Hundreds of cases spanning three states and a territory have been reported amid fears the highly contagious infection has claimed a life in an outback community.
Almost all the cases have involved Indigenous Australians, prompting health authorities to work with Aboriginal agencies to try to curb the outbreak, including provision of vaccines.
Diphtheria was a feared childhood disease and common cause of death in children until the 1940s, when vaccines were rolled out.
Immunisation expert Milena Dalton said the outbreak highlighted how quickly vaccine-preventable diseases could re-emerge when there were immunity gaps.
"Although diphtheria remains rare in Australia this outbreak shows it hasn't disappeared," she told AAP.
"Vaccination has made it more uncommon, but protection needs to be maintained."
The National Notifiable Disease Surveillance System reports 133 notifications of the disease in the Northern Territory since the outbreak began in March.
It has since spread to Western Australia where 79 cases have been reported plus another six in South Australia and up to five in Queensland.
NT health authorities are also awaiting results from an autopsy about a possible diphtheria-related death in a remote territory community.
Federal Health Minister Mark Butler described it as the biggest diphtheria outbreak in Australia for decades.
"There's no question this is serious," he told ABC Radio on Tuesday.
A response to the outbreak needed to be in partnership with Aboriginal community-controlled health services and local leaders, Dr Dalton said.
The outbreak required governments to support rapid vaccination, booster delivery, testing, treatment and contact tracing, the expert from Melbourne's Burnet Institute said.
"We do have the tools to stop it spreading further so we really need to ensure that those tools reach the communities that need them most," she said.
NT Health said it was working with community organisations to undertake a territory-wide vaccination program, focusing on vulnerable people and at-risk areas.
"Vaccination remains the most important measure for preventing, protecting and reducing transmission," it said in a statement.
Vaccination is free under a national program for children aged six weeks to two months, four months, six months, 18 months, four years and 12 years.
Pregnant women from 20 weeks are also eligible and adults are encouraged to get a booster vaccine every 10 years.
Diphtheria can easily spread person to person through inhalation of respiratory droplets when an infected person coughs or sneezes.
Respiratory diphtheria symptoms can include a sore throat, mild fever, loss of appetite and in severe cases, trouble breathing, in some cases leading to death if untreated.
The less harmful strain of the disease is cutaneous diphtheria, spread by direct skin contact on lesions of infected people, with symptoms including sores or ulcers and slow-healing wounds.
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