For Gram negatives

What is the impact of antibiotics and vaccines in the prevention and control of gram negative bacterial infections?

The ability to prevent, treat and in some instances even cure infectious diseases is a key to the success of present day medicine. Antimicrobial agents – in particular antibiotics – have contributed to improved health and expanded the lifespan of humans like no other invention in medicine. However, the emerging antibiotic resistance has revived the search for alternative nonantibiotic strategies. Among them, prophylaxis by vaccination is an appealing concept. Community acquired infections caused by meningococci and haemophilus influenza pose a major threat to patients at risk and can be successfully prevented by effective vaccines. Over the past decade new technologies such as DNA-vaccines and vector-based vaccines facilitated the development of innovative vaccine strategies that are currently under investigation for their potential to prevent health care-associated infections caused by pathogens such as Pseudomonas aeruginosa and Klebsiella pneumoniae. In addition, other substances that have demonstrated antimicrobial activity in vitro may present a future alternative.

Which antibiotic or vaccine preparation is central to the prevention and control of health care-associated infections?

The impact of individual substances on the prevention and control of health care-associated infections varies greatly depending on factors like epidemiology and individual risk of the patient. In neutropenic patients for example, broad-spectrum beta-lactams such as piperacillin/tazobactam or carbapenems have made a tremendous impact. The introduction of echinocandins has also contributed significantly to the prevention of health-care associated fungal infections inthese highly compromised patients, dramatically improving their outcome. Fidaxomycin, of the new group of macrocyclines, offers an option for treatment of severe clostridium difficele infections, promising fewer recurrences of disease, which would ultimately contribute to infection control.

What are the common antibiotics or vaccines used to prevent and control infections, and what are key distinguishing features?

When discussing antimicrobial agents and in particular antibiotics, it is important to distinguish between prophylaxis (i.e. prevention) and treatment (i.e. control) of infection. For the former, beta-lactams are most commonly used, mainly to prevent surgical site infections. For the latter, substances applied depend largely on the susceptibility of the pathogen, numerous host-related factors (age, gender, underlying conditions etc.) and the availability of the agent, which – in particular in third world countries – can be an important limiting factor.

Table I lists the currently available classes of antibiotics with gram-negative coverage with their key distinguishing features.

Table I.

Available agents and their features, efficacy and safety.

Table II lists currently available agents with their distinguishing features, Table III their respective spectrum of activity. This table represents an overall estimate, however, due to the considerable differences in resistance, therapy in a specific patient should always be guided by local or national guidelines, as well as take into account the specific situation of the patient. In addition a susceptibility profile of the causative pathogen obtained with suitable methods is highly recommended especially in patients with severe infections.

Table III.

Available agents, with important PK/PD data, dosing information for prevention versus treatment, drug-drug interactions, and adverse reactions.

Table IV summarizes the currently available data. Even though data have been compiled with great care, this table cannot account for country-specific differences nor substitute for the respective package inserts. For specific details regarding individual drugs other sources such as the country specific package inserts should be consulted.

Drugs in development.

In contrast to a fair number of antimicrobial agents that are active against gram-positive pathogens, there are very few substances that may be active against gram-negatives, as summarized in Table V.

Table V.

Summary of current controversies.

The best agent would be easy applicable with good distribution in all tissues, fast acting, bactericidal, with no side effects and no interactions with other drugs. Since this is currently impossible to achieve, there must inevitably be some kind of compromise. A general discussion on the pros and cons of antimicrobial classes and individual agents is of only limited value, because a lot of these depend on the clinical situation of the individual patient rather than the overall characteristic(s) of the drug. Characteristics that may be considered a pro or con depending on the individual situation are listed in Table VI.

With almost all agents – especially the newer ones, where clinical experience is sparse – there is some discussion about the risk-benefit ratio of the specific drug in a specific setting. Again, a discussion of the individual features in an abstract setting would not provide any useful information. Most of the general discussion is limited by the extensive pre-clinical and clinical studies, aimed at answering most of the important questions about efficacy and safety before an antimicrobial agent is administered to a large group of patients.

With the increase of resistance in gram-negative organisms and the limited choice of agents that remain active, there is an increasing interest in “older” drugs such as fosfomycin and colistin, which display good in vitro activity. However, some of them have been approved in times when the amount of data required was considerably less than by modern standards, therefore a lot of the commonly known facts regarding clinical efficacy and safety have not been tested in controlled clinical trials, but are rather based on individual reports and case series.

Are there specific guidelines for the use of some or all of these agents?

There are a number of guidelines for the use of antimicrobial agents and vaccines. These are usually issued by the WHO and other international organizations, as well as national regulatory agencies (e.g., the FDA) or medical societies that focus on Infectious Diseases (such as the Infectious Diseases Society of America (IDSA)).

These guidelines are usually written by a committee of recognized experts in the field. For example the endocarditis guideline entitled “Infective Endocarditis in Adults: Diagnosis, Antimicrobial Therapy, and Management of Complications” is endorsed by the Infectious Diseases Society of America and was written by members from the American Heart Association Committee on Rheumatic Fever, Endocarditis, and Kawasaki Disease of the Council on Cardiovascular Disease in the Young, Council on Clinical Cardiology, Council on Cardiovascular Surgery and Anesthesia, and Stroke Council.

While guidelines of the WHO are usually internationally recognized, other societies usually issue guidelines on a national basis.

In addition, most large hospitals and medical institutions issue their own guidelines which are mostly adaptations of the national or international guidelines that take into account local circumstances such as resistance rates or specific patient populations. Guidelines are usually published in the respective journals and made available through the issuing society.

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