Saturday, August 22, 2009

Penicillins

Beta lactams: penicillins

Narrow-spectrum penicillins

Narrow-spectrum penicillins are active mainly against Gram-positive organisms, but they are inactivated by beta-lactamases.

Benzylpenicillin (penicillin G) is administered parenterally and remains the treatment of choice for susceptible infections if parenteral treatment is warranted.

Procaine penicillin is an intramuscular preparation designed to extend the half-life of benzylpenicillin. It provides blood levels for up to 24 hours, but these are adequate only against highly susceptible organisms.

Benzathine penicillin is given intramuscularly and provides low levels of benzylpenicillin for up to 4 weeks.

Phenoxymethylpenicillin (penicillin V) is acid-stable, so it can be given orally, although food impairs absorption. It is intrinsically less active than benzylpenicillin.

Narrow-spectrum penicillins with antistaphylococcal activity

Dicloxacillin, flucloxacillin and methicillin are stable to beta-lactamase produced by staphylococci. Flucloxacillin and dicloxacillin are reliably absorbed by the oral route; however, food reduces absorption and they are best taken half to one hour before food. Methicillin, the parent drug, is not used in clinical practice. Laboratories test with either oxacillin or cefoxitin rather than methicillin to determine susceptibility to antistaphylococcal drugs.

Flucloxacillin is generally well tolerated, but is occasionally associated with cholestatic jaundice, particularly in older patients on prolonged therapy. This may occur after oral or intravenous administration and up to 6 weeks after treatment. It may last for months, can be irreversible and, rarely, may be fatal. Dicloxacillin appears to cause less irreversible hepatotoxicity but results in more infusion phlebitis (see Intravenous administration of antimicrobials) and interstitial nephritis. Dicloxacillin may be preferable to flucloxacillin for oral therapy or in patients requiring prolonged therapy. In these guidelines, di/flucloxacillin refers to dicloxacillin or flucloxacillin.

MRSA should be regarded as clinically resistant to all beta lactams.

Moderate-spectrum penicillins

The aminopenicillins, amoxycillin and ampicillin, have greater activity than benzylpenicillin against some Gram-negative organisms (eg Escherichia coli, Haemophilus influenzae), but are destroyed by beta-lactamase–producing strains. They are drugs of choice for enterococcal infections. Amoxycillin is better absorbed orally than ampicillin, is not affected significantly by food and requires fewer oral doses per day, but when administered parenterally they are equivalent. In these guidelines, amoxy/ampicillin refers to amoxycillin or ampicillin.

Broad-spectrum penicillins (beta-lactamase inhibitor combinations)

The beta-lactamase inhibitors clavulanate, sulbactam and tazobactam inhibit the enzymes produced by Staphylococcus aureus and Bacteroides fragilis and also the beta-lactamase enzymes found in Escherichia coli, Klebsiella species, Neisseria gonorrhoeae and Haemophilus influenzae. These three drugs possess little inherent antibacterial activity, but significantly extend the spectra of activity of amoxycillin, ticarcillin and piperacillin when given with them. Reserve these combinations for the treatment of infections due to organisms in which resistance to the beta lactam is due to enzymes that the beta-lactamase inhibitors are able to inhibit. The combinations are often more expensive than the beta-lactam antimicrobials alone.

Amoxycillin+clavulanate can cause diarrhoea and hepatotoxicity, which occur more frequently than with amoxycillin.

Broad-spectrum penicillins with antipseudomonal activity

Piperacillin and ticarcillin are the only penicillins that have activity against Pseudomonas aeruginosa, but high doses are required. The addition of clavulanate to ticarcillin and tazobactam to piperacillin extends their spectra of activity, with piperacillin+tazobactam having greater in vitro activity against enterococci and Klebsiella species. Piperacillin+tazobactam is more expensive than ticarcillin+clavulanate, and both are more expensive than most other penicillins.

Community Acquired Pneumonia

The commonest treatment for use in the community is to give BOTH amoxycillin (or cefuroxime...because it is a cef that covers H. inf) and either roxithromycin or doxycycline or a quinolone.

UTI

Use either trimethoprim, Augmentin or a first generation cephalosporin (e.g. cephalexin).

It used to be that you could use amoxycillin but too many E.coli are now resistant to TMX and amoxycillin, and indeed in parts of the world the commonest way to treat UTI is with a fluoroquinolone.

CEPHALOSPORINS

This is potentially a crazy confusing topic.

The basic principles are that the 1st generation ones, derived from fungus, are good for most G+ bugs, including ones that make Beta-lactamase (i.e. = staphs!), but are useless against most G- bugs, with the important exception of E. koli and Klebsiella.
The only aerobic G+ they won't kill are MRSA, Listeria and Enterococcus.

So, they can be used for any aerobic G+ infection and for most UTI's.

Examples are cephalothin, cephalexin, cefazolin.

The second generation ones can be broken down into:-
* " 1st generation spectrum cephalosporins with activity against H.inf" such as cefuroxime, cefaclor.
* "1st generation spectrum cephalosporins with a bit of anaerobic activity" such as cefoxitin.

The second generation are not true cephalosporins. They are cephamycins.

The third generation cephalosporins are called "broad spectrum cephalosporins".
They have sacrificed anti-staphylococcal and anaerobic activity for G-activity.
The only G-'s that they won't kill are the ESBL's (i.e. those bugs with extended spectrum beta-lactamases, e.g. Enterobacter) and Pseudomonas.
The only G+'s that they will kill with certainty is Streptococci (except for enterococci).
They are ceftriaxone, cefotaxime.

There is also a subfamily of third generationers that are "third generation cephs with anti-pseudomonal activity". They are ceftazidime, cefipime.

Friday, August 7, 2009

DEET

Re the DEET, I think of things this way:- the only 100% way to ensure you
don't get malaria is to not get bitten (i.e. there's definitely reports out
there about travellers who took all of their tablets religiously and still
got malaria)...so, the DEET is the most important thing. Yes, it's toxic -
they used to spray it on malarial areas to kill mosquitoes - so, if it can
kill mosquito cells, it can kill human cells. However, I used the tropical
strength version liberally on my body when I was in Thailand and sparingly
on my face, but making sure I covered all areas of the face (I'm not sure if
this is true but I think the skin of the face is thinner than on the body
and hence, I assumed that there was more chance that it might penetrate into
my blood).
I was also strict about the use of mosquito coils in my room (bought them
when I got to Thailand), always had the fan on (harder for mosquitoes to
land), slept with some light clothes on so that some areas of the body were
always covered, and used a fine mosquito net to cover my bed that was
impregnated with "permethrin" (which is also a recognized carcinogen) and
that I bought back in Australia. You can also spray your clothing with
Permethrin - "treated clothing will effectively repel mosquitoes for more
than one week even with washing and field use" (Reference 1 at end of
email)...I chose not to do that though - just didn't like the idea of
spraying my clothes with this stuff.

What's the strength of DEET to consider getting? I used tropical strenght
RID because that's what was in the www.traveldoctor.com.au shop at the time
, which, if I remember correctly, was about 30% too. It's sticky and gluggy
and if you get it on to plastic, it will melt the plastic! (I kid you
not...oh, it also melts spandex and rayon).

However, the principle of DEET is that the higher the % formulation, the
longer the protection. It's generally felt that the effectiveness of DEET
reaches a plateau at 50% concentrations. To be sure of getting a few hours
protection though, you need to use the 30% version (e.g. the 25% version
provided less than 90% protection two hours after repellent application
against one strain of mozzie in field testing...Reference 2 at end of
email).

So, it's DEET yeah? Well...there is now an alternative. It's called Picardin
- it's odorless, does not feel sticky when applied, and does not damage
clothing. But...from what I know it's only available commercially in
Australia as the 9.3% formulation (based on this Choice article from 2005:
Reference 3). Here's what the report said: " The 9.3% picaridin formulation
provided greater than 95% protection for only two hours. In daytime tests, a
20% controlled-release deet formulation (Sawyer, 20% deet) provided greater
than 95% protection for six hours, and both 19.2% picaridin and the US Army
extended-duration repellent formulation (which contains 33% deet in a
polymer) provided greater than 95% protection for eight hours" (Reference
4).
So, if the 19.2% formulation is available then I would snap that one up and
use it instead of the DEET...but if you can only get the 9.3% formulation
then I'd go for the >/30% DEET instead.
Do you know anyone in the armed forces? Maybe they'd be able to get you some
"Autan Repel Army 20" which is the brandname for the 19.2% solution.

REFERENCES:
1) TI Effects of weathering on fabrics treated with permethrin for
protection against mosquitoes.
AU Gupta RK; Rutledge LC; Reifenrath WG; Gutierrez GA; Korte DW Jr
SO J Am Mosq Control Assoc 1989 Jun;5(2):176-9.

Permethrin-impregnated and untreated fabrics were evaluated for their
toxic and repellent effects against Anopheles stephensi and Aedes aegypti
after both types of fabrics were subjected to accelerated weathering for 9
weeks, under a simulated wet/tropical environment. The toxic (knockdown)
effect of permethrin-impregnated fabrics against both species of mosquitoes
diminished rapidly after 1 week compared to the repellent effect. After 6
weeks of weathering, the remaining low amounts of permethrin provided fair
protection from mosquito bites; however, no knockdown was observed at those
levels. Permethrin-treated fabric was effective in providing protection from
mosquito bites and appears to be a means of attenuating both the nuisance
effects and, possibly, disease transmission by mosquitoes.

AD Letterman Army Institute of Research, Presidio of San Francisco, CA
94129-6800.


2) J Med Entomol. 1996 Jul;33(4):511-5.
Laboratory and field evaluation of deet, CIC-4, and AI3-37220 against
Anopheles dirus (Diptera: Culicidae) in Thailand.Frances SP, Klein TA,
Hildebrandt DW, Burge R, Noigamol C, Eikarat N, Sripongsai B, Wirtz RA.
Department of Entomology, Armed Forces Research Institute of Medical
Sciences, Bangkok, Thailand.

Laboratory and field tests of the repellents diethyl methylbenzamide (deet),
1-(3-Cyclohexen-1-yl-carbonyl)-2-methylpiperidine (AI3-37220), and
(2-hydroxymethylcyclohexyl) acetic acid lactone (CIC-4) were conducted
against Anopheles dirus Peyton & Harrison, the principal malaria vector in
Thailand. In the laboratory, An. dirus was more sensitive to CIC-4 than
either AI3-37220 or deet. The duration of protection provided by each
repellent in laboratory tests increased with higher concentrations of
repellents and when exposed in cages containing fewer mosquitoes. A field
study in Chanthaburi Province, southeastern Thailand, during November 1993
tested 25% (wt:wt) ethanol solutions of each repellent against An. dirus. In
contrast to the laboratory experiments, protection provided by AI3-37220 was
significantly better than either deet or CIC-4 and there was no significant
difference between deet and CIC-4. Protection provided by deet and CIC-4
fell to below 95% 2 h after repellent application, whereas AI3-37220
provided > 95% protection for 4 h. The protection provided by all repellents
fell to < or = 65% 7 h after repellent application.

3)
http://choice.com.au/viewarticleasonepage.aspx?id=105015&catId=100281&tid=100008&p=1

4) J Med Entomol. 2002 May;39(3):541-4. Links
Field evaluation of repellent formulations against daytime and nighttime
biting mosquitoes in a tropical rainforest in northern Australia.Frances SP,
Van Dung N, Beebe NW, Debboun M.
Australian Army Malaria Institute, Enoggera, Queensland, Australia.

Field trials to compare repellent formulations containing either picaridin
or deet against rainforest mosquitoes in northern Queensland, Australia,
were conducted. Three repellents were compared at night: 9.3% picaridin and
19.2% picaridin (Autan Repel and Autan Repel Army 20, respectively, Bayer,
Sydney, Australia) and 35% deet in a gel (Australian Defense Force [ADF]).
During the day, the following three repellents were compared: 19.2%
picaridin, 20% deet in a controlled release formulation (Sawyer Controlled
Release Deet), and 33% deet in a polymer formulation (U.S. Army Extended
Duration Topical Insect and Arthropod Repellent [EDTIAR]). The predominant
mosquito species collected was Verrallina lineata (Taylor), with smaller
numbers of Ochlerotatus kochi (Donitz), Anopheles farauti s.s. Laveran,
Ochlerotatus notoscriptus (Skuse), and Coquilletidia xanthogaster (Edwards).
In nighttime tests, 19.2% picaridin provided >94.7% protection for at least
9 h, and ADF deet provided >95% protection for 7 h. The 9.3% picaridin
formulation provided >95% protection for only 2 h, and provided 60%
protection at 9 h. In daytime tests, Sawyer 20% deet provided >95%
protection for 6 h, and both 19.2% picaridin and U.S. Army EDTIAR provided
>95% protection for 8 h. In both nighttime and daytime tests 19.2%
picaridin provided similar or better protection than deet formulations.

Malaria prophylaxis advice








For Brazil, the current recommendations are that you need prophylaxis if you
are going to be travelling through the Amazon Basin (which includes the
cities of Manaus and Belém) or will be in Mato Grosso State (in the West of
Brazil, bordering Bolivia) or Maranhao State (in the North-East of the
country, bordering the sea).
 
The options for what you can take are five as all these areas have malaria
that is resistant to a drug called "chloroquine".
 
When I went to Thailand in 1996 I chose to take one 100mg tablet of
Doxycycline daily as I felt it would have the least amount of side-effects.
It did cause - after a few weeks - fairly severe stomach inflammation in me,
but Iwas able to sort this out with some local stomach acid suppressing
tablets that I bought. If you choose to go this route then I suggest that
you start taking such tablets - for example, "LOSEC" - at the same time as
you start the Doxycycline. I would take two 20 mg tablets. I would be very
surprised if you had stomach troubles if you were to do that.
There are several cousins of "Losec" that will do the same thing - "somac",
"pariet", etc., and none of them have any side-effects to speak of.
The only other things to be aware of if you are taking doxycycline is that
you will burn easier in the sun, and that you need to take it for 4 weeks
after you leave the malarial area.
 
The other tablet options are:
 
1. Mefloquine ("Lariam" is the other name you may hear). One tablet a week.
Needs to be taken for four weeks after you leave the malarial area.
This is the one that CAN (but not necessarily will) cause the bad dreams,
concentration difficulties and anxiety. My gut feeling from the reading that
I've done is that the standard line about "these effects being uncommon at
preventative doses but common at treatment doses" is not correct. I think
that the chance of developing some such effect is "moderate".
 
2. Malarone ("Atovoquone-Proguanil" is the other name you may hear). One
tablet a day. Needs to be taken for only a week after leaving malarial
areas. I can't remember it being around back in 1996. It's said to be
"generally well tolerated" with the commonest effects being tummy pain. I
think this will probably also be due to inflammation of the stomach caused
by the contact of the chemicals with the stomach lining. Hence, should be
preventable with those anti-acid drugs I mentioned.
It's also said to be able to cause headaches- I think that this is part of
those brain group of symptoms that any drug with "-quine/quone" can cause
(chloroQUINE, mefloQUINE, atovaQUONE), which really means that it could also
cause all those bad dreams, etc., that are mentioned for Lariam and
Chloroquine (though this seems to be unusual with atovaquone).
 
3. Primaquine is not felt to be as effective at prevention as the other two
mentioned (i.e. greater incidence of break-through malaria).
 
4. Tafenoquine is, as far as I'm aware, not available on the PBS. It's main
advantage is the long time that a single tablet produces effective blood
levels, which means that it only needs to be taken once a week. It's said to
be "well tolerated" and "effective" but I'm sure that as soon as it starts
being widely used, a truer picture of adverse effects will emerge.
 
Here's a reference:
 
TI Efficacy of monthly tafenoquine for prophylaxis of Plasmodium vivax and
multidrug-resistant P. falciparum malaria.
AU Walsh DS; Eamsila C; Sasiprapha T; Sangkharomya S; Khaewsathien P;
Supakalin P; Tang DB; Jarasrumgsichol P; Cherdchu C; Edstein MD; Rieckmann
KH; Brewer TG
SO J Infect Dis 2004 Oct 15;190(8):1456-63. Epub 2004 Sep 20.
 
We assessed monthly doses of tafenoquine for preventing Plasmodium vivax and
multidrug-resistant P. falciparum malaria. In a randomized, double-blind,
placebo-controlled study, 205 Thai soldiers received either a loading dose
of tafenoquine 400 mg (base) daily for 3 days, followed by single monthly
400-mg doses (n = 104), or placebo (n = 101), for up to 5 consecutive
months. In volunteers completing follow-up (96 tafenoquine and 91 placebo
recipients), there were 22 P. vivax, 8 P. falciparum, and 1 mixed infection.
All infections except 1 P. vivax occurred in placebo recipients, giving
tafenoquine a protective efficacy of 97% for all malaria (95% confidence
interval [CI], 82%-99%), 96% for P. vivax malaria (95% CI, 76%-99%), and
100% for P. falciparum malaria (95% CI, 60%-100%). Monthly tafenoquine was
safe, well tolerated, and highly effective in preventing P. vivax and
multidrug-resistant P. falciparum malaria in Thai soldiers during 6 months
of prophylaxis.
 
 
All up, were I to travel to Brazil, visit those areas where there is risk
and stay in them for a while, I would either take Doxycycline with a stomach
acid suppressing drug, or Malarone with a stomach acid suppressing drug.
 
If I was only going to be there a short time then I would seriously consider
using Lariam/Mefloquine, and think about switching to Primaquine for a week
after I'd left. The reason is that you only need to take it for a week after
you leave the malarial area (as opposed to 4 weeks for Lariam/Mefloquine)
and it kills the liver form of the disease. I think the blood levels would
be high enough to have done their thing after a week because it takes "three
to five half-lives" for blood levels to get up to where they want to be, and
the half-life of primaquine has to be less than 24 hours because it's given
as a daily dose. So, you should have reached necessary blood levels by 3-5
days. If you then wanted to be really sure, you would take it for a week
after that. All in all, 12 days at the most (i.e. 5 + 7).
It would need to be taken with stomach-acid suppressing drugs based on the
findings of this report:
 
TI Primaquine prophylaxis against malaria in nonimmune Colombian soldiers:
efficacy and toxicity. A randomized, double-blind, placebo-controlled trial.
AU Soto J; Toledo J; Rodriquez M; Sanchez J; Herrera R; Padilla J; Berman J
SO Ann Intern Med 1998 Aug 1;129(3):241-4.
 
  BACKGROUND: Primaquine had a prophylactic efficacy of 90% to 95% against
infection with Plasmodium falciparum and P. vivax in Indonesian settlers.
OBJECTIVE: To evaluate the efficacy of primaquine prophylaxis for protecting
nonimmune persons from malaria. DESIGN: Randomized, double-blind,
placebo-controlled field study. SETTING: A malaria-endemic area in Colombia.
PATIENTS: 176 healthy, young, nonimmune adult male soldiers. INTERVENTION:
Primaquine, 30 mg/d, or matching placebo during 15 weeks of patrol in the
endemic area and 1 week afterward. MEASUREMENTS: Symptomatic parasitemia was
determined over the 16-week intervention period and for 3 weeks in base
camp. RESULTS: Protective efficacy in the primaquine group (122
participants) was 89% (95% CI, 75% to 96%) against all types of malaria, 94%
(CI, 78% to 99%) against P. falciparum malaria, and 85% (CI, 57% to 95%)
against P. vivax malaria. Six primaquine recipients had mild to moderate
gastrointestinal distress, and three had severe distress. CONCLUSIONS: For
prophylaxis against P. falciparum malaria, primaquine has an efficacy and
toxicity competitive with those of standard agents. A potential advantage of
primaquine is that prophylaxis may be discontinued 1 week after the
recipient has left the endemic area.
 
AD Universidad Militar Nueva Granada, Consorcio de Investigaciones
Bioclinicas, Direccion de Sanidad Ejercito, Bogota, Columbia.
PMID 9696733
 
Here's another one which is very interesting and was published in the most
prestigious/important medical journal in the world ("New England Journal of
Medicine").
 
TI Delayed onset of malaria--implications for chemoprophylaxis in travelers.
AU Schwartz E; Parise M; Kozarsky P; Cetron M
SO N Engl J Med 2003 Oct 16;349(16):1510-6.
 
  BACKGROUND: Most antimalarial agents used by travelers act on the
parasite's blood stage and therefore do not prevent late-onset illness,
particularly that due to species that cause relapsing malaria. We examined
the magnitude of this problem among Israeli and American travelers. METHODS:
We examined malaria surveillance data from Israel and the United States to
determine the traveler's destination, the infecting species, the type of
chemoprophylaxis used, and the incubation period. RESULTS: In Israel, from
1994 through 1999, there were 300 cases of malaria among returning travelers
in which one species of plasmodium could be identified. In 134 of these
cases (44.7 percent), the illness developed more than two months after the
traveler's return; nearly all of these cases were due to infection with
Plasmodium vivax or P. ovale. In 108 of the 134 cases (80.6 percent), the
patient had used an antimalarial regimen according to national guidelines.
In the United States, from 1992 through 1998, there were 2822 cases of
malaria among travelers in which the cause could be evaluated. Late illness
developed in 987 (35.0 percent) of these travelers. The infection was due to
P. vivax in 811 travelers, P. ovale in 66, P. falciparum in 59, and P.
malariae in 51; 614 (62.2 percent) of those with late-onset illness had
appropriately taken an effective antimalarial agent. CONCLUSIONS: In more
than one third of malaria-infected travelers, the illness developed more
than two months after their return. Most of these late-onset illnesses are
not prevented by the commonly used and effective blood schizonticides.
Agents that act on the liver phase of malaria parasites are needed for more
effective prevention of malaria in travelers.
 
AD Center for Geographical Medicine and the Department of Medicine, C. Chaim
Sheba Medical Center, Tel Hashomer, Israel. elischwa@post.tau.ac.il
PMID 14561793
 
I'd discuss this option with a travel doctor. You'd need to have a blood
test to make sure you were not "glucose-6-phosphate dehydrogenase deficient"
before you left Australia, as Primaquine causes destruction of red blood
cells in people who are born with this enzyme deficiency.