Six years after a federal government warning that lifesaving antibiotics were losing their punch, an update Wednesday revealed that the problem of antibiotic-resistant infections is by some measures getting worse.

Across the nation, more than 2.8 million people become infected with drug-resistant bacteria and fungi each year, and at least 35,900 die as a result, the U.S. Centers for Disease Control and Prevention said.

An additional 12,800 deaths annually were attributed to bacteria called Clostridium difficile. These infections typically are not resistant to antibiotics, but are associated with their overuse for other conditions.

The original 2013 report estimated the annual death total at 23,000, though the agency says that number was a significant underestimate and the actual number of deaths likely has declined, in part due to hospital efforts to use the drugs more judiciously.

Yet the overall number of infections appears to be on the rise. And outside the hospital setting, the impacts from certain infections have grown worse, agency officials said.

For example, more than a half-million drug-resistant gonorrhea infections occur each year, double the number reported in 2013. Half of all such infections are resistant to at least one antibiotic. Gonorrhea infections can contribute to infertility in women, and raise the risk of HIV infections, especially in men.

“Antibiotic resistance remains a significant enemy,” CDC Director Robert R. Redfield said in a conference call with reporters. “We must remain vigilant.”

Hospitals have tackled the problem by prescribing fewer antibiotics, avoiding them in cases where there is no clear benefit. Better hospital hygiene protocols and vaccines also have helped.

Research to develop new drugs is needed, as no new class of antibiotics has been developed in decades, agency officials said. Instead, drugmakers have tweaked existing medicines.

CDC officials said patients can help by steering clear of antibiotics when not needed. (Physicians have been known to succumb to the pleas of patients with flu-like symptoms and other respiratory ailments, even though antibiotics do nothing to combat the flu.)

Bacteria can develop resistance even when antibiotics are used appropriately. Every time such a drug is used, a handful of the target bacteria may survive by employing some sort of natural defense mechanism, such as flushing out the drugs through channels in their cell walls.

These resisters can reproduce and multiply. What’s more, their successful recipes for fighting the drugs are encoded in their DNA and can be shared with other microbial species.

The CDC did not provide state-level data. But roughly 300 drug-resistant infections were reported by Philadelphia hospitals in 2018, said Kristin Privette, surveillance coordinator for the city Department of Public Health.

Philadelphia’s is one of six large city health departments tasked by the CDC to track drug-resistant infections in local hospitals, and help arrange for sophisticated laboratory testing where needed, said Steve Alles, the department’s director of disease control.

A separate Inquirer analysis of billing data from the Pennsylvania Health Care Cost Containment Council indicates that drug-resistant infections have gained a foothold throughout the region.

In 2017 and 2018, hospitals in Philadelphia and its four suburban Pennsylvania counties reported that 866 patients had infections that were resistant to multiple antibiotics, and 12 of the patients died, the data show. Nearly all of the infections were said to have occurred before the patients arrived.

The true number may be higher. The state figures come from billing data, and in many cases insurers have not allowed hospitals to seek additional reimbursement for treating infections that resist multiple types of drugs.

While older people can be more susceptible to drug-resistant infections, these deadly bugs can strike patients of any age. One in seven of the 866 Philadelphia-area infections occurred in people under 40, including children and newborns.

Specialists in antibiotic policy said the CDC report represented a welcome call for renewed vigilance.

Kathy Talkington, director of the Antibiotic Resistance Project at the nonprofit Pew Charitable Trusts, agreed that hospital efforts seem to be keeping the problem in check. But the apparent increase in out-of-hospital infections is cause for concern.

“We have to continue keeping our foot on the gas," she said.

Pediatrician David Hyun, also a member of Pew’s antibiotic resistance team, said physicians can use better strategies to dissuade patients from unnecessary antibiotics.

“Research has shown that sometimes what the patient really wants is not the antibiotic itself, but some form of plan that reassures the patient that the doctor or clinic is going to follow through and help them with the illness,” Hyun said.

Antibiotics carry risks in addition to fostering drug resistance and clearing the way for C. difficile. By killing “good” bacteria as well as the ones causing an infection, they can disrupt a person’s microbiome to result in diarrhea or a yeast infection.

And certain stronger antibiotics can be toxic, raising the risk of liver and nerve damage, aortic rupture, or seizures.

The agency listed 18 drug-resistant microbes of particular concern, of which five were deemed to be urgent. Two of those five were new additions since the 2013 report: a type of yeast called Candida auris and a bacterium called Acinetobacter that is resistant to powerful antibiotics called carbapenems.