Methicillin-resistant Staphylococcus aureus

• 1. Introduction

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  Methicillin-resistant Staphylococcus aureus, or MRSA, was linked to more than 100,000 deaths worldwide in 2019 that were attributable to antimicrobial resistance. Yet the bacterium behind it is an everyday neighbor. Ordinary Staphylococcus aureus lives in the upper airway, on the skin and along the lining of the gut. Like similar species that can live in symbiosis, it can cause disease when it takes over the tissues it has colonized or invades new ones. That lifestyle has earned it the label pathobiont.

  MRSA is a group of strains that have learned to survive the β-lactam antibiotics. This broad drug class includes methicillin, oxacillin and the cephalosporins. Strains that still fall to those drugs are called methicillin-susceptible S. aureus, or MSSA.

  This documentary asks how a familiar microbe acquired such armor. It asks why a menace that began in hospitals now turns up in schools, on farms and in locker rooms. And it asks what still works against it.

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• 2. The Resistance Gene

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  The gene mecA is the biomarker that defines MRSA. Penicillin-like antibiotics normally stop bacterial growth by blocking the enzymes, called transpeptidases, that build the cell wall. The mecA gene encodes a substitute protein named penicillin-binding protein 2a, or PBP2a. Its active site does not bind methicillin or other β-lactams, so it keeps cross-linking the wall's peptidoglycan even while the drug is present. Because PBP2a ignores the whole class, acquiring mecA brings resistance to almost every β-lactam, not only methicillin.

  Plasmids, transposable elements and genomic islands are the extrachromosomal packages that carry resistance genes of this kind. Bacteria pass them to one another by horizontal gene transfer. Once mecA arrives, it must also be integrated and localized in the S. aureus chromosome.

  Two regulatory genes, mecI and mecR1, control mecA. MecI usually sits on the mecA promoter and acts as a repressor. When a β-lactam appears, MecR1 starts a signaling cascade that cleaves MecI and lifts the repression.

  Two co-repressors, blaI and blaR1, add a second layer. They resemble mecI and mecR1 and normally regulate blaZ, the gene behind penicillin resistance. The DNA sequences bound by mecI and blaI are identical, so blaI can also sit on the mecA operator and silence it.

  The gene does not float free inside the cell. It travels inside a larger genetic island, and that island has a name.

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• 3. A Mobile Cassette

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  Staphylococcal cassette chromosome mec, or SCCmec, is the genomic island that carries mecA. Its origin is unknown, though it is thought to have come from a close relative, Mammaliicoccus sciuri, and moved horizontally into S. aureus. The cassette holds more than the resistance gene. Its ccrA and ccrB genes encode recombinases that cut the element out of the S. aureus chromosome and splice it back in. Its psm-mec gene encodes a cytolysin that may suppress virulence in hospital strains. The locus also produces strain-dependent regulatory RNAs called psm-mecRNA.

  Six SCCmec types, numbered I to VI, have been identified. They range from 21 to 67 kb and differ in their mec and ccr gene complexes. Given the cassette's size and the limits of horizontal transfer, researchers think at least five clones drove the spread of MRSA. Clonal complex 8 is the most prevalent.

  Types I to III are large, usually carry extra resistance genes, and are typically isolated from hospital strains. Types IV and V are smaller and carry no resistance genes besides mecA. They go with community strains.

  Work by Collins and colleagues in 2001 explained the split through fitness. Carrying a large element is costly, and the bacterium compensates by expressing less virulence. In a hospital that trade works, because hospital strains target hosts who are already immunocompromised. Community strains must infect healthy people. They carry cheaper elements that leave virulence and toxin production high.

  The arginine catabolic mobile element, or ACME, is common in MRSA but not in MSSA. Its SpeG-positive form lets S. aureus tolerate polyamines that would otherwise harm it. That supports stable skin colonization, wound infection and spread from person to person.

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• 4. Where It Spreads

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  Catheters, open wounds and weakened immune systems made hospitals and nursing homes the first home ground of MRSA. Infection acquired there is called HA-MRSA. Its community and livestock counterparts are CA-MRSA and LA-MRSA. Surgical site infections begin on the skin surface but can reach internal organs and the blood, causing sepsis. Transmission between providers and patients can occur when hand-washing is skipped between examinations. Patients treated by a doctor generally stay infected for just under 10 days, though this varies.

  In February 2008, the Tulsa County jail in Oklahoma began treating an average of 12 S. aureus cases per month. Crowding, confinement and poor hygiene raise the risk in prisons and military barracks. Cases in these groups were reported first in the United States and later in Canada. The earliest reports came from the Centers for Disease Control and Prevention, in state prisons. Hundreds of news reports of prison outbreaks appeared between 2000 and 2008. A report on the Cook County jail in Chicago found MRSA the most common cause of skin and soft-tissue infections among inmates in 2004-05.

  Three studies by the Texas State Department of Health put the infection rate among football players at 16 times the national average. One study tied MRSA to abrasions caused by artificial turf. In October 2006, a high-school football player was temporarily paralyzed by MRSA-infected turf burns. His infection returned in January 2007 and required three surgeries to remove infected tissue and three weeks in hospital. In 2013, Lawrence Tynes, Carl Nicks and Johnthan Banks of the Tampa Bay Buccaneers were diagnosed. In 2015, Los Angeles Dodgers infielder Justin Turner was infected while the team visited the New York Mets.

  One study found that 4.6% of patients in US health-care facilities were infected or colonized, a group that presumably includes hospital nurseries. Injection drug use made up 24.1% of cases, or 1,839 individuals, in one Tennessee hospital discharge system. Unsanitary injection gives the bacteria a direct path into the bloodstream.

  In 2004, MRSA was first isolated on a Dutch pig farm. That finding started the study of livestock-associated MRSA. The strain CC398 is found in intensively reared pigs, cattle and poultry, and it can pass to humans. Animals generally show no symptoms. LA-MRSA has been observed in Korea, Brazil, Switzerland, Malaysia, India, Great Britain, Denmark and China. Antibiotic use in livestock raises the risk, so the World Health Organization advocates regulating antibiotics in animal feed.

  Dogs and cats can also carry MRSA. Owners hug and kiss their pets or let them sleep in their beds, and transmission to humans can occur. Even so, infections in humans seem to originate from HA-MRSA rather than from pet-acquired CA-MRSA. Health departments advise a visit to the veterinarian if infections keep recurring among people who touch the pet.

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• 5. Strains and Detection

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  The first MRSA strain, ST250 MRSA-1, arose when SCCmec integrated into an ST250 MSSA. Later hospital clones included ST239-MRSA-III, known as the Brazilian clone. It was highly transmissible and spread through Argentina, the Czech Republic and Portugal. In the UK, the most common strains are EMRSA15 and EMRSA16. EMRSA16 is identical to the US strain ST36:USA200. It carries SCCmec type II plus genes for enterotoxin A and toxic shock syndrome toxin 1, and it is now called MRSA252.

  Community strains emerged from the late 1990s to 2000, infecting healthy people who had never been near a healthcare facility. Genome comparisons indicate they did not evolve from hospital strains. Each acquired SCCmec on its own. By the middle of the 2000s, CA-MRSA had entered healthcare systems, and telling it apart from HA-MRSA became difficult. It is more easily treated and more virulent. The Panton-Valentine leukocidin genes are a unique feature of CA-MRSA, and researchers are still studying how it gains its virulence.

  In the United States, most CA-MRSA cases come from ST8:USA300. It carries SCCmec type IV, Panton-Valentine leukocidin, PSM-alpha and enterotoxins Q and K. It causes skin infections, necrotizing fasciitis and toxic shock syndrome. A second strain, ST1:USA400, causes necrotizing pneumonia and pulmonary sepsis. USA300 first appeared in Canada in 2004. Other regions have their own leaders. Australia sees ST93, continental Europe sees ST80, and Taiwan sees ST59, some of which resist many non-β-lactam drugs.

  Diagnosis is harder than it sounds. No quick and easy method exists, so initial treatment often rests on what physicians call "strong suspicion". Laboratories culture the bacterium from blood, urine, sputum or other body fluids. Quantitative PCR can detect MRSA quickly, and a rapid latex agglutination test looks for the PBP2a protein. PCR remains the most precise way to identify strains.

  Under the microscope, MRSA is a gram-positive sphere about 1 micron across. It forms no spores and cannot move. Cells often sit in grape-like clusters or chains. It grows more slowly than MSSA on a variety of media. The mecA gene is always present in MRSA and usually absent in MSSA, though some MSSA carry it without expressing it.

  Laboratories also grade resistance by drug concentration. If vancomycin at 4 μg/ml or less inhibits S. aureus, it is called susceptible. If more than 32 μg/ml is needed, it is called resistant.

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• 6. Search and Destroy

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  Until the mid-1990s, every hospital in the UK followed a strategy called search and destroy. All hospitalized people with MRSA were isolated immediately. All staff were screened and barred from work until they finished an eradication course proven to work. Mathematical models show how control can collapse after years of success. Colonised people are discharged into the community and later readmitted. Once their number in the community passes a threshold, the strategy is overwhelmed. The Netherlands is one of the few countries not overwhelmed by MRSA. An important part of its success may be that it tries to eradicate carriage when patients leave hospital.

  Screening rests on the fact that about 2% of people carry MRSA, often in the nostril and without symptoms. Swabbing the nostrils identifies the bacteria. Combined with extra sanitary measures for people in contact with the infected, swab screening on admission has been effective in hospitals in the United States, Denmark, Finland and the Netherlands. On the 19th of October 2006, the CDC issued guidelines that cited the need for more research and declined to recommend such screening.

  In hospitals, contact isolation can end after one to three negative cultures. Before a patient is cleared, the advice is to use dedicated or single-use patient-care equipment. Otherwise the equipment must be properly disinfected before the next patient.

  For community settings, including prisons, childcare centers and athletic teams, the CDC recommends washing hands thoroughly with soap and water or an alcohol-based sanitizer. It also recommends keeping wounds clean and covered and avoiding other people's wounds. Razors and towels should not be shared. Athletes should shower after exercise, and everyone should shower before using swimming pools or whirlpools. At home, health departments suggest laundering items that touched an infected person separately with a dilute bleach solution. They also advise disinfecting sinks, tubs, kitchen counters, light switches, doorknobs and computer keyboards.

  Fluoroquinolones in particular, along with glycopeptides and cephalosporins, raise the risk of MRSA colonisation. Current guidelines recommend cutting back on those classes.

  A 2015 Cochrane review set out to test whether gloves, gowns and masks stop MRSA spreading in hospitals. It found no eligible studies, and its authors called for randomized controlled trials.

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• 7. Counting the Toll

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  Worldwide, an estimated 2 billion people carry some form of S. aureus. Up to 53 million of them, or 2.7% of carriers, are thought to carry MRSA. S. aureus ranked among the six leading pathogens for deaths associated with resistance in 2019. In the United States, an estimated 95 million people carry it in their noses, and 2.5 million of those, or 2.6% of carriers, carry MRSA.

  In 2009, an estimated 463,017 US hospitalizations were due to MRSA, a rate of 11.74 per 1,000 hospitalizations. The CDC estimates 80,461 invasive MRSA infections and 11,285 deaths each year. In 2003, a hospitalization for MRSA cost US$92,363, compared with $52,791 for MSSA. MRSA sepsis within 30 days after a surgical infection carries a 15-38% mortality rate. Within one year the rate is around 55%.

  Researchers have debated whether the higher death rate reflects sicker patients. Studies that adjusted for underlying disease, including one by Blot and colleagues, still found higher attributable mortality for MRSA bacteremia than for MSSA bacteremia. Wyllie and colleagues reported a 30-day death rate of 34% among people with MRSA and 27% among those with MSSA.

  The first known MRSA isolates were reported in a British study in 1961. Infrequent hospital outbreaks followed in Western Europe and Australia until 1967, and methicillin was then licensed in England. By 1995 the rate had climbed to 22%. By 1997, half of hospital S. aureus infections were due to MRSA.

  In 1981 and 1982, a large outbreak of CA-MRSA struck intravenous drug users in Detroit, Michigan. Outbreaks followed among Australian Aboriginal populations that had never been exposed to hospitals. A comparison by the University of Chicago Children's Hospital of 1993-1995 with 1995-1997 found a 25-fold rise in MRSA hospitalizations among US children. In 1999, the University of Chicago reported the first deaths from invasive MRSA among otherwise healthy US children. A San Francisco study of 2004-05 found that nearly one in 300 residents had an infection in a year, and more than 85% of those occurred outside the healthcare setting.

  Hospital rates stabilized between 1998 and 2008 while community rates kept rising. Then the trend turned in hospitals. MRSA central line bloodstream infections in hundreds of intensive care units fell 50-70% from 2001 to 2007. A separate system tracking all hospital MRSA bloodstream infections found a 34% drop between 2005 and 2008.

  The 2006 SENTRY program put the share of bloodstream infections that were MRSA at 35.9% in North America, 29% in Latin America and 22.8% in Europe. Across Europe, the rate for all MRSA infections ran from 50% in Portugal down to 0.8% in Sweden. Data mostly from 2013 showed low hospital levels in Iceland, Norway, Sweden, the Netherlands, Denmark, Finland and Estonia. As of 2010, vancomycin was still the drug of choice.

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• 8. The Race to Treat

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  MRSA infection starts as small red bumps that resemble pimples or spider bites, sometimes with fever and occasional rashes. Within a few days the bumps grow and hurt more, and they open into deep, pus-filled boils. About 75% of CA-MRSA infections stay in the skin and soft tissue and can be treated effectively. For skin abscesses, the primary treatment is removal of dead tissue, incision and drainage. Draining boils needs care, because disrupting the surrounding tissue can lead to larger infections, including sepsis. Mupirocin 2% ointment can reduce the size of lesions.

  Treatment of serious infection is urgent, and delays can be fatal. Both HA-MRSA and CA-MRSA resist traditional anti-staphylococcal β-lactams such as cephalexin. CA-MRSA responds to a wider range of drugs, including sulfa drugs like co-trimoxazole, tetracyclines like doxycycline and minocycline, and clindamycin for osteomyelitis.

  Vancomycin and teicoplanin are glycopeptides. Because they are barely absorbed by mouth, they are given intravenously for systemic infections. Vancomycin succeeds in approximately 49% of people, and linezolid in 87%. Linezolid belongs to the oxazolidinones, which became available in the 1990s. Ceftaroline, a fifth-generation cephalosporin, was the first β-lactam approved in the US to treat MRSA in skin and soft tissue or community-acquired pneumonia.

  Resistance has followed the drugs. Strains with intermediate resistance to vancomycin began appearing in the late 1990s. The first identified case was in Japan in 1996, and strains have since reached hospitals in England, France and the US. The first documented strain with complete resistance, VRSA, appeared in the United States in 2002. In 2011, a variant of vancomycin was tested that binds both the altered target and the original one, restoring potent activity. Linezolid resistance was reported in 2001 but has stayed rare. No linezolid resistance was found in staphylococci from bacteremia cases in the United Kingdom and Ireland between 2001 and 2006. Current guidelines recommend daptomycin for bloodstream infections and endocarditis caused by vancomycin-intermediate strains.

  Deeper infections demand longer care. Endocarditis can call for up to six weeks of antibiotics and a review of whether a prosthetic valve should be replaced. Pneumonia may be treated with vancomycin or linezolid for up to 21 days. Bone and joint infections can take up to 3 months or longer. An implant placed within the last 3 weeks may be kept during treatment, while an older one may be removed. People with cystic fibrosis face a heavy burden. MRSA accounts for 26% of their lung infections, and its incidence rose fivefold from 2000 to 2015.

  Research is widening the options. Inhaled antibiotics given alongside systemic drugs are in development. Phage therapy has been used for years in eastern countries, and studies continue in western ones. Host kinase inhibitors and antimicrobial peptides are under study. Extracts from sweetgum trees of the genus Liquidambar, including cinnamic acid and vanillin, have been tested for activity against MRSA. In an animal study with diabetic mice, a paste of 70% sugar and 3% povidone-iodine treated MRSA-infected ulcers.

  One remedy comes from the Middle Ages. A 1,000-year-old eye salve recipe in Bald's Leechbook, held at the British Library, showed activity against MRSA in vitro and in skin wounds in mice.

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