Greek Doctors Battle Hospital Superbug as Crisis Depletes Budget

Greek doctors are fighting a new invisible foe every day at their hospitals: a pneumonia-causing superbug that most existing antibiotics can’t kill.

The culprit is spreading through health centers already weighed down by a shortage of nurses. The hospital-acquired germ killed as many as half of people with blood cancers infected at Laiko General Hospital, a 500-bed facility in central Athens.

The drug-resistant K. pneumoniae bacteria have a genetic mutation that allows them to evade such powerful drugs as AstraZeneca Plc’s Merrem and Johnson & Johnson’s Doribax. A 2010 survey found 49 percent of K. pneumoniae samples in Greece aren’t killed by the antibiotics of last resort, known as carbapenems, according to the European Antimicrobial Resistance Surveillance Network. Many doctors have even tried colistin, a 50-year-old drug so potent that it can damage kidneys.

“We’re not used to seeing people die of an untreatable infection,” said John Rex, vice president for clinical infection at London-based AstraZeneca, which is developing a new generation of antibiotics. “That’s like something in a novel of 200 years ago.”

The superbug is one among many challenges facing the home of the Hippocratic oath, to "do no harm.” The government, confronting a 14.5 billion-euro ($19.3 billion) bond payment on March 20, is trying to arrange financing to avert a collapse of the economy. Partly as a result, the health system is in crisis, with some life-saving drugs in short supply and hospitals struggling to pay their bills.

Nurse Ratio

Greece has the lowest nurse-to-patient ratio in Europe and one of the highest rates of antibiotic use -- and abuse -- on the continent, hindering the attack on the infection.

George Daikos, an associate professor of medicine at Laiko General, won one battle last year in the ward for people with leukemia and other blood disorders by separating people carrying the bacteria from uninfected patients and forcing busy nurses to wash their hands more often. Fighting the infection in the rest of the hospital, where one nurse cares for as many as 20 patients, casts Daikos as Sisyphus, the mythological king doomed to roll a boulder up hill, only to watch it tumble down again, over and over for eternity.

“We know what to do, but if you don’t have the personnel, you can’t do it,” Daikos said in an interview in his office, deep in a side wing of the sprawling hospital. “If you don’t have enough nurses, how can I assign a dedicated nurse to carriers?”

Spreading Superbug

The superbug, dubbed KPC, first appeared in Greece in 2007 after spreading through the U.S. and then Israel. By 2010, Austria, Cyprus, Hungary and Italy were also experiencing an increase in cases, the European Centre for Disease Prevention and Control said in a surveillance report in December.

In the worst outbreaks, as many as half of the people who develop a blood infection due to KPC are killed, doctors in Toronto said in a review article in the journal of the Canadian Medical Association last year.

While Greece is striving to curb KPC, the country faces fewer problems with multi-drug resistant, so-called Gram-positive bacteria such as methicillin-resistant Staphylococcus aureus, the superbug better known as MRSA, than do other nations, said Spyros Pournaras, an associate professor of medical microbiology at the University Hospital of Larissa. Pournaras helped write the Oxford Journals article that identified KPC’s first sweep of a Greek hospital in 2007.

‘Not a Threat’

“We have problems,” he said in an interview in Athens. “But let’s not generalize that we’re a threat for Europe.” Greece also doesn’t have so-called Gram-negative bacteria with gene mutations known as NDM, IMP and OXA-48, which are common elsewhere, Pournaras said.

Even so, Greece has a bigger dilemma than do other countries because its doctors over-prescribed antibiotics, said George Dimopoulos, an associate professor of intensive care medicine at Attikon University Hospital in Athens. Greeks used more antibiotics than residents of any other European country, according to a 2009 survey by the European Surveillance of Antimicrobial Consumption. Antibiotic use outside hospitals was more than twice the median.

Another issue is the lack of nurses, Dimopoulos said. For example, an overworked nurse might change a catheter or a wound dressing without washing her hands, he said -- a prime opportunity for bacteria to hop from one patient to another.

He held up his hands. “This is number one,” Dimopoulos said, for transmission of the bacteria. “This and the stethoscope.”

Blood Poisoning

Once a patient is infected, the bacteria can attack almost anywhere in the body, damaging the lungs and urinary tract or poisoning the blood. Patients whose immune systems are weakened by chemotherapy or who are already critically ill are the most vulnerable, Dimopoulos said. The bugs can kill via a lung infection, with patients coughing up a bloody mucus, or in the most severe cases by causing sepsis and shutting down organs one by one.

“The bacteria are more clever than the human beings,” Dimopoulos said in an interview in his office in December, a few steps from where three KPC-infected patients were being isolated from other people at the hospital.

A team from the Hellenic Center for Disease Control and Prevention is organizing hospital visits to push clinics to separate infected and uninfected patients and implement hygiene measures like hand-washing, the Greek health surveillance agency, which goes by the acronym Keelpno, said in an e-mailed response to questions. The program doesn’t include funding for hospitals to hire more nurses or other personnel, the agency said.

25,000 Deaths

Keelpno didn’t provide specific numbers on resistance. Multi-drug resistant infections are more common in very sick patients in intensive care than in regular hospital wards, the agency said. About 25,000 people die each year across Europe from antibiotic-resistant infections, the agency said.

Greece has little extra money to fight the germ or to buy expensive new antibiotics. Greek hospitals ran up so many unpaid bills from 2007 to 2009 that the government agreed in 2010 to issue more than 5 billion euros of non-interest paying bonds to hospital suppliers to cover the debts.

People hospitalized or treated in Greece and then transferred to other European countries pose a risk for introducing resistant germs, the ECDC said in a November 2011 report. Studies of cross-border transmission show patients arriving in a European country with a carbapenem-resistant infection are almost four times more likely to have just been in Greece than any anywhere else.

Health-Care Bugs

“These are bacteria that are not commonly found in the community; these are health-care bugs,” said Alex Kallen, a medical officer for the U.S. Centers for Disease Control and Prevention, in a telephone interview. “For people admitted to the hospital, this is a huge issue. They tend to circulate in hospitals and long-term care facilities and places like that. The problem you have is that once you get an infection with one of these, the mortality rates are much higher, and you’re also severely limiting your treatment options.”

The more infected patients are housed together and the fewer nurses there are to treat them, the more easily such bugs can spread, Kallen said.

“If you’re on a ward with five other patients who have this, your risk is higher for developing infection regardless of how healthy you are,” he said.

Double-Wrapped Germs

KPC is part of the so-called Gram-negative group of bacteria, which also includes E. coli and Pseudomonas. Companies developing new antibiotics so far have focused more on Gram-positive bacteria such as MRSA.

Gram-negative bugs are more sophisticated organisms, easily able to acquire and pass resistance between each other, AstraZeneca’s Rex said. They are also tougher, he said.

“Have you ever gotten a Christmas present where you get a wrapped box and inside there’s another wrapped box?” he said. “The Gram-negatives are like that. They’re double-wrapped, whereas the Gram-positives are only single-wrapped. Each one of those wraps is a layer of defense for the organism.”

AstraZeneca is among the drugmakers taking the fight to Gram-negatives. Working with Forest Laboratories Inc. of New York, the company is in the final stage of clinical trials in an antibiotic called CAZ-AVI. Greece is among the places where it’s being tested in humans. AstraZeneca aims to have approval to sell the drug by 2014, Rex said.

Glaxo, Cubist

Fellow U.K. drugmaker GlaxoSmithKline Plc said it’s also testing a candidate in humans, including in Greece, though it’s not as far along. Cubist Pharmaceuticals Inc., a U.S. biotechnology company, is testing antibiotics that may work against KPCs in the lab, though not yet in humans, Chief Scientific Officer Steven Gilman said in a telephone interview.

A new crop of drugs “could buy us another decade” of effective treatment, said Karen Bush, an adjunct professor of biology at Indiana University in Bloomington and former head of antimicrobial drug discovery research at Johnson & Johnson. Bush’s lab analyzes changes in bacteria that allow them to resist drug treatment. “I’m hoping it will be more than that.”

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