It is recognized that a substantial proportion of antibiotic prescribing is sub-optimal. Common errors include: use of an agent with an inappropriate spectrum, administration of an antibiotic when there is little evidence of bacterial infection, unnecessarily prolonged courses and overuse of intravenous agents. The result is an increase in avoidable side effects for the patient, expense for the funding body and resistance to antibiotics for the community as a whole.<xref ref-type="bibr" rid="bib001">1</xref></sec><sec id="sec002"><title>The antibiotic crisis

There is an impression that excessive antibiotic use selects for antibiotic resistant bacteria. Broad spectrum antibiotics are more potent selectors of antibiotic resistance than narrow spectrum antibiotics. India has an enormous and growing problem of antibiotic use and abuse in newborn care.^2,3 This is resulting in the selection of increasingly resistant Gram negative and Gram positive bacteria. Gram negative bacteria like Klebsiella can produce extended spectrum beta lactamases (ESBL) which render the Klebsiella resistant to almost all antibiotics. Gram positive bacteria can carry genes conferring vancomycin resistance, such as vancomycin resistant enterococci (VRE) and genes coding for methicillin resistance, such as methicillin resistant Staphylococcus aureus (MRSA) and methicillin resistant Staphylococcus epidermidis (MRSE). Prolonged use of broad-spectrum antibiotics is also causing a rising incidence of severe fungal sepsis in India.^4,5 Studies have consistently shown that duration of antibiotic use, particularly broad spectrum antibiotics, is the major risk factor for neonatal fungal infection.⁶

Why do the bacteria become resistant?

McGowan and Tenover¹ have summarized the pathways by which resistance can be introduced, selected, maintained and spread in health institutions:

Introduction of a few resistant organisms into a population where resistance was not present, usually by transfer from another healthcare system but also from the community.

Acquisition of resistance by a few previously susceptible strains through genetic mutation in reservoirs of high organism concentration such as abscess.

Acquisition of resistance by a susceptible strain through transfer of genetic material, for example in the gut or the skin.

Emergence of inducible resistance that is already present in a few strains in the bacterial population usually from direct selection by antibiotic prescribing.

Selection of small resistant subpopulation of organism, again by antibiotic prescription.

Dissemination of inherently resistant organisms locally within the specified setting due to poor infection control procedures.

Consideration of epidemiology and specific mechanism of resistance help in understanding where and how rational use and antibiotic policy are likely to control resistance. In the dynamics of resistance the patient, the drug, the organism & environment interact (Fig. 1) Figure 1The dynamics of resistance

Development of resistance is also dependent upon the antimicrobial being used. Recently the various beta lactam antibiotics have been graded according to whether resistance developed during use. (Fig-2)¹ One may prefer using antibiotics which have less potential to develop resistance. Figure 2Rank order of various antibiotics in respect of frequency of association of drug use with resistance in gram-negative aerobes

What is the remedy?

It is now appreciated that any effort to control antimicrobial resistance must be underpinned by effective infection-control practices.⁷ Beyond this, many different interventions have been constructed.^8,9 Firstly; techniques have been devised to enlist the support of prescribers in managing the resistance problem. This includes promoting understanding about the linkage between antibiotic prescribing and resistance, as well as the concept of ‘antimicrobial stewardship’. Secondly, schemes have been pursued to persuade patients and the public that pressurizing doctors to prescribe antibiotics inappropriately is harmful to both the individual and the greater good. Thirdly, measures have been invented to improve antimicrobial administration to patients. These include the production of antibiotic policies, computer-assisted prescribing and ‘stop’/‘switch’ orders etc. Finally, strategies have been built around controlling drug choice. Examples of this are restricted antimicrobial availability or reporting, the use of special antimicrobial request forms and antibiotic cycling.

Antibiotic cycling or antibiotic rotationWhat is antibiotic cycling?

This strategy entails a regimented preference for a specified antibiotic in a given environment over a fixed period, after which preference is switched to an alternative agent with a similar spectrum of activity. The assumption underlying this strategy is that the exposure to each antibiotic in the schedule is sufficiently short to preclude the emergence of significant populations of organisms resistant to any one of them.

What is the mechanism?

While the basic principle of rotating antibiotics is simple, behind it lie a number of conceptual and practical issues that are much more complex. A first antibiotic regimen is chosen for a group of patients during a specific period of time, then a second regimen is selected for another period, and then perhaps a third, and even a fourth, regimen may follow. The same sequence of antibiotic regimen is then repeated. The basic idea is that a bacterium that becomes resistant to the first regimen would remain susceptible to the second regimen. If it is resistant to the second regimen, the third regimen should cope with the resistance, and so on. Acquiring successive mechanisms of resistance can have metabolic consequences for the bacterium. For instance, if the resistance comes from a plasmid, the bacterium may require more energy during bacterial multiplication or for producing large amounts of beta-lactamases. It may alternatively lead to variations in the bacterium's ability to take up nutrients. The multiplication of resistance mechanisms in the same bacterial cell line should hence be detrimental to its optimal propagation, allowing sensitive bacteria (with supposedly better fitness) to take over. The expected consequence would be a decline in resistance and easier management of infected patients.

The evidence

Raymond et al.¹⁰ from the University of Virginia, USA published work on rotating empirical antibiotics in an intensive care unit in June 2001 This was the first time that a quarterly rotation of empirical antibiotics used for 1 year was compared with the previous year of non-protocol-driven use in critically ill patients. The research showed that rotation was associated with a significant reduction in infection episodes caused by Gram-negative, antibiotic-resistant organisms. The paper also showed that rotating antibiotics resulted in a lower incidence of Gram-positive coccal infections, less (MRSA) and gentamicin-resistant enterococci infections, and a clear reduction in mortality associated with infection. In fact, antibiotic rotation was an independent predictor of survival.

A suggested protocol

Recently a scheme for antibiotic rotation has been proposed for empiric treatment of sepsis. (Fig-3) Two months periods of use seem rather frequent but are proposed to prevent any resistant mutants becoming established. Figure 3Suggested scheme for cycling of empiric treatment of sepsis in units where there is no major established resistance problem¹

The threat to antibiotic rotation

Bacteria possess mechanisms that allow them to become resistant to several structurally unrelated antibiotics at once. Mobile genetic elements that encode for numerous resistance mechanisms can become incorporated into the stable genetic structures of bacteria. These could jeopardize the rotation strategy¹² Besides the well-known plasmids, bacteriophages, and transposons, the more recently described integrons can capture multiple gene cassettes, express them, and then integrate them into the chromosome.¹³ The genes found in integrons often encode antibiotic resistance, including proteins such as efflux pumps, acetyltransferases, dihydro-folate reductases, and beta-lactamases.¹⁴ Furthermore, co-selection of resistance determinants can be achieved by numerous other molecular mechanisms of resistance, representing additional threats to the rotation strategy. For instance, the combination of quinolone and methicillin resistance is often observed in S. aureus¹⁵ Multidrug active efflux systems can pump out an astonishing number of unrelated antibiotics, any of these substrates acting as a potential trigger.¹⁶

The unresolved issues

Unfortunately, whereas there is a broad agreement at a high level about the meaning of antibiotic cycling, other important issues of detail are not defined and so the schemes to date have been widely different.^8,17 It has not been clear whether the cycling process applies between or within antibiotic classes. If it were to be within an antibiotic class then it must reflect issues about different mechanisms of action, since otherwise cross-resistance would make the cycling scheme fail. For example, within b-lactam agents subclasses could be defined for the various generations of cephalosporins and the b-lactam/b-lactamase inhibitor combinations. Equally, it is unspecified whether cycling means within a unit(s) or across an entire hospital, or whether it is equally relevant to apply the concept to both community and hospital scenarios. Furthermore, the duration of the withdrawal of the antimicrobial agent is undefined, as is the periodicity between repeats in the cycles. Finally, antibiotic cycling programmes have been assumed to be the same, whether they are applied where the process is being introduced to control developed resistance within an institution, as opposed to the intended primary prevention of the emergence of such problems. All of this has led to significantly varied studies conducted largely within projects pragmatically addressing resistance challenges

The role of antibiotic policy

Several studies confirm the ability of the policies to reduce antibiotic use and the beneficial effect this had on resistance rates. Frank et al. recently described an antibiotic improvement programme, which substantially reduced the use of most broad-spectrum agents over two years period. There was a significant decrease in rate of nosocomial bacteremia, selected gram-negative bacteremia, MRSA colonization or infection and Stenotrophomonas maltophilia colonization and infection. The decrease could not be attributed to changes in infection control practices, number of outbreaks or patient demographics.¹⁸

In response to a multiply resistant Acinetobacter species infection, which was not controlled by infection control procedures, a restrictive antibiotic policy was introduced requiring approval for certain key drugs including amikacin, aztreonam, ceftazidime, imipenem, ciprofloxacillin and ticarcillin/clavulanate. Over the following six months there was a significant decrease not only in resistant Acinetobacter but also in resistance to these antibiotics among E.coli, P aerugenosa, and Klebsiella pneumoniae.¹⁹

The concept of antibiotic stewardship

Some UK hospitals have appointed microbiologists or infectious diseases physicians with antibiotic management as a specific role. However, experience has shown that this is a full-time task and these medical professionals have many other functions to fulfill. A dedicated antibiotic pharmacist has the time and skills to monitor antibiotic prescribing and manage it appropriately, lessening the demand on hard-pressed microbiologists and infectious disease physicians. Key roles for antibiotic pharmacists include education of medical, pharmaceutical and nursing staff, audit of local practices, monitoring of antibiotic consumption, participation in infection control, formulary development and appraisal of new antimicrobials.²⁰

These benefits are achieved in a variety of ways but central to the role of the antibiotic pharmacist is the monitoring and enforcement of hospital antibiotic policy. Awareness of local guidelines by junior doctors is often low, and they are seldom consulted in daily practice. An antibiotic pharmacist has the skills and time to monitor day-to-day use of antimicrobials, and any areas of gross deviation from a hospital antibiotic policy. There have been a number of studies showing that a pharmacist dedicated to the monitoring of antibiotics can develop and apply guidelines²¹

The local solutions

While it is true to say that there is no absolute proof of a causative association between antibiotic use and resistance; most authorities believe the association to be certain. Given the worldwide escalation in resistance and overwhelming evidence of much over-use of antibiotic, the pragmatic and essential approach to control of antibiotic resistance is to control antibiotic use. The important question is how not whether. Much research is still needed in this area. To a large extent local problems are best addressed by local solutions

Ten steps to reduce misuse of antibiotics

A ten-point plan to reduce antibiotic resistance in neonatal units had been put forward by Issacs.²² (Table - 1) Table 1

Ten Point Plan on Antibiotic Use

1.	Always take cultures of blood (and/or CSF and/or urine) before starting an antibiotic
2.	Use the narrowest spectrum antibiotics possible, almost always a penicillin (e.g., piperacillin-tazobactam) and an aminoglycoside (e.g. amikacin)
3.	Do not start treatment with a third generation cephalosporin (e.g. cefotaxime, ceftazidime) or a carbapenem (e.g. imipenem, meropenem)
4.	Develop local and national antibiotic policies to restrict the use of expensive, broad-spectrum antibiotics like imipenem for emergency treatment
5.	Trust the microbiology laboratory: rely on the blood culture results
6.	Stop believing that a raised CRP means the baby is definitely septic
7.	If blood cultures are negative at 2–3 days, it is almost always safe and appropriate to stop antibiotics
8.	Try not to use antibiotics for long periods
9.	Treat sepsis but not colonization
10.	Do your best to prevent nosocomial infection, by reinforcing infectioncontrol, particularly hand washing

Suggested protocol for neonatal sepsis

There can not be single recommendation for the antibiotic regimen for neonatal sepsis in all settings. The choice of antibiotic depends on the prevailing flora responsible for sepsis in the given unit and their antimicrobial sensitivity. This write up does not aim to provide a universal recommendation for all settings but lays down broad guidelines for the providers to make a rational choice of antibiotic combination. Decision to start antibiotics is based upon clinical features and/or a positive sepsis screen. However, duration of antibiotics therapy is dependent upon the presence of a positive blood culture and meningitis. (Table 2) Table 2

Duration of antibiotic therapy in neonatal sepsis

Diagnosis		Duration

•	Meningitis	21 days
•	Blood culture positive (no meningitis)	14 days
•	Culture negative, clinically probable, Sepsis screen positive	7–10 days
•	Culture negative, clinically probable, sepsis screen negative	5–7 days

Choice of antibiotics

Empirical antibiotic therapy should be unit specific and determined by the prevalent spectrum of etiological agents. Subseqently, antibiotic therepy should be modified according to culture sensitivity reprorts. The empirical choice of antibiotics is dependent upon the probable source of origin of infection. For early onset sepsis where organisms are likely to be community – acquired and where resistant strains are unlikely, a combination of ampicillin or penicillin with gentamicin may be a good choice for first line therapy. Cefotaxine or ceftriaxone should be added for treatment of meningitis.

For late onset sepsis where organisms are likely to be hospital acquired and where resistant pathogens are likely a combination of cloxacillin and gentamicin or third generation cephalosporin (cefotaxime or ceftriaxone) with amikacin may be appropriate.

Reserve antibiotics

Third generation cephalosporins including cefotaxime, ceftriaxone and ceftazidime have excellent antmicrobial activity against gram negative organisms (including Klebsiella) and have a very good CSF penetration, Ceftazidime is particularly effective against pseudomonas infections. These antibiotics are an excellent choice for treatment of nosocomial infections and meningitis. Newer antibiotics like aztreonam and imipenem are now available in the market. Aztreonam and imipenem are effective against extended spectrum beta lactamose producing organisms which are resistant to most of the antibiotics including third generation cephalosporins. Other antibiotics which may help against ESBL producing organisms are cefoperazone – sulbactam and piperacillin – tazobactam. The empirical use of these antibiotics is best avoided and should be reserved for situations where sensitivity of the isolate justifies the use. Ciprofloxacin is another antibiotic with excellent activity against of gram – negative organisms although it does not have a very good CSF penetration. Hence ciprofloxacin may be used for the treatment of gram-negative bacteremia after excluding meningitis.

A combination of piperacillin or ceftazidime with amikacin should be considered if pseudomonas sepsis is suspected. Penicillin resistant staphylococcus aureus should be treated with cloxacillin, nafcillin or methicillin. Addition of an aminoglycoside is useful in therapy against Staphylococcus. (MRSA) should be treated with Vancomycin. Vancomycin should also be used for the treatment of Entecococcus resistant to the first line of therapy.

Conclusions

Modern neonatal intensive care would be impossible without antibiotics. Their effectiveness can only be preserved if they are used rationally and with great care. Irresponsible use can quickly lead to the selective appearance of organisms that are resistant to most forms of treatment.

Rational use of antibiotics