trying to understand how that works.
Perspective
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William Shafer, PhD
My group studies the genetics and molecular biology of antibiotic resistance. Specifically, we study the genetic regulation of the MTR drug efflux pump, which exports antimicrobials. The overexpression of the pump seems to be absolutely essential for high-level resistance to beta-lactam antibiotics like penicillins and cephalosporins. We know that if we genetically inactivate the pump, a penicillin-resistant strain will become sensitive to penicillin. The way we detect whether a strain is overproducing the pump is by testing the susceptibility of strains to various antimicrobials. But that’s not routinely done by clinical labs, which use molecular diagnostics that simply identify the presence of gonorrhea, and do not determine the antimicrobial susceptibility of the gonococcus. We are performing whole genome sequencing on gonococcal strains that have been provided to us from Canada, Europe and the Atlanta GISP program. If we’re not going to go back to performing cultures to conduct antimicrobial susceptibility testing, then we have to have some way to determine what strains are sensitive and what strains are resistant to specific treatments. If we know what mutations and genes confer resistance, we can predict whether a strain is going to be sensitive.
Strains of gonorrhea found on the West coast are showing a trend of decreased susceptibility to cefixime. This is particularly true for those isolated from the MSM population. We are seeing the same trends that we saw in the 1950s with penicillin. There is initially a very low percentage of strains that show decreased susceptibility to a drug and then we see full-blown resistance. When we look at the data out of the Atlanta GISP program, most strains are still sensitive to antibiotics like penicillin, ciprofloxacin and tetracyclines. However, the treatment regimens for the East coast are being driven by West coast data, where the prevalence of strains that are less-susceptible to cefixime is higher. If we start to see cefixime or ceftriaxone resistance, and if we don’t develop new antibiotics, we’re going to have to rely on being able to identify other antibiotics that the strain may be sensitive to. For instance, a strain may be resistant to ceftriaxone, but sensitive to ciprofloxacin or a tetracycline. In the first case of cefixime resistance identified in Japan, spectinomycin was successfully used to treat the patient. However, this drug is not readily available throughout the world. We’re going to have to be a little bit more innovative to find ways to treat patients with cefixime-resistance, and this includes determining whether the strain is susceptible to antibiotics that already exist.
Right now, we don’t have the technology to do whole genome sequencing with urine samples that patients provide for gonorrhea testing. We are only able to perform this procedure on the cultures that we receive, where we grow the gonococcus and extract the DNA. What we would like to do in the future is to be able to obtain enough DNA from a urine sample to perform sequencing. Once we know what mutations that we are looking for, we can design primers to amplify specific regions and sequence those. We’re not yet at the point. For now, culturing is only advised when a patient fails therapy. Clinical microbiologists would have to retool their laboratories to do routine drug-susceptibility testing. This would be a significant economic concern so I don’t envision us going back to routine culturing. Our ultimate goal is to be able to look for specific regions in the genome where there are resistance determinants. Right now, we know the specific region for overexpression of the MTR drug efflux pump and we can determine that quickly from PCR sequencing. We can also determine quickly if it has the mosaic penA gene. We know these two genetic changes are important for resistance to ceftriaxone, so being able to identify those changes easily and rapidly without culture is a significant goal.
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